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