Hedley Rees' Expert Statement on SARS-CoV-2 injections, Written December 17, 2021: PART 1
If you are a lawyer, or know one, this is all you need
EXPERT REPORT, Prepared By: Hedley Rees Managing Consultant, at PharmaFlow Limited.
This is the first part of an expert report I wrote 17th December 2021:
SUMMARY
Injections to reduce the symptoms of Sars-Cov-2 have been developed by AstraZeneca, Johnson & Johnson, Pfizer and Moderna. AstraZeneca and Johnson & Johnson are Adenovirus vector injections and Pfizer and Moderna are mRNA injections. The development and manufacture of the Sars-Cov-2 injections has been carried out by various Contract Development & Manufacturing Organisations (CDMOs) Each Product has been given approval in Great Britain by the Medicines and Healthcare Products Regulatory Agency (MHRA) under a Conditional Marketing Authorisation (CMA).
The companies named above will have done the laboratory experiments only. What enters the patient’s body is the fully developed and produced Product. The companies named above simply submit the application for a Conditional Marketing Authorisation and then market the product and collect the profits. The development and manufacture of all the Sars-Cov-2 injections is carried out by Contract Development & Manufacturing Organisations (CMDOs). The company sponsoring any clinical trial (CTS) or holder of the marketing authorisation (MAH) has total responsibility for what happens in the supply chain, even if they have outsourced the physical activities to third parties.
There must be a written agreement between the CTS/MAH and any company carrying out the work on the Product, known as the Quality & Technical Agreement (QTA) which sets out the steps required to develop and manufacture the Product. Normally the CMDOs will have a regulatory inspection history that regulators can use to assess the suitability of a facility to manufacture a particular kind of Product. There could be no such history in this situation as the Products are so new which would mean that the regulators would have no idea what was happening inside a production plant. Virtual inspections would not work.
The development of new medicines takes many years. On average it takes 12 years for a new medicine to progress from preclinical testing through clinical trials and regulatory review to approval. Advanced Therapy Medicinal Products (ATMPs) require the most rigorous approval of all. The Sars-Cov-2 injections were authorized for use in less than a year from the time Sars-Cov-2 was identified as a threat to public health. In my opinion this process could not safely be carried out in such a short time frame.
There are various stages involved in developing a new medicine. Preclinical trials involve small quantities and a small supply chain. If the product seems to be safe, then it progresses to clinical trials where larger quantities and a larger supply chain is needed. Finally, after authorization the production will be scaled up again. At each stage it is vital to assess the Product in great detail as each time production is scaled up the Product can change and may become toxic. The public has repeatedly been told that the trials for the Sars-Cov-2 injections took place in parallel instead of in series, in order to speed up the process. It is my opinion that by developing the injections in this way, without following the accepted protocols and proceeding through the steps in order, the vital checks on scaling up the Product will have been missed. It is possible that the finished Product will be toxic to the recipient. In my opinion, this is dangerous and leads to serious safety concerns.
Pfizer’s own report Document 5.3.6 Cumulative Analysis of Post-Authorization Adverse Event Reports of PF-07302048 (BNT162B2) Received Through 28-Feb-2021 (annexed to this statement) shows a shockingly high rate of death and injury. This should be compared to the Swine Flu vaccine. The rollout was halted after no more than 50 deaths attributed to the vaccine.
Safety of Final Product and Supply chain
The safety and quality of any medicine must be assessed on the final Product of the manufacturing and distribution supply chain before use in humans. This applies to both clinical trials and marketed products. This is important as many factors including but not limited to production in different facilities, component parts from different sources, scaling up of quantities, and differences in insulated packaging could change the Product that is ultimately administered to humans. Any undetected error or omission could cause considerable patient harm or even death.
An example of this would be the tragic event described in a report from PEW Health in 2012, titled Heparin: A Wake-Up Call on Risks to the U.S. Drug Supply.[i]
Below are some extracts:
The adulteration of heparin, a widely used blood thinner, is a tragic example of the risks resulting from an increasingly globalized and complex pharmaceutical manufacturing system…
…as a result of the heparin adulteration, dozens of patients in the United States suffered adverse events, and several lost their lives. Investigations into this occurrence have revealed a number of systemic failures, including inadequate oversight and supply chain management…
…investigation revealed that a synthetic adulterant with toxic effects, over-sulfated chondroitin sulfate (OSCS), had been introduced during heparin's manufacture in China. OSCS costs nearly 100 times less to produce than heparin and is so similar to the actual drug that it was undetected by standard tests…
…dozens of Americans suffered adverse reactions, including death. Baxter Healthcare, the major U.S. manufacturer of heparin, along with 14 other U.S. companies recalled at least 11 drug products and 72 medical devices containing heparin…
…according to local health agencies and news reports, heparin products were also recalled in Australia, Denmark, France, Germany, Italy, Japan, Sweden, and Switzerland.
Despite intense activity by multiple stakeholders in the pharmaceutical industry, this could still happen today, or any time in the future. This is because the safety measures that have subsequently been implemented since, including the Falsified Medicines Directive (FMD) 2011, only apply to movement of a manufacturers fully finished products to wholesalers and then on to community and hospital pharmacies.[ii]
Any material or product adulteration occurring and incorporated into the upstream supply chain, would appear genuine, as was the case with heparin. In an environment of incredibly high demand for materials to produce SARS-CoV-2 injections, and the consequent potential shortages, adulteration for economic advantage is a very real and serious threat.
Non-compliance with GMDP
To carry out the development and manufacture for SARS-CoV-2 injections in less than 12 months, many critical non-compliances with GMP and GDP would have to have taken place.
Below is an example of the regulatory requirements from Chapter 5 ‘PRODUCTION’ of the Orange Guide:
“Principle
Production operations must follow clearly defined procedures; they must comply with the principles of GMP in order to obtain products of the requisite quality and be in accordance with the relevant manufacturing and marketing authorisation.
Validation
5.23 Validation studies should reinforce GMP and be conducted in accordance with defined procedures. Results and conclusions should be recorded.
5.24 When any new manufacturing formula or method of preparation is adopted, steps should be taken to demonstrate its suitability for routine processing. The defined process, using the materials and equipment specified, should be shown to yield a product consistently of the required quality.
5.25 Significant amendments to the manufacturing process, including any change in equipment or materials, which may affect product quality and/or the reproducibility of the process should be validated.”
The upshot of this regulation is that a master validation protocol (MVP) must be compiled for any new process or piece of equipment, to define the activities required to prove it produces what it is supposed to produce.
This is typically authoured in draft by the quality department and goes through a number of reviews by staff involved. Once agreed, it is signed off and then needs to be implemented. The timeframe for completion is measured in weeks and months. For a biologic/ATMP product, it would take considerably longer.
For a new product, this applies to every stage of production, from starting materials to finished Product (see Figure 3); and for every process and piece of equipment involved.
For each process change, such as scale-up, it would need to be repeated.
Note also that production must “be in accordance with the relevant manufacturing and marketing authorisation.” Since approval has been under a conditional authorisation only, there will be no marketing authorisation for those required to know the contents to refer to.
Please refer to the section below, SUMMARY OF GMP OBLIGATIONS OF A CLINICAL TRIAL SPONSOR (CTS) OR MARKETING AUTHORISATION HOLDER (MAH) for more details on areas of potential non-compliance. Examples can be provided if required.
STAGES INVOLVED IN DEVELOPING A NEW MEDICINE
The development of a new medicine is time consuming and very, very few drugs make it through the lengthy trial and regulatory process to be approved for the market.
Figure 1 shows a diagram reproduced from the US Government Accountability Office Report GAO-07-49, published November 2006, titled NEW DRUG DEVELOPMENT: Science, Business, Regulatory, and Intellectual Property Issues Cited as Hampering Drug Development Efforts[iii]
Figure 1: US Government Accountability Office Report GAO-07-49 Diagram
The failure rates and timelines are generally regarded as being unchanged today, and while this is US data, the global nature of product launches in pharmaceuticals means this reflects a worldwide picture.
In summary, for every 10,000 screened molecules, 250 are selected as candidates for preclinical development. 245 fail to satisfy regulatory requirements, having expended many thousands of animal lives and £ millions in costs. Of every five to enter clinical trials, just one is approved for market, having expended many more animal lives, incurred £billions in costs, and cruelly dashed patient hopes for themselves and their loved ones.
In terms of timelines:
· Preclinical testing, and manufacture of the molecular compound for preclinical testing, takes about 3.5 years.
· Clinical trials take 7 years on average.
· Regulatory review and approval takes 1.5 years.
In total, that is an average of 12 years.
It is hard to see how, even with unlimited funds being applied to the Sars-Cov-2 injections, how a medicine, especially an ATMP, could complete this process in such a reduced timescale. It is extremely difficult to obtain authorisations for ATMP products.
The claim that manufacturing activities had been carried out in parallel to account for the speed of innovation doesn’t hold up.
There is a Regulatory limit on the multiples of a batch size can be scaled up – SUPAC, at 2.5 times the existing batch – molecular structure can change during scale-up, and become toxic, termed a polymorph.
GLOBALLY HARMONISED PROCESS FOR DEVELOPING A NEW MEDICINE
The process for developing a new medicine, and the data required, has been established by Governments and regulatory bodies over decades, responding to real-world events demanding improvements in safety, efficacy, and quality of medicines
he electronic Common Technical Document (eCTD) format that has been agreed by the three major regulatory bodies around the word – FDA (US), EMA (EU), and PMDA (Japan), following regulatory collaboration and the work of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for human use.
The three required modules are at the bottom of the pyramid are:
· Module 3: Chemistry (short for CMC - ‘chemistry, manufacturing, and controls’) also termed ‘Quality Module’
· Module 4: Nonclinical Study reports
· Module 5: Clinical Study Reports
The sections above the modules provide overviews and summaries. The CMC section is where all the details of suppliers, including site(s) of manufacturer and inspection history, material and product specifications, analytical test procedures, and process development protocols, must be submitted for review by regulators.
There is an amount of regulatory flexibility when it comes to standards in the supply-chain for producing preclinical test material, given the early stage of development.
However, for trials in humans, which is what the current rollout of the SARS-CoV-2 injections is, production in the supply-chain must comply with GMP and GDP.
ADVANCED THERAPY MEDICINAL PRODUCTS
SARS-CoV-2 injections are Biologics. They are also classed by regulatory authorities as Advanced Therapy Medicinal Products (ATMPs). ATMPs are defined as medicines for human use that are based on genes, tissues, or cells.[iv]
SARS-CoV-2 injections fall under the heading of gene therapy, with the following description:
“…contain genes that lead to a therapeutic, prophylactic or diagnostic effect. They work by inserting 'recombinant' genes into the body, usually to treat a variety of diseases, including genetic disorders, cancer, or long-term diseases.”
“A recombinant gene is a stretch of DNA that is created in the laboratory, bringing together DNA from different sources.”
It is generally accepted the regulatory terrain for ATMPs is in its infancy, and very few ATMPs have received regulatory approval.
For example, a leading therapy area in ATMPs is CAR-T, a treatment for blood cancers
First to market was Novartis’ Kymriah[v], launched August 2017. This is the warning on the labelling:
Warning: Cytokine Release Syndrome and Neurological Toxicities
Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving KYMRIAH. Do not administer KYMRIAH to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab, or tocilizumab and corticosteroids.
Neurological toxicities, which may be severe or life-threatening, can occur following treatment with KYMRIAH, including concurrently with CRS. Monitor for neurological events after treatment with KYMRIAH. Provide supportive care as needed.
Kymriah is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Kymriah Rems.
It is interesting to note that Oxford BioMedica manufacturers the viral vector for Kymriah (Lentiviral vector) as well as the vector for AZ/Oxford University.
ATMPs have their own GMP regulations. The full extent of the regulatory requirements can be viewed here. They are extensive, and far more challenging to implement in practice than any other medicine. Given the known dangers of ATMP products, it is clearly vital that procedures for development and testing are followed in full.
[i] Heparin: A Wake-Up Call on Risks to the U.S. Drug Supply, PEW Trust (now PEW Health), May 16, 2012: https://www.pewtrusts.org/en/research-and-analysis/issue-briefs/2012/05/16/heparin-a-wakeup-call-on-risks-to-the-us-drug-supply
[ii] Implementing the Falsified Medicines Directive: Safety Features; https://www.gov.uk/guidance/implementing-the-falsified-medicines-directive-safety-features
[iii] NEW DRUG DEVELOPMENT: Science, Business, Regulatory, and Intellectual Property Issues Cited as Hampering Drug Development Efforts https://www.gao.gov/assets/gao-07-49.pdf
[iv] Support for advanced-therapy developers: https://www.ema.europa.eu/en/human-regulatory/research-development/advanced-therapies/support-advanced-therapy-developers#gmp-requirements-section
[v] KYMRIAH: https://www.hcp.novartis.com/products/kymriah/acute-lymphoblastic-leukemia-children/
[vi] Rules and Guidance for Pharmaceutical Manufacturers and Distributors 2017 (The Orange Guide): https://www.pharmpress.com/product/9780857112859/orangeguide?utm_source=mhra_email&utm_campaign=orange17&utm_medium=email
[vii] Medicines & Healthcare products Regulatory Agency: https://www.gov.uk/government/organisations/medicines-and-healthcare-products-regulatory-agency
[viii] Clinical trials for medicines: apply for authorisation in the UK:
[ix] About Investigational Medicinal Product Dossiers:
https://www.imp-dossier.eu/
[x] Conditional Marketing Authorisations, exceptional circumstances Marketing Authorisations and national scientific advice, Medicines and Healthcare products Regulatory Agency, Published 31 December 2020:
More to come soon, comments welcome.