Paul-Ehrlich-Institut

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Heterogeneous Design of Studies Hampers Demonstration of Potential Efficacy of Convalescent Plasma as a COVID-19 Therapeutic Agent

12 / 2021

Since the onset of the pandemic, therapeutic options and potential vaccines against COVID-19 have been the subject of rapid investigation in clinical trials. One of the most frequently examined therapies is the treatment with COVID-19 convalescent plasma (CP). Demonstrating clinical efficacy on the basis of a purpose-designed clinical trial could be achieved through analysis and comparison of the results of previous studies, but is hampered by the multiple different approaches and the varying methodologies of the studies. Researchers from the Paul-Ehrlich-Institut (PEI) analysed the different designs of the clinical trials, thus laying the groundwork for improved study designs in future clinical trials that should aim to demonstrate potential CP efficacy in COVID-19 therapy. The findings were published in "Clinical Pharmacology & Therapeutics" on 17 June 2021.

Plasma donation (Source: sfam/shutterstock.com)

CP is a treatment using blood plasma from individuals who have successfully recovered from an infectious disease and have developed an immunity to the corresponding pathogen. The blood plasma of recovered patients contains, among other things, antibodies that are able to combat the specific pathogen – this is referred to as passive immunisation when CP is administered to third parties to treat or prevent an infectious disease. The use of CP as a prophylactic or for treatment of severe cases of a disease has already been investigated in the past for various infectious diseases triggered by viruses, as was the case for severe respiratory infections relating to the SARS-CoV pandemic from 2002 to 2004, the H1N1 influenza virus pandemic in 2009 and the MERS-CoV epidemic in 2012. Proof of the efficacy of CP from controlled clinical trials, however, is still very limited. 

Comprehensive testing of quality, safety and efficacy of CP as a therapy requires various different trial concepts. In particular, trial end points and patient groups must be determined, along with the size of the study. Therapeutic strategies also need to be optimised. These include, among other things, demonstration of a sufficiently high concentration of neutralising antibodies in the CP by means of suitable testing systems (titres for neutralising antibodies), identification of the optimum point in time to administer the therapy and its duration, and achieving sufficiently high titres of neutralising antibodies for an adequate period of time in the blood of the patients undergoing treatment. The high number of trial concepts required and the simultaneously low global coordination of these clinical trials means there is a risk of apparently contradictory trial results, thus hampering decision-making regarding an optimal and effective use of CP in treating COVID-19 patients. 

In the recently published article, a COVID-19-specific database was used to compare the study designs of more than 140 clinical trials of CP. The scientists at the Paul-Ehrlich-Institut, working in the Haematology and Transfusion Medicine section led by Dr Anneliese Hilger, came to the conclusion that the heterogeneous study designs used thus far make it difficult to prove the efficacy of COVID-19 treatment with CP. 

Overall, numerous methodological differences relevant to clinical proof of efficacy were identified in the studies considered. Differences in the production of convalescent plasma, insufficient possibilities for comparing different treatment regimens, and the varying statistical models for calculating study size and efficacy analysis proved to be particularly critical here.

However, given the fluctuating tense pandemic situation in Europe since 2020, a thus favourable ratio of available study participants, and a high number of ongoing controlled clinical trials, it could be possible to answer important questions on the efficacy of convalescent plasma treatment. "Convalescent plasma is a rapidly available therapeutic agent, so we urgently need clarification of the efficacy of this concept for COVID-19 therapy, including for future outbreaks," said Dr Müller-Olling, who was the lead author of the analysis. The analysis presented here can be used to help provide convincing evidence of the clinical efficacy of CP against COVID-19 with improved study designs.

Original Publication

Müller-Olling M, Vahlensieck U, Hilger A (2021): Heterogeneity in COVID-19 Convalescent Plasma Clinical Trials.
Clin Pharmacol Ther 111: 995-1000.
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Updated: 08.07.2021