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Feature

EMA recommendation on hydroxyethyl starch solutions obscured controversy

BMJ 2018; 360 doi: https://doi.org/10.1136/bmj.k1287 (Published 20 March 2018) Cite this as: BMJ 2018;360:k1287

Feature

Data too important to share: do those who control the data control the message?

Opinion

Even normal saline is harmful if used wrongly, so why did EMA single out hydroxyethyl starch?

  1. Peter Doshi, associate editor, The BMJ
  1. pdoshi{at}bmj.com

As the EMA’s recommendation to suspend HES solutions from the market heads to the European Commission for a final decision, scientists who were asked to provide independent advice say that they were completely ignored. Peter Doshi reports

For decades, intensive care doctors have used hydroxyethyl starch (HES) solutions to treat hypovolaemia and acute blood loss. But within days, the European Commission will register a deciding vote on the fate of HES, possibly suspending their licence across the EU.

The vote is the culmination of five years of controversy sparked by the publication of two randomised trials which reported that HES solutions carry serious risks.12 Based on these trial publications, in 2013, regulators began issuing warnings. The US added boxed warnings to drug labelling about increased risk of death and need for renal replacement therapy,3 and the EMA contraindicated HES solutions in critically ill patients or patients with sepsis or burns but allowed their continued use to treat acute blood loss when treatment with crystalloids alone is insufficient.4

Now the future of HES solutions is once again in the balance after the Swedish regulator called on the EMA to review the matter, citing drug use studies suggesting that the medicines continue to be used in prohibited populations.5 After an 11 week process, in January the EMA recommended HES solutions be withdrawn from market.6

But experts from whom the EMA sought independent advice are crying foul.

Obscuring a controversy

Before the EMA’s public recommendation, the medicines agency asked Thomas Scheeren, professor of anaesthesiology at the University of Groningen in the Netherlands, to chair an expert group to provide independent advice on whether a role remained for HES products.

But Scheeren says his group’s advice—to keep HES on the market—was ignored.

“Why are [the EMA] inviting independent experts, [then] experts come to clear statements, and you completely ignore these statements and don’t even mention it on your website and in your decision?” Scheeren asks.

According to confidential minutes of the meeting, leaked to The BMJ (see data supplement on bmj.com), the expert group found “there definitely is a place for [HES] containing medicinal products in the authorised indication.” Of the seven committee members, one disagreed. This member also declared relevant interests to the EMA and as such was not allowed to take part in the final conclusions of the meeting.

Despite the expert group’s recommendation, the EMA advised taking HES off the market. And in no public statement has it even acknowledged the expert group’s recommendation.

Scheeren says he got the impression that the EMA’s decision “was predetermined before they even invited the experts.

“It was a useless exercise for us going there and giving our opinion, which was not at all taken into account.”

Jean-Louis Vincent, professor of intensive care medicine at the Université Libre de Bruxelles, who was not a member of the expert group, commented: “I went to EMA twice to defend HES, and I know the story quite well. I did not appreciate that the EMA did not follow the advice of the jury it put together itself, and just said there were ‘other influences’ that it cannot speak about ... this is unacceptable.”

A spokesperson for the EMA denied it had ignored the advice of its expert group. “To reach its conclusions, the PRAC [Pharmacovigilance Risk Assessment Committee] took into account all the body of evidence available, which included the ad hoc expert group contributions, but also the stakeholders’ submissions, and all the available evidence on the benefits and risks and the use of HES in clinical practice.”

Is the evidence clear cut?

Not willing to be written out of history, five of the seven members of the expert group took to the Lancet on 9 February to protest. “There is no evidence to support suspending HES,” they wrote, concluding: “We strongly believe that the EMA recommendation to suspend HES is not scientifically grounded and is potentially hazardous to patients.”7

The EMA's press release states that its recommendation followed a review of drug use studies as well as “currently available data on benefits and risks from clinical trials and observational studies and feedback received from stakeholders and experts.”6

But a 74 page internal assessment, seen by The BMJ, suggests that the EMA’s latest evaluation of the safety profile of HES is based on the same data as in 2013—primarily, the CHEST and 6S randomised trials. New studies were “not considered to contribute any robust new data with respect to safety in any indication or patient population.”

The expert group, however, took a different view, arguing the evidence was not clear cut. It questioned the relevance of the CHEST and 6S trials, noting that “patients were partly or fully “volume-resuscitated” before they entered the study (baseline central venous oxygen saturation (ScvO2) >70%).” Scheeren suggested this might be due to the long interval from intensive care admission to randomisation (average time around 11 hours in CHEST).

Vincent, too, raised concerns about CHEST: “I am not convinced it [HES] is so toxic—the CHEST trial shows a greater need of renal replacement therapy but less renal dysfunction, as assessed by RIFLE criteria.”

In addition, a 2016 investigation by The BMJ highlighted allegations that CHEST was improperly reported and showed that regulators had made decisions on HES based on journal publications alone and without conducting an independent analysis of the underlying trial data. That remains true for the EMA’s latest recommendation.

The 2016 BMJ report also noted the calls to submit the underlying CHEST trial data for independent re-analysis, something the study investigators firmly refused.8 Subsequently, the New England Journal of Medicine published corrections to the CHEST study,910 and in 2017, the study investigators coauthored an “independent” reanalysis.1112 But the trial data have yet to be made publicly accessible, something the expert group has called for in its confidential report to the EMA.

More dissent obscured?

Scheeren’s expert group was apparently not the only committee to see a continued place for HES in critical care medicine. The EMA’s recommendation was forwarded to an EU body known as the “Coordination Group for Mutual Recognition and Decentralised Procedures—Human” (CMDh), which voted on the matter on 24 January. But the committee did not reach a consensus and endorsed the EMA’s recommendation only by a close 15 to 13 vote. This caused the decision to be referred yet again, for a final judgment from the European Commission.

But just like Scheeren’s expert group, the CMDh vote was also secret. The EMA told The BMJ that the CMDh’s vote will be made public four weeks after the EC decision. However, the Lancet letter by Scheeren and colleagues revealed the information early.

Celebration and dismay

Scheeren speculates that there must be a huge amount of lobbying going on to convince the European Commission that HES’s dangers outweigh the benefits.

One group that has already celebrated the EMA’s recommendation is the principal investigators of the CHEST and 6S studies. John Myburgh, Anders Perner, and colleagues in an open letter also published by the Lancet, called on the World Health Organization’s director general, “to protect patients by banning the use of HES solutions worldwide.”13

But Scheeren, Vincent, and others see a ban on HES as “hazardous.”7

Scheeren and expert group colleagues wrote that the EMA “has not considered our warning that suspending HES might result in serious unmet medical needs when crystalloids are not sufficient … Their withdrawal from the European market will increase the use of albumin—a product derived from pooled human plasma—and lead to cost issues and shortage of albumin in many countries.”7

Vincent, who said certain people are on a “crusade” against HES, warned: “Those who are against HES claim there are enough other solutions, but this is not true: we do need some colloids, and without HES we will have only albumin (and gelatin, which is a less effective substance)—and this may have serious financial consequences. The entire debate does not concern the US, where HES is hardly cheaper than albumin.”

Footnotes

  • Competing interests: I have read and understood BMJ policy on declaration of interests and have no relevant interests to declare. The BMJ submitted comments to the EMA committee last November, neither for nor against HES, but urging the EMA to “obtain the full [CHEST] trial data, including the original protocol and statistical analysis plans, and perform its own, independent assessment.”

  • Provenance and peer review: Commissioned; not externally peer reviewed.

References

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