MHRA are in here auditing as we speak, it ain’t a pleasant experience I can assure you.

Well this is my day job and I’m one of those in the middle. I can tell you that the rigour with which data is collected, produced, analysed and debated is staggering. It’s also routinely inspected. I have colleagues who’ve had to stand up in US courts to defend just these points under aggressive cross examination.

More likely, things go wrong with over-interpretation or absence of information. A new drug will typically be approved for a chronic common indication with about 1000 patient-years of exposure. More for some areas (cardiovascular) less (sometimes much less) for rare or terminal conditions like oncology. Vaccines have more patient-years of data, and for these vaccines, assume a median of four months, giving about 7000 patient-years of exposure. That’s typical for other vaccine submissions. You don’t wait long after unblinding a trial for submission. Nothing has been skipped – the agreed (with FDA and EMA) endpoint for registration was infections at 28 days post last dose, not 280 days. The sample size is defined by the power to detect the difference of interest and the rates of events (infections). The collation and analysis of data will have been expedited by throwing people at it, not cutting corners.

If rare events occur, they may not reveal themselves in Phase 3 trials. Anything rarer than about 1/10000 is challenging. Once used widely, post-marketing monitors safety on an ongoing and never ending basis. Vaccines are no different in this regard.

Sometimes disaster happens unwittingly not due to malice. Thalidomide is the textbook example. It passed ALL required safety tests and clinical studies of the time. It was only after release that it showed the devastating teratogenic effects in the first trimester when used for morning sickness. The US did not approve thalidomide NOT due to these effects. It was because the Phase 3 study showed a signal for increased peripheral neuropathy. Right decision for the wrong reason and basically luck. The outcome was increased scrutiny and additional animal teratogenic tests. Thalidomide when used for the right patients is an amazing drug.

[tl:dr] there is always a limit to what can be seen in Phase 3 trials. Rare events are rare and will be monitored in wide use very carefully. Never ascribe to malice what can be explained by absence of knowledge.

Speaking diplomatically about the CAA, that means nothing.

I was talking about independence not competence – I’m familiar with the CAA too but thats another story 😉

I’ve experienced audits from CAA, FAA, EASA, and many other aviation authorities (Chinese Aviation Authority are off the scale bonkers) but MHRA and FDA are another level.

nobeerinthefridge

How do you end up on the receiving end of inspections from both the FAA/CAA and the MHRA?

I’m in Engineering, bailed out of aviation 6 years ago into Pharma. Different business, but Engineering is Engineering.

Do we expect the discussed issues with the Ox/AZ trial to affect MHRA certification?

We have audits in clinical from the individual patient clinic visits (where we employ site monitors), through to data entry, right up to generation of the submission pdf documents. It’s a continuous chain and when the agencies come, they expect to see every part of that chain. All of it in our systems – which they have access to. We also of course submit all the source data and analysis codes for that data to regenerate all analyses. The FDA routinely run their own analyses on the data (and everyone else’s too!).

Manufacturing of the drug product is even more heavily inspected! That’s noBeer’s day job.

As I said, it’s not malice or poor practice, it’s knowledge gaps.

I always love the idea that fda inspectors are actually allowed to carry guns as the are federal agents.
the thought that always amused me was the idea of someone running across a car park with paperwork being winged by one to stop them getting away.

On a serious note, all the gmp inspectors and agencies I have interacted with (Fda, mhra, cofepris, ema, and others) are all independent and take their roles incredibly seriously. The are nice people generally but they are incredibly thorough and will dig if there is something they don’t like (annoying when it is their opinion though not in the regs).
As tired said, the vaccines are safe for use of authorised, but there is always a risk of rare events causing issues -this is the reason for the mhra yellow card system which is for reporting adverse events and also the reason pharma companies have pharmacovigilance groups that follow and monitor for any safety issues post approval. in addition the pfizer vaccine has been approved for temporary use so if anything comes up during use the chances are it will be pulled from further use immediately

Edit for context- I worked for 12years in gmp qc labs and now am a gcp auditor.
the levels of auditing required are substantial and by both internal local groups and internal independent groups. This is in addition to corporate audits and of course the regulatory inspections

Do we expect the discussed issues with the Ox/AZ trial to affect MHRA certification?

I expect the guys at Cobra the manufacturer who filled the vials for one arm of the OX/AZ study are sweating. I would still expect approval of the standard two doses. Not the low dose until another trial.

Presumably they can refine the size of dose in a trial run parallel or at least concurrent with their phase 3? In which case if they get approval based on phase 3 two full dose they can expect quick approval on changing the volume of the first dose if that is demonstrated to be more effective?

Steve, I understand your concern and more broadly I’ve heard it voiced by plenty of others for various reasons, but in my view you’re over-thinking. There are many reasons this is happening so quickly. The primary drivers in my view are that there really is no limit to the amount of money that can be thrown at this objective and neither is there a practical limit to test subjects.

What I find really notable about the guests on the r4 program, who are in positions where knowing your shit is not optional, when asked if they would take this vaccine not one has hesitated to say yes.

Also, for those in their 20s, 30s or 40s who don’t feel they’re at any great risk from the virus, and view getting the vaccine as more of a potential risk for little gain, it’s worth pointing out that by the time it’s available to them it will already be in the arms of those for whom the risk vs. reward calculation is quite different. The risks will be well known by the time it’s their turn.

Probably best to avoid threads entitled “The Coronavirus Discussion Thread” then 🙂

You can hardly complain about that considering you clicked on it.
There are tons of other topics on here. Coronavirus has been limited to just a few threads

, I understand your concern and more broadly I’ve heard it voiced by plenty of others for various reasons, but in my view you’re over-thinking. There are many reasons this is happening so quickly.

I think batfink’s post a few days back covered this very well, think he’s involved in Australian drug licensing. It answered all the questions I had

If I read it correctly, we have half a million threads on the forum and someone came on this one to complain about Covid threads 🤔

This thread really is one of the best things on STW right now. It’s fascinating.

Having seen other Coronavirus threads on other forums this one stands out as having real frontline insight from a group of people who are willing to share what can’t be learned from watching a YouTube video on how to be a pharma/vaccine expert.
There is also very little dick swinging just a willingness to educate and explain.
It’s priceless.
For anyone who doesn’t see the value in that they can piss off to Facebook.

Del

Steve, I understand your concern and more broadly I’ve heard it voiced by plenty of others for various reasons, but in my view you’re over-thinking. There are many reasons this is happening so quickly. The primary drivers in my view are that there really is no limit to the amount of money that can be thrown at this objective and neither is there a practical limit to test subjects.

What I find really notable about the guests on the r4 program, who are in positions where knowing your shit is not optional, when asked if they would take this vaccine not one has hesitated to say yes.

Firstly good news from consultant … that out of the way I don’t personally have any ieeues with the vaccines, indeed just spoke to my octagenarian mother saying the same.
With her auto immune system and age risk of complications from SARSA-Cov19 >> possible risk from vaccine.

However my mother is a perfect example … she has zero trust in anything this government tells her and its been lower every week since she voted for Brexit and believed that.

@mudmuncher: no

Two key points:……

@gray, thanks, I see where I was going wrong now.

If it’s 29/70 really need to think in terms of 140 infections rather than 99 which is what it would likely have been with an ineffective vaccine.

It’s 3/30 (90%) and 27/71 (62%), combined 30/101 (70.3%). I think they originally said 60% and 70% but this is now on the press release. They definitely saw 131 total infections. I’m running an analysis to compare the various vaccine arms.

If you’re rich you don’t have to quarantine

Makes no logical sense. Lewis Hamilton despite being rich and in a tremendously well organised F1 bubble got COVID. Why would we allow random CEOs “whose work creates or preserves 50 jobs” skip the sensible rules to stop transmission?

Makes no logical sense.

What’s this bit?

as of 15 December people will be able to pay for a private coronavirus test to reduce their isolation time to as little as five days, as long as they return a negative result.

Is this only for execvs and sport/celebs or is that for everyone.
Still no-one has explained to me why someone with 2 negatives tests a week apart is a bigger risk than someone who hasn’t been tested.

Makes no logical sense.

I just watched the ITV report on Russia. Absolutely horrific. Body bags piled up against walls and in corridors, virtually empty cemeteries now full.

There is absolutely no doubt that countries with authoritarian, (excluding China) populist leaders have faired very poorly in their response to Covid.

Including the UK I’m ashamed to say.

To our resident experts – are we close to licensing antibody treatments for severe COVID and will any be available?

Only dexamethasone has been shown to be efficacious in doubleblind randomised clinical trials. The next on the list is a class of antibodies against a pro-inflammatory cytokine called GM-CSF. We will see. Then will come the antiviral antibodies, but these have failed in US studies not hospitalised patients. Antivirals should be given early for prevention. Other treatments for emergency use are the JAK inhibitor baricitinib that has emergency use. I collate a database of about 80 treatments undergoing testing. There are many assets but relatively few modes of action.

One could claim that prevention by vaccination is a good outcome. Reducing COVID-19 to a dry cough would be a very good outcome with sufficient vaccine coverage. That coverage will be 2H21 when the mainstream spike protein vaccines come to bulk up capacity.

Nothing approved on the immediate horizon I am afraid. GMCSF has four mAbs in trials.

I think batfink’s post a few days back covered this very well, think he’s involved in Australian drug licensing. It answered all the questions I had

Welcome. I’m based in Australia (previously the UK) – but I run global trials. Not involved in covid, other than figuring out how to keep my trials running through various states of lockdown. Currently trying to figure out how to run a lung cancer study in Bangladesh and Sri Lanka.

Fun fact – one of my trial patients in China (Wuhan!) had covid back in Oct 2019. We didn’t know it was covid at the time – just a really nasty pneumonia that required ICU.

https://www.theguardian.com/uk-news/2020/dec/03/experts-call-for-end-of-rapid-covid-tests-in-universities-and-care-homes-in-england

Is this how Liverpool managed to go from the worst in the country to being dropped to tier 2?🤔

2nd / Booster injection on the Novavax trial for me yesterday. No side effects etc.
Speaking to the consultant no body he has seen on either the active dose or placebo has mentioned any side effects..

Back in 2 weeks for a general check up.
The Pfizer vaccine was mentioned, basically that in the rare chance I’m offered a dose, to call them and the will “unblind” me so I can decide.
They are hoping to know the efficacy of the Novavax one by the 2nd week in January.
Let’s hope it’s another weapon hey!

My only dissapointment is that so far I haven’t been given a lollipop or a sticker saying I was a brave boy. It’s a bloody big needle! 😂

I imagine it must be hard to get patients to sign up for a trial that has a 50/50 chance of being offered a placebo, when they think they can have Dexamethasone instead?

Considering that even now it’s Joe Public’s best chance of being vaccinated ASAP I’d think not.

Sorry – a drug trial in hospital on potential new treatments.

placebo, when they think they can have Dexamethasone instead?

That’s not quite how it works. Once a medicine has proven efficacy it becomes “standard of care”. Then the future tests will be against either the historic placebo patients or the active concurrent standard of care.

We don’t really like historic controls. Patients being treated in the NHS RECOVERY trial now are getting better management than they did in April – even before dex was approved. Mortality has called by 25%. Also because of this, the gap for improvement is smaller (incremental benefit) and smaller differences need more patients to show significant differences over chance.

Oncology is the classic case in point. Standard of care now looks nothing like it did ten years ago for many tumour types. Other diseases have placebo issues. It’s still just about ethical to use placebo in Rheumatoid Arthritis but not for too long. It’s not for Multiple Sclerosis trials. Instead active controls drugs are used that don’t work very well. Mild but chronic diseases and diseases with no approved treatments still use placebo, normally on top of standard of care.

Vaccines are not therapeutic, so pure placebo is an ethical option.

[th:dr] We say placebo-controlled, but normally it’s placebo plus standard of care because of ethical concerns.

I’m getting a sense that the same old ‘battle-lines’ are being drawn up for everyone to follow on the vaccines.

I always wonder why it’s so easy to guess someones opinion on things these days, I’d wager than if I asked someone who said “masks don’t work” and said the lockdown was pointless because it stopped them going down the pub, they’re the exact kind of people who’ll tell you that they’re not having the vaccine because it’s untested. You could explain, until you’re blue in the face the difference between rushing something, and doing something quickly by throwing huge resources it, but there’s always a Social Media factoid that’s bullshit, but somehow more compelling that they can ‘prove’ the opposite.

Still, I’m pleased to hear that supposedly Phase 1 will reduce the number of Deaths and Admissions by 99%, I hope that’s true.

I always wonder why it’s so easy to guess someones opinion on things these days, I’d wager than if I asked someone who said “masks don’t work” and said the lockdown was pointless because it stopped them going down the pub, they’re the exact kind of people who’ll tell you that they’re not having the vaccine because it’s untested. You could explain, until you’re blue in the face …..

Masks don’t work, Hancock said so….
Pubs are safe …
Care homes are safe…
Schools are safe …

Then the same government tells them the complete opposite and you wonder why they stopped believing?

Then the same government tells them the complete opposite and you wonder why they stopped believing?

A lot of the non believers I know still think Brexit is brilliant.

Thanks Tired – that makes more sense re drug trials.

One of Madames colleagues has just tested positive for a second time. First time in the Summer she was moderately ill, this time no news on her state so far other than the test result, a positive PCR test which I believe is quite reliable for positive results.

@Edukator – crikey, that’s not good.

Do you think the first test was a false positive?

Everything points to both test results being reliable: consistent with her Covid symptoms the first time and her contacts the second time.

USA has recorded 1 million cases in the first 5 days of December 😱😱