Thread by @peripatetical

I'm seeing commentary asking why Australia isn't just rolling out the vaccine prior to regulatory approval, or why the TGA just doesn't register the vaccine based on approvals in other countries.

A thread on what's involved in vaccine regulation. (I'm the chair of the Advisory Committee for Vaccines, which is appointed by Minister Hunt. It's the TGA's responsibility to assess drugs and vaccines but this committee provides advice)

It's obvious that vaccines need to be effective, safe and made to a high quality. Most vaccines are given to millions of people who are otherwise well to prevent disease - this is very different to treatments that are given to people who are unwell.

Efficacy - the degree of protection given by a vaccine - is generally the simplest question to answer. For COVID vaccines, the benchmark was set by WHO at 50%, and most of the vaccines being considered appear to be much more effective. who.int/publications/m…

I've previously discussed some of the issues of interest when considering how effective the vaccine is. The primary question is whether the vaccine prevents disease.

https://twitter.com/peripatetical/status/1340803261314449408

Several other questions are very important to the COVID vaccine program - the degree to which vaccines prevent transmission, and whether they work in high risk subgroups (esp older people)

Safety requires larger numbers of participants in trials. What we're looking for is a "safety signal" - anything that might hint that something serious might be caused by a vaccine, and how common it is.

We look at common side effects, severe side effects, those severe enough to discontinue the course, deaths that occur after vaccination, lab abnormalities. For COVID vaccines we want to make sure the vaccine doesn't make severe disease worse.

It is worth noting that many diseases have a "background rate" - for example flu-like illnesses occur quite commonly in both groups. In the Pfizer study, a third of participants in the placebo arm had fatigue or headache.

https://twitter.com/marklewismd/status/1336754605435174912?lang=en

The Brighton Collaboration has been working on a list of potential side effects to specifically look out for. brightoncollaboration.us/covid-19/

These include adverse events that might be related to vaccines generally (eg allergies), those related to specific vaccine types, and those related to COVID vaccines (eg enhanced severe disease)

The phase 3 studies have generally included about 20,000-25,000 people who received the vaccine. This is sufficient to exclude moderately uncommon side effects, but not serious but rare side effects (eg those occurring in less than 1 in 10,000 people).

If you see a single case of a serious side effect, it can be hard to work out if it is chance or something to worry about. An example are the cases of transverse myelitis (spinal cord inflammation) that were reported in the AstraZeneca trial. thelancet.com/journals/lance…

There were three cases in this study - one occurred 14 days after the COVID vaccine, another occurred 10 days after vaccination but on further review was felt to be due to pre-existing multiple sclerosis, and the third case occurred in the control (non-COVID vaccine) group.

There is information not only in the phase 3 trials, but also in all other studies before that, and in countries that are now starting to roll out the vaccine ("post-marketing surveillance").

An example of side effects only picked up later are the cases of anaphylaxis that have been reported in the UK and the US gov.uk/government/new…

Quality is one of the most important questions (I'm not an expert in vaccine manufacturing, but I've seen enough to know how complex it is). During the manufacturing process,"controls" are put in place to make sure that vaccines are made to a high standard.

We want to know that there is the correct amount of vaccine in each dose. We want to know they are free from contamination. That there are no differences between different batches or those made in different factories. We need to know the shelf life under different conditions.

That's not all - there are questions about toxicology of the vaccine or its components (such as the lipid layer used in mRNA vaccines, or adjuvants used in protein vaccines).

Whether they can be used safely in pregnant or breastfeeding women. Whether they can be given with other vaccines such as the flu vaccine.

For COVID vaccines, we have published papers that report that the vaccines appear to be effective and generally safe. Many people think that published papers are the gold standard in evidence, but they just scrape the surface of what we want to know.

Regulatory submissions contain much more information - they run to tens of thousands of pages (I've read ones in the past that were more than 100,000 pages).

Ultimately, the question is whether the benefit of using the vaccine outweighs the known risks and the uncertainties. Countries where there are hundreds or thousands of deaths each day are clearly willing to tolerate some uncertainty to prevent this, and this is appropriate.

It is worth noting that other regulatory agencies have generally given "temporary" approvals or "emergency use authorisation" reflecting that not all the data is available yet.
fda.gov/emergency-prep…
gov.uk/government/pub…

But we're in a different position in Australia - even with the current situation in NSW and VIC, we can afford to wait for the TGA to do its job and make sure we're getting a safe, effective and quality vaccine.