Re: The EMA covid-19 data leak, and what it tells us about mRNA instability
Dear Editor
Reading this important article has reminded me of a concern I had when reading what the MHRA's Public Assessment Report [1] on the Pfizer/BioNtech vaccine said about the lipid nanoparticles used as excipients - ALC-0315 and ALC-0159.
They are novel excipients (at least in UK-authorised medicinal products) and the justification for not having conducted pharmacokinetic (PK) studies is that they “are generally not considered necessary to support the development and licensure of vaccine products for infectious diseases (WHO, 2005; WHO, 2014)”.
But on reading WHO, 2005 - which is a reference to WHO Guidelines on nonclinical evaluation of vaccines [2]- I see that PK studies are not normally needed but should be considered on a case-by-case basis (para 4.2.6) ), and toxicity studies should be performed where new excipients (and preservatives) are used for which no toxicological data exist (para 5.2).
I also note that the still extant EMA 2006 guidance [3] states “Pharmacokinetic studies are usually not required for vaccines. However, such studies might be applicable when new delivery systems are employed or when the vaccine contains novel adjuvants or excipients. The need for PK studies and their design should be considered on a case by case basis and it is recommended that applicants should obtain scientific advice from EU Competent Authorities” (para 4.1). The 2006 guidance is being revised, and this text is missing from the current draft revised version [3].
I would have expected therefore at least an explanation as to why PK studies were not considered necessary.
I also see that the EMA's Public Assessment Report [4] states that in January 2021 (and April 2021) “additional information about the synthetic process and control strategy for” ALC-0315 and ALC-0159 “should” be provided by BioNTech, with final reports in July 2021, in order to “confirm the purity profile and ensure comprehensive quality control and batch-to-batch consistency throughout the lifecycle of the finished product”.
I have no pharmacological expertise, but it seems to me that an explanation should be given as to why PK studies were not considered necessary, and the additional information that was due to be provided in January 2021 should be disclosed, along with the April and July updates when provided. The EMA should also explain why paragraph 4.1 of its 2006 guidance has been dropped from its draft revised guidance.
Rapid Response:
Re: The EMA covid-19 data leak, and what it tells us about mRNA instability
Dear Editor
Reading this important article has reminded me of a concern I had when reading what the MHRA's Public Assessment Report [1] on the Pfizer/BioNtech vaccine said about the lipid nanoparticles used as excipients - ALC-0315 and ALC-0159.
They are novel excipients (at least in UK-authorised medicinal products) and the justification for not having conducted pharmacokinetic (PK) studies is that they “are generally not considered necessary to support the development and licensure of vaccine products for infectious diseases (WHO, 2005; WHO, 2014)”.
But on reading WHO, 2005 - which is a reference to WHO Guidelines on nonclinical evaluation of vaccines [2]- I see that PK studies are not normally needed but should be considered on a case-by-case basis (para 4.2.6) ), and toxicity studies should be performed where new excipients (and preservatives) are used for which no toxicological data exist (para 5.2).
I also note that the still extant EMA 2006 guidance [3] states “Pharmacokinetic studies are usually not required for vaccines. However, such studies might be applicable when new delivery systems are employed or when the vaccine contains novel adjuvants or excipients. The need for PK studies and their design should be considered on a case by case basis and it is recommended that applicants should obtain scientific advice from EU Competent Authorities” (para 4.1). The 2006 guidance is being revised, and this text is missing from the current draft revised version [3].
I would have expected therefore at least an explanation as to why PK studies were not considered necessary.
I also see that the EMA's Public Assessment Report [4] states that in January 2021 (and April 2021) “additional information about the synthetic process and control strategy for” ALC-0315 and ALC-0159 “should” be provided by BioNTech, with final reports in July 2021, in order to “confirm the purity profile and ensure comprehensive quality control and batch-to-batch consistency throughout the lifecycle of the finished product”.
I have no pharmacological expertise, but it seems to me that an explanation should be given as to why PK studies were not considered necessary, and the additional information that was due to be provided in January 2021 should be disclosed, along with the April and July updates when provided. The EMA should also explain why paragraph 4.1 of its 2006 guidance has been dropped from its draft revised guidance.
Yours sincerely,
Peter Roderick
1. https://assets.publishing.service.gov.uk/government/uploads/system/uploa...
2. https://www.who.int/biologicals/publications/trs/areas/vaccines/nonclini...
3. https://www.ema.europa.eu/en/clinical-evaluation-new-vaccines#current-ef...
4. https://www.ema.europa.eu/en/medicines/human/EPAR/comirnaty#product-info...
Competing interests: No competing interests