The Comirnaty Vaccine Files - Part 1

The evidence for provisional registration - structuring our review

Because of our experience with antivirals, we decided to avoid articles published in peer-reviewed literature and ignore media and diatribes published on the topic. In effect, we decided to focus on what regulators saw before granting provisional registration (which has different names given by various regulators).

This entailed an effort on two fronts. First, we must explain what regulatory data looks like, its functions, what it contains, and what some terms mean. Second, we have to record and present our findings in the data.

The importance of regulatory data lies in its structured and detailed nature compared to biomedical journal literature.

Because of the presence of publication bias, reporting bias of harms, lack of access of authors to "their own datasets" in our work on antivirals and the inconsistencies of the data presented to different regulators, we decided to ignore the published evidence initially and concentrate on the regulator and internal Glaxo and Roche clinical study reports (CSRs).

The Antiviral Story Against Influenza: Part 8

Above the water line is the research you can see - the journal publications, maxing out at about 3,000 words with tables and appendices and only representing a small amount of the details of a trial. This issue leads to substantial problems with reporting bias: ‘a systematic distortion that arises from the selective disclosure or withholding of information by parties involved in the design, conduct, analysis, or dissemination of a study or research findings.’

A CSR is an unabridged report of a clinical study written for regulators following E3 reporting guidelines developed by the regulatory industry. They represent the most complete reporting of the planning, execution, and results of a clinical trial. While they contain some of the same information as a journal article, they are substantially more detailed, with numerous large tables, figures, and datasets not constrained by page limits.

Regulatory submissions follow an internationally recognised format agreed by The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (henceforth ICH). ICH brings together the foremost regulatory authorities and the pharmaceutical industry. The guideline on how clinical study reports (CSRs) should be written is E3. CSRs are one of the five parts or modules that make up the Common Technical Document or CTD:

Any registration application must follow the layout and content of the CTD, which again follows the relevant ICH guidance. CSRs are found in Module or M5 (at the bottom right of the CTD pyramid).

Having a standard format globally is sensible and efficient. Everyone knows what to do and what to expect. ICH E3 was gradually introduced in 1996. During the work around the Antivirals review, we accessed some pre-1996 CSRs. They had a heterogeneous structure, with each manufacturer using slightly different terms and formats, making them difficult to read and follow.

CSRs report the guts of the evidence development plan for a pharmaceutical or biologic (such as vaccines). The evidence plan is what regulators want to see. How and why was the candidate conceived and tested in pre-clinical and clinical phases, and what arrangements were made to carry out post-marketing surveillance? This is a brief overview of a complex process that usually takes years. Just to remind you, this process does not apply to devices or diagnostics, which are subject to their own rules and regulations.

Medical Device Regulation (MDR) 2017

A CSR (which is what we will be looking at for the Comirnaty original temporary licence)

reports a lot more information than its summary published (if published at all) in a biomedical journal. The ratio of CSR to published pages for the same study we dubbed the compression factor.

For example, for every page of the statin clopidogrel published in a journal, there were 8,805 pages of an underlying CSR for the same trial. The compression factor is a crude measure of how much is compressed or simply left out of each publication, affecting the reliability of the appraisal and interpretation of trials. The compression and other factors, such as ghostwriting, publication bias, and non-access to data by the “authors” (the names appearing in the article byline), confirmed our reasons for avoiding journal publications.

If you’re already getting lost in all this jargon, which is a million miles from your standard journal article, dont worry. As we go, we’ll keep explaining the terms. Some parts of the CSR are self-explanatory. Most include a synopsis, a statistical analysis plan in some form and a protocol. The Protocol generally refers to a Trial Protocol; Case Report Forms (CRFs) are the original paper or electronic forms on which individual participants’ data (demographic, efficacy, safety, etc.) are recorded during the clinical trial. The results are reported as an efficacy and safety evaluation along with individual listings, a colloquial term referring to a document or electronic dataset containing data recorded at the individual participant's level.

CSRs make critical technical contributions to the design, conduct, and reporting of the Cominarty trials. However, in our experience, journal publications fail to record many essential details, particularly the harms, resulting in the loss of critical information.

However, the main problem is the abundance of information on the Comirnaty vaccine. The advantage, however, is that we will only concentrate on data from the period ending with the various provisional registrations granted by multiple countries: EU, UK, US and Canada. All were granted before Christmas 2020. The second advantage is that thanks to the ICH standardised format, we can find our way around quickly and use the shortcuts we picked up when learning the trade on antivirals.

The best thing to follow what went on is to build an outline timeline. Build the start and finish for 2020 (for now), and then go back and fill in as many spaces as possible by recording as many milestones. As we pointed out in our first post of the series, we do not necessarily have to follow regulatory sources to do so, but these are the most trustworthy.

The second step is to build an overview of the studies carried out during this period and those planned. The significance of the planned studies is twofold. They may not fall into the period of interest to us, but they show aspects which pharma and regulators wanted to study more accurately. The second aspect is that all registrations have conditions attached, especially conditional registrations like the one granted to Comirnaty. Both regulators and manufacturers want to know how the product fares once it’s on the market. This is routine and sensible and allows us to follow it, too.

To make sure you understand, we can do the two things together.

We begin by looking for the earliest signs that BioNTech and Pfizer worked together on a candidate vaccine. Two studies started in April 2020.

You’ll have to bear with us as understanding what happened is complex; we found it easy to get lost in the numbers naming the trials and understanding what happened.

The first is BNT16201, divided into b1 and b2—abbreviated to BNT162b1 (120 participants) and BNT 162b2 (96). The trial was a phase 1 dose-ranging study run in Germany.

The trial design was stated to be in Part A and Part B. However, Part B involves trialling the vaccine in a higher-risk population, such as the elderly and/or immunocompromised populations, which never occurred.

The other trial, which kicked off on 28 April 2020, was run in Argentina, the US, Brazil, Turkey, South Africa, and Germany. This trial’s ID is C4591001. To add to the confusion, it is sometimes called BNT162-02. It ran as a rolling trial, starting with 105 participants and ending with 44,047.

The MHRA explains how time constraints dictated running the trial and the assessment:

“All vaccines are tested through three phases of clinical trials to ensure they meet the required standard. Phase 1 trials are conducted with a small group of people to ensure no safety concerns and to determine the appropriate dosage for the best immune response. Phase 2 trials are conducted on a larger group to check whether the vaccine works consistently and whether the immune response is sufficient. Phase 3 trials test the vaccines on thousands of people so that scientists can assess if the vaccine produces immunity that will prevent disease. Usually, these phases are run in sequence, but in an effort to find a safe and effective COVID-19 vaccine as quickly as possible, once safety has been ascertained through Phase 1, Phases 2 and 3 are being run in parallel. Extensive checks and balances are required at every stage of vaccine development, and this is no different for a Covid-19 vaccine. No stages in the vaccine development processes were bypassed”.

The easiest way to check the details of the evidence development plan is to review the tabular listing of clinical studies:

Bnt162b2 Tabular Listing Of Clinical Studies

1.72MB ∙ PDF file

Download

Download

This tabular view document is the most complete and authoritative source of outlined information on the trials and the evidence presented to regulators.

The PDF tabular view is one of the early versions (April 2021). It was obtained with the original licensing documents by a group of us led by an attorney who won an injunction to make the data available from the FDA. It is part of Module 5 of the application. With a tabular view accessible, you can avoid database searches for other trials. This is the real McCoy because there is no publication bias. Pharma would not declare a study to a regulator—stupid, they are not.

Two old geezers wrote this post, which is not commercially in confidence.

Readings

Doshi P, Jefferson T. Clinical study reports of randomised controlled trials: an exploratory review of previously confidential industry reports. BMJ Open 2013;3:e002496. doi: 10.1136/bmjopen-2012-002496.

RIAT initiative Glossary: https://restoringtrials.org/glossary/