Skip to main content

Advertisement

Table 1 Timeline of HES regulatory key events between 2010 to current practice

From: Comparison of hydroxyethyl starch regulatory summaries from the Food and Drug Administration and the European Medicines Agency

Safety concern 2010 – Publication of Cochrane review of HES effects on kidney function. Increased risk in septic shock patients with 10% HES 200/0.5 or 6% HES 200/0.6 [28] (Not based on US studies, i.e. HES formulations studied are different from those FDA approved.
2012 – Publication of CRYSTMAS (May 2012), 6S (Jul 2012), & CHEST (Nov 2012) trials (plus others) [12,13,14]
Timeline FDA EMA
Before 2010 1972 – Approval of HESPAN (6% HES 450/0.7)
1991 – Approval of Hetastarch (6% HES 450/0.7)
1999 – Approval of Hextend (6% HES 450/0.7)
2007 – Approval of Voluven (6% HES 130/0.4)
HES-containing medicinal products (>60 available throughout Europe) in use for decades [29]
2012 May Change to Voluven labelling to include increased frequency and duration of renal replacement therapy among Voluven patients and info on paediatric dosage (in response to CRYSTMAS study) [30]  
2012 Sept Expert workshop set up by FDA to discuss HES products in light of recent data [27]  
2012 Nov   Article 31 referral received following concerns over safety of HES products – review conducted by PRAC [31]
2013 Jun   PRAC recommends suspending marketing authorisations (MA) for all HES products and their use in all patient populations [32]
2013 Jun   MA holders appeal against decision [32]
2013 Oct   PRAC revises recommendation upon completion of review. HES solutions may continue to be used in restricted patient population and additional studies should be conducted [16]
2013 Oct   CMDh endorses PRAC recommendations, decision sent to European Commission [16]
2013 Nov Addition of black box warning to product information regarding increased mortality and kidney injury in critically ill patients [28]  
2013 Nov Additional warning about excessive bleeding needed in the Warnings and Precautions Section of the package insert - considered a class effect [27]  
2013 Nov Voluven label change: “Severe liver disease” added to contraindication due to data from CHEST trial [30]  
2013 Dec   EU-wide decision to allow HES product use in restricted patient population [16]
2014 Mar   Revised product information formally issued across entire EU [16]
2014 Sept Additional precaution added to paediatric use section (Voluven) [33]  
2014 Oct   PASS protocol rejected by PRAC due to issues with the study design [34]
2015 Mar   PASS protocol approved by PRAC [35]
2015 Jul   Another PASS protocol rejected by PRAC due to inadequate sample size [36]
Benefits of HES products in approved indications remain favourable. No changes to labelling or MA [36]
2015 Oct   PRAC issued advice and recommendations (requested by EU member states) regarding submitted PASS protocols [37]
2015 Nov   PASS protocol approved by PRAC [38]
Current Two post-marketing commitments fulfilled (Voluven) [13, 39, 40]
Routine surveillance using FAERS.
HES products listed under ‘Medicines under additional monitoring’ by EMA since 2013 as further PASS required and all data reviewed periodically (PSUR)
Post-authorisation commitment to perform additional studies in patients with trauma and in elective surgery [16]
MAH (Serum Werke Bernburg) HES products licence suspension for 1 year from Sept 2015 to Sept 2016 [41]
Further, PASS protocol submitted to be discussed at Sept 2016 meeting [42]
Future   Use of HES in perioperative settings and the potential dose dependency of HES administration in relation to acute kidney injury to be assessed [36]
  1. Abbreviations: CMDh Coordination Group for Mutual recognition and decentralised Procedures – human, FAERS FDA Adverse Event Reporting System, MAH Marketing Authorisation Holder, PASS Post-Authorisation Safety Study, PRAC Pharmacovigilance Risk Assessment Committee, PSUR Periodic Safety Update Report