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With COVID-19 Vaccine (Chadox1-S [Recombinant]) – Vaxzevria (Previously COVID-19 Vaccine Astrazeneca) (Other Viral Vaccines) EPITT No:19683

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With COVID-19 Vaccine (Chadox1-S [Recombinant]) – Vaxzevria (Previously COVID-19 Vaccine Astrazeneca) (Other Viral Vaccines) EPITT No:19683 08 April 2021 EMA/205598/2021 Pharmacovigilance Risk Assessment Committee (PRAC) Signal assessment report on embolic and thrombotic events (SMQ) with COVID-19 Vaccine (ChAdOx1-S [recombinant]) – Vaxzevria (previously COVID-19 Vaccine AstraZeneca) (Other viral vaccines) EPITT no:19683 Confirmation assessment report 12 March 2021 PRAC assessment report 17 March 2021 Adoption of first PRAC recommendation 19 March 2021 Written adoption of the updated PRAC assessment report 24 March 2021 AHEG remote meeting 29 March 2021 (1:30 pm-7 pm) EMA EudraVigilance analysis 30 March 2021 PRAC assessment report on additional data 3 April 2021 Deadline for comments 5 April 2021 – 12 noon CET Updated rapporteur assessment report 6 April 2021 am Adoption of second PRAC recommendation 07 April 2021 1 Administrative information Active substance (invented name) Vaxzevria (previously COVID-19 Vaccine AstraZeneca) Marketing authorisation holder Astra Zeneca Authorisation procedure Centralised Mutual recognition or decentralised National Adverse event/reaction:1 embolic and thrombotic events Signal validated by: BE Date of circulation of signal validation 11 March 2021 report: Signal confirmed by: Belgium Date of confirmation: 12 March 2021 PRAC Rapporteur appointed for the Jean-Michel Dogné (BE) assessment of the signal: 1 Please use MedDRA terminology whenever possible Signal assessment report on embolic and thrombotic events (SMQ) with COVID-19 Vaccine (ChAdOx1-S [recombinant]) – Vaxzevria (previously COVID-19 Vaccine AstraZeneca) (Other viral vaccines) EMA/205598/2021 Page 2/117 Table of contents Administrative information ........................................................................................... 2 1. Background ............................................................................................. 4 2. Initial evidence ........................................................................................ 4 2.1. Signal validation ................................................................................................... 4 2.2. Signal confirmation ............................................................................................... 5 2.3. Proposed recommendation .................................................................................... 5 3. Additional evidence ................................................................................. 5 3.1. Assessment of additional data ................................................................................ 5 3.2. Rapporteur’s proposed recommendation ................................................................ 45 3.3. Adopted PRAC recommendation ................................. Error! Bookmark not defined. 3.4. Assessment of additional data - round 2 ................................................................ 46 3.5. Updated proposed recommendations – round 2 ...................................................... 82 3.6. Comments from other PRAC members and MAH – round 2 ...................................... 90 3.7. Adopted PRAC recommendation – Round 2 ............................................................ 90 4. References .......................................................................................... 111 Annexes .................................................................................................. 115 Signal assessment report on embolic and thrombotic events (SMQ) with COVID-19 Vaccine (ChAdOx1-S [recombinant]) – Vaxzevria (previously COVID-19 Vaccine AstraZeneca) (Other viral vaccines) EMA/205598/2021 Page 3/117 1. Background Seriousness: 258 serious cases, 45 fatal. Evidence: 269 cases in EudraVigilance for the SMQ ‘Embolic and thrombotic events’ ROR: NA Exposure: as of 11 March 2021, over 5.5 million doses of the AstraZeneca vaccine had been administered in EU/EEA countries [source: ECDC COVID-19 Tracker] [1]; in the UK, exposure was approximately 9.7 million doses as of 28 February 2021 [source: weekly summary of Yellow Card reporting] [2]. At the time of the PRAC meeting on 18 March 2021, it was noted that the latest overall exposure in EU/EEA and UK combined, as of 14 March 2021, was close to 20 million first doses administered [1]. Regulatory context: NA COVID-19 Vaccine AstraZeneca is an adenovirus vector vaccine which received a conditional marketing authorisation in the EU on 29 January 2021 for active immunisation against COVID-19 in individuals 18 years of age and older. Cases of thromboembolic events have been reported following administration of COVID-19 Vaccine AstraZeneca in several EEA countries, some leading to local suspensions of specific batches or to the use of the vaccine itself. An observed-to-expected analysis performed on 8 March 2021 identified no increased risk of thromboembolic events following administration of the vaccine although there were limitations. Venous thromboembolism is an important potential risk included in the RMP of the recently approved COVID-19 Vaccine Janssen, another adenovirus vaccine, due to a numerical imbalance of cases reported in clinical trials. Natural infection with SARS-COV-2 has been associated with hypercoagulability, microangiopathy and venous or arterial thromboembolic events. One of the mechanisms hypothesised for the hypercoagulable state seen in patients with severe COVID-19 is related to the high-grade systemic inflammatory response. 2. Initial evidence 2.1. Signal validation A search performed in EudraVigilance on 11 March 2021 for cases of ‘Embolic and thrombotic events’ (SMQ) yielded 269 cases, mostly from the UK (224 cases). Thrombotic thrombocytopenic purpura was not reported as such in any of the cases. Two additional cases were retrieved under the MedDRA PT ‘coagulopathy’, both from the UK, but were excluded from the review due to limited information. The majority (60%) of cases occurred in female patients. Median age was 70 years. Forty-five (45) cases had a fatal outcome. Thirty (30) cases originated from the EEA: Germany (6), Sweden (5), Austria (5), Ireland (2), France (2), Denmark, Norway, Italy, Finland, Croatia, Latvia, Cyprus, Estonia, Greece, Czech Republic (1 each). Of these, 19 were in women, 11 in male; 8/30 were consumer reports. Time-to-onset ranged from 0 to 16 days. Thrombotic events were reported in 10 cases, e.g. deep vein thrombosis, hepatic vein Signal assessment report on embolic and thrombotic events (SMQ) with COVID-19 Vaccine (ChAdOx1-S [recombinant]) – Vaxzevria (previously COVID-19 Vaccine AstraZeneca) (Other viral vaccines) EMA/205598/2021 Page 4/117 thrombosis, mesenteric vein thrombosis, portal vein thrombosis, carotid artery thrombosis, peripheral artery thrombosis, cerebral venous sinus thrombosis. Other reported events included pulmonary embolism (8), thrombocytopenia (6), disseminated intravascular coagulation (4), deep vein thrombosis (4), hepatic vein thrombosis (2). In 14 cases the vaccinee had risk factors for thromboembolic events such as hypertension, thyroiditis, obesity or chronic hepatitis B. Fourteen (14) cases have limited information. Seven (7) cases had a fatal outcome, in vaccinees were aged 24 to 60; disseminated intravascular coagulation occurred in 3 of them. 2.2. Signal confirmation In total there were 269 cases of ‘Embolic and thrombotic events’ , median age was 70 years. Thirty (30) cases originated from the EEA. Seven (7) cases had a fatal outcome, in vaccinees aged 24 to 60; disseminated intravascular coagulation occurred in 3 of them. Thrombotic thrombocytopenic purpura was not reported as such in any of the cases. Although an observed-to-expected analysis performed on 8 March 2021 identified no increased risk of thromboembolic events following administration of the vaccine, further investigation is needed as these cases led to local suspensions of specific batches or the use of the vaccine itself. Besides, Venous thromboembolism is an important potential risk in the RMP of the recently approved COVID-19 Vaccine Janssen, another adenovirus vaccine, due to a numerical imbalance of cases reported in clinical trials. Therefore the signal is confirmed. 2.3. Proposed recommendation Following the suspension of a batch (number ABV5300) of COVID-19 Vaccine AstraZeneca [3] and the pause of the vaccination campaign with COVID-19 Vaccine AstraZeneca in Denmark and some other Member States [4], the MAH has been requested as part of a late breaking request for the Summary Monthly Safety Report (due date 15 March 2021) to provide: A cumulative review of reports of Embolic and thrombotic events (SMQ Broad). The review should include at a minimum a discussion of fatal and serious events, if any batch clustering is observed with focus on ABV5300 batch, other risk factors – if they can be identified, an observed versus expected analysis, and risk-benefit considerations. 3. Additional evidence 3.1. Assessment of additional data 3.1.1. Introduction The COVID-19 Vaccine AstraZeneca was granted a conditional marketing authorisation by the European Commission on 29 January 2021. Over 6.9 million doses have been administered in the EU/EEA countries [1] and over 9.7 million doses in the UK [2]. In EU countries, COVID-19 Vaccine AstraZeneca was administrated mainly in adults <60 years, while e.g. Comirnaty has been more evenly administered in all age groups and COVID-19 Vaccine Moderna more in adults >60 years [5]. The following events highlight the ongoing insights regarding the issue of thromboembolic events: Signal assessment report on embolic and thrombotic events (SMQ) with COVID-19 Vaccine
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