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Swine Flu Vaccine in 5 Days?

by: SusanC

Wed Jul 15, 2009 at 03:26:09 AM EDT


They say "there's no smoke without fire".  

There's been recent reports that a swine flu vaccine will be fast-tracked for use in Britain within five days after it's made.  Since this appears to come from official sources, I believe we'd be remiss not to check out what this is about.

SusanC :: Swine Flu Vaccine in 5 Days?
Even though the Director of the WHO said yesterday that you need 2-3 months for clinical trials, our Chief Medical Officer, Sir Liam Donaldson, appears adamant that first doses will arrive in early autumn.  Although he back-peddled a little by saying "We then have to license it properly and that may take a little time", still he appeared rather confident (and I might add more than a little self-congratulatory), that we'd be one of the first nations to receive vaccines, that all 60 million doses will be available before the end of the calendar year, presumably to be given out asap to protect the British people against this H1N1 virus.

Which got me thinking, what exactly is going on here?  I mean, Margaret Chan notwithstanding, Sir Liam appears to be quite certain that we could be doing mass vaccinations pretty d****d quickly, and not several months down the road after clinical trials are all done.  So what's the deal here, with the 'fast-tracking in 5 days' thing?  Can they really license and roll out a pandemic vaccine for tens of millions of people in 5 days, without clinical trials?

I looked, and the answer is, YES THEY CAN.  

What's more, it's perfectly legal - they don't even need to change any laws or invoke such things as Emergency Use Authorization like what the US government would need.  At least that is as far as I can determine.

Let's take a look at how pandemic vaccines are licensed in the EU.  I must first raise a caveat, that this is a much simplified exploration of a complex subject, by no means comprehensive.  Also, for the sake of clarity, I'd prefer that specific issues about individual vaccines be explored separately, some time hopefully in the near future.

First of all, the European Medicines Agency (EMEA) is the EU regulatory body, the equivalent of the FDA.  There are, however, important differences.  Since the EU is made up of sovereign member states, there are 2 tracks to licensure.  Companies can license their product with individual regulatory agencies, like the MHRA in the UK, but since approval from the EMEA allows marketing in all 27 member states, companies of course much prefer the EMEA route.  Assessment of applications in the EMEA is under the Committee for Medicinal Products for Human Use or CHMP, made up of one expert from each member state.  Since not all countries have similar levels of expertise or excellence in governance, there are IMO consequences from this practice.  

OTOH, member states do have the discretion to approve or deny a license to any product approved by the CHMP/EMEA.  After all, they are sovereign countries.  An example is Fluad, the adjuvanted seasonal flu vaccine that is approved for use in the EU for those aged 65 or older.  Even though the approval is there, not every country has licensed or used it.  

With regards to influenza vaccine approval, the EMEA has 3 different tracks - interpandemic, pandemic, and pre-pandemic vaccines.  

  1. An interpandemic vaccine is basically your seasonal flu vaccine, made with the circulating seasonal strains.  
  2. A pandemic vaccine is a vaccine made with a virus of pandemic potential, and intended to be used only when a pandemic breaks out.  
  3. A pre-pandemic vaccine is made with a virus of pandemic potential, but licensed to be used before a pandemic breaks out.

Since a pre-pandemic vaccine will be used in the absence of a pandemic, the risk/benefits calculations are different from a pandemic vaccine.  In essence, the EMEA requires a pre-pandemic vaccine to fulfill the same standards as the interpandemic or seasonal vaccine, for safety and immunogenicity etc.  

For pandemic vaccine, however, the EMEA offers a different procedure for fast-tracking, where companies submit a 'mock-up dossier' for approval, and, when a pandemic happens, they file for strain variation.  The process is shown in these 2 slides (source).  

As you can see from the flow-chart, the idea is when a pandemic is declared, the manufacturer does not need to re-submit the whole dossier, only information on the new strain used, to apply for 'pandemic variation'.  Here's what the EMEA guideline says:

In the case of an actual pandemic, the vaccination programme would need to be implemented as soon as possible.  Provided that the mock-up and final pandemic vaccines are similar other than in strain content and the dose schedule is unchanged, the final pandemic vaccine may be approved for use by means of a variation that addresses only the quality issues and without the provision of clinical data.

In other words, once the vaccines are made, the EMEA can grant approval for marketing the vaccines based solely on product quality assessments, and no further clinical trials are required before the vaccines are properly, legally, approved, to be given to the citizens of these 27 countries.

No wonder Sir Liam is so optimistic, that we WILL have a vaccine in early autumn.  Exactly what kind of vaccine(s), and how safe they are without clinical trials, is another story.  

Now, let's take a closer look at the fast-tracking requirements.  First question is, would a vaccine now made for H1N1 be considered 'similar other than in strain content' from the H5 vaccines used to support the mock-up dossier approval?  I haven't found a definite answer to that but reading between the lines, especially the recently updated Revised recommendations for pharmacovigilance plans for H1N1 pandemic, which details the post-approval clinical trials that need to be done, I believe the answer is yes.  

So, apart from these requirements for post-approval clinical investigations, no clinical data on either safety or effectiveness is needed BEFORE approval by the EMEA.  Assuming of course they do not vary the dose, but since any dose variation

  1. requires clinical trials (how else are you going to find out what is the appropriate dose, without testing it?)
  2. automatically voids the fast-track option (see box above),
  3. giving an advantage to your competitors, and
  4. if you don't test, nobody can say your dose is inappropriate,
how likely do you think companies will voluntarily do dose-ranging studies to determine the safe and effective dose?  

Bear in mind that this protocol was developed with H5N1 in mind.  All 3 vaccines were approved based on the H5N1 virus, which is notoriously non-immunogenic, requiring 90ug to induce an immune response in the absence of an adjuvant, as compared to 15ug per strain in the seasonal vaccine.  The Novartis vaccine uses 7.5ug, GSK 3.8ug, both with adjuvants.  I have a suspicion that the low immunogenicity of H5 may have been due to the modification of the HA (to remove/change the part that makes it HP), since the Baxter whole virus vaccine made from wild-type (ie unmodified) virus is immunogenic without adjuvant at 7.5ug.

We have NO idea how immunogenic the vaccine seed virus for current pandemic H1N1 will be.  Can data generated from H5N1, a very unusual virus that is/was not well adapted to humans AND genetically modified (except for the Baxter vaccine), be extrapolated to H1N1, a pandemic virus with a totally different origin and much more adapted to humans?  The issue of dose-ranging is made more acute by the use of adjuvants, since adjuvants lack universality in their actions, ie how an adjuvant behaves with one antigen may be drastically different when the antigen is substituted.  If H1N1 is a more immunogenic strain than H5, and we use the same dose of antigen and adjuvant, what is the risk of excessive immune response causing adverse reactions?  I don't think anyone has any idea.

In addition, the current pandemic has a CFR a couple of logs lower than H5, so the risk/benefits tolerance from the public will be correspondingly different.  Would parents be willing to let their kids be vaccinated, or would HCWs roll up their sleeves to take the shot in the spirit of public service, if they know the following?  

From the EMEA guidance (emphasis mine):

Unless the mock up vaccines are also suitable for use as final pandemic vaccines, ALL the safety data on the final pandemic vaccines will have to come from real life use.  

In other words, we/they will be the guinea pigs.  Or ferrets.  Or whatever...

The reason why this is such a concern, is because, to start with, the standard required for the mock-up dossier submission, is already much lower than what is required for normal vaccines, eg for seasonal or pre-pandemic use.  Indeed, the EMEA guidance admits that:

However, even if mock-up vaccines are suitable, the post-marketing safety data will be extremely important, since the core pandemic dossier will be too limited in size for full assessment of safety.

Exactly how limited?  The EMEA guidance says

the database should be sufficient to detect adverse reactions or events at a frequency of approximately 1%

Is that good enough, to support a mass vaccination campaign without clinical trials?  If you vaccinate half the UK population, ie 30 million people, a severe adverse event with an incidence of 0.1% would affect 30,000 people, but this would NOT be detectable with the trials.  In any case those were done with a different virus at doses that may or may not be appropriate for the current pandemic.  And so on and so forth...

Is that good enough, Sir Liam?  In case you didn't notice, this is not H5N1.  This is not a catastrophic or even a severe pandemic; we don't have to take drastic measures, at least, not just yet, and not without careful deliberation.  It's SWINE flu, not BIRD flu, did anyone brief you on that?  

Hello, is anyone home?  

Can someone please make sure the UK government has a remote control with a PAUSE button that WORKS?  

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btw notice that ALL 3 vaccines
with EMEA pre-approval, use technology that are NOT currently used in the seasonal flu vaccine in the UK.  These are un-tested vaccines,  with a novel virus in a naive population.    What exactly will the immune response be like?  I don't think anyone has any idea.  Also, clinicians have NO experience to guide them on what kind of vaccine-related problems that they need to be alert to.

Without clinical trials, we'd be driving in the dark.  



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


size of clinical trials
from the CHMP assessment reports:

Baxter - a total of 845 subjects in 2 multi-centered, uncontrolled trials, of whom 606 received at least one dose of the final formulation

Novartis - 562 subjects given at least one dose of MF59 adjuvanted vaccine of either H5N1, H5N3, or H9N2

GSK - 4002 subjects received the AS03 adjuvanted vaccine.  GSK had the biggest database because they more or less filed for both pandemic and pre-pandemic vaccine approval at the same time.  It's the same product except the requirements are different.  

Novartis also submitted a dossier for prepandemic vaccine, but it was withdrawn after several clinical trial sites failed inspections.  This is the subject of another diary I'm writing.  

Just for comparison, the 2 most recently licensed vaccines in the US are Gardasil, with 20,000, and Prevnar with 38,000 subjects in prelicensure clinical trials respectively.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
Yikes!
And my guess would be that none of the info you just dug up would be widely explained to the public before they queued up for shots! It sounds like the kind of plan that should only be authorized in the case of an incredibly severe pandemic (like if H5N1 combined with H1N1) and people were indeed dropping like flies. Anything less than that, let people who want early untested vaccine volunteer for the testing trials - that seems like the logical answer.

[ Parent ]
you kidding me?
And my guess would be that none of the info you just dug up would be widely explained to the public before they queued up for shots!

It took me DAYS, and a LOT of sleuthing, to get this far.  I'll tell you the information is NOT easy to find.  I doubt that anybody will volunteer to explain this to the public.  ;-/

It sounds like the kind of plan that should only be authorized in the case of an incredibly severe pandemic (like if H5N1 combined with H1N1) and people were indeed dropping like flies.

YOu're right.  I think the EMEA protocol was designed with H5N1 in mind.  This H1N1 coming out of the left field has just thrown everything upside down.  That said, MY complaint is, there's NO rule that says our government has to go on autopilot, and not THINK, before they go all out on vaccination.  This really is a different virus, with different considerations, IMO.

Anything less than that, let people who want early untested vaccine volunteer for the testing trials - that seems like the logical answer.

I agree.  I'd like to see them vaccinate smaller groups in clinical trials before rolling this out without monitoring, to the general public.  



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
The question is why...
is the British gov't moving so quickly to vaccinate every Brit even though there will be no clinical trials of the vax? Is it political? I would think they are taking a huge risk doing this for a flu virus that while troubling is not devestating at this point. Why are they rushing this? What do they think the public's reaction will be if there are significant negative reactions to the vax?

I'm a strong believer in vaccines but I would not want to get this vax. The risk/reward ratio just doesn't work at this time.


Two possibilities
1) This vax is being rushed into production without due attention to the risk/reward ratio.

2) This vax is being rushed into production because there are concerns that risky measures may indeed be justified by the potential or emerging  severity of the situation.

Neither option is reassuring.


[ Parent ]
Possibility 2.5: They expect to see morbidity and mortality increase soon
and want to keep people calm, whether or not they actually start giving the jabs. ("Soon, soon....everything will be better.")

"The truth does not change according to our ability to stomach it."  Flannery O'Connor

[ Parent ]
This is what concerns me.
Either they are totally inept or there really is something coming up over the horizon.

[ Parent ]
don't see it just with flubie eyes ;-)
would be my advice.  Don't get tempted to think, just cos tptb are doing something drastic, that it necessarily mean that they know something about this pandemic that you don't.  I'm sure that is true, they DO know things that we don't know.  The challenge is to get beyond our own filters, to tease out which is which.  It's not easy, and I am by no means suggesting I've got the answers.  The more I investigate this, the more questions I have.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
I agree Susan
drastic actions doesn't necessarily imply that they know something about the outcome that we don't-like all of us, they are crystal ball gazing, though their interpretations of what the fog means are perhaps backed up by more data than our speculations. I think the drive to offer a vaccine as quickly as possible has as much to do with how they perceive public reaction to be if they don't, than how it really is or is going to be on the ground tbh.. obviously, given the age groups being targeted by this virus their is some degree of urgency to mitigate deaths, but much could be achieved in this regard by planning now for school closures etc, rather than offering a half-cooked vaccine as the only panacea to our ills. I guess a jab is an easier option to push for as it has fewer economic consequences in the short run and would be supported by the general public who expect a solution to be provided asap if not sooner. I do sometimes wonder if we haven't painted ourselves into the mushroom corner with our expectations of what can and can't be done by central government, so that now, they feel obliged to act without due process on our behalf.

[ Parent ]
Problem is . . .
. . . it could be both - they could be totally inept and there could be something coming over the horizon.


[ Parent ]
yes, all of the above
I don't have a crystal ball, just speculating like everyone else.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
another possibility
3) This vax is being rushed into production for whatever reason, and then people go all complacent, don't do any NPI at all, then get the vax and it doesn't protect them much and has some side effects.

Not sure we need more complacency at all!

Where did the swiss-cheese approach go?   In this case, the swiss-cheese approach, doing several different things at once for greater effect, would mean pushing everything at once:
- protecting students through whatever means, including but not limited to early and proactive school closure.
- other non-pharmaceutical interventions
- community resilience, including busines resilience and family resilience and community mutual aid
- good treatment plans, as in good delivery of antivirals, good home care, good community care (as spartan as need be, and then better), other treatments to complement antivirals or to be used in case antivirals fail
- safe, abundant vaccines

Am I asking for too much?  This will not be mild with many mild patients, and with many severe patientes it may get even worse.  But even if it stays "individually mildish" it's at the very least good training for the second 21st century pandem.ic, which might or might not be H5N1

You arm yourself to the teeth just in case.  You don't leave the gun near the baby's hand.


[ Parent ]
Swiss cheese, please!
I vote for increased emphasis on the Swiss Cheese approach. I'd like to see us examine the feasibility of an alternative distance learning model for schools.  Schools might be open on a very limited basis - with social distancing measures in place - for families who must rely on them. Right now we are not facing the school problem head on, even though kids are our most easily infected group.  We can't ignore the school issue because it's hard, and we can't wish it away by just telling kids to wash their hands, given droplet and aerosol transmission of the virus.

Vaccines aren't going to be an early "easy button," however much we might wish they could be - that much is clear.


[ Parent ]
it could just be incompetence
which I have learned never to underestimate.  And/or there's always the power of vested interests.  

Remember life does not begin or end with pandemics, or even THIS pandemic.  There are LOTS of products in the pipeline, and adjuvants, immune modulators, and novel delivery systems, which btw all work in similar ways, are the hottest game in town, in every single vaccine meeting I've been to.  

But the barrier to acceptance for novel adjuvants are very high, especially in the US.  Consider that MF59 has been 'licensed' for elderly use since 1997, but they have not succeeded in breaking through into mainstream market.  Until recently with Cervarix, the HPV vaccine in Europe, although it is receiving very bad press (together with its cousin Gardasil in the US) because of the severe adverse reactions that some girls experience.  

btw if you want to discover the world of vaccine adverse reactions, try reading forums like this http://www.jabs.org.uk/forum/d... , especially stories on the HPV vaccines, cos they are recent, and most likely to be adjuvant-related.  Read their stories with a critical eye, don't take people's words for it.  And don't judge their opinions based on their ignorance about flu, cos it's not their area of interest. Most importantly, bear in mind that most parents of vaccine-damaged children are not intrinsically anti-vaccine, cos if they were, they would not have allowed their kids to be vaccinated in the first place!

Here's another site with lots of eye-opening documents  http://www.theoneclickgroup.co... especially this one, one of the most enlightening piece of investigative journalism I've read in recent years, on the close relationship between government, pharmaceutical companies, the medical establishment, MSM.

For more 'mainstream' opinion, try this, transcripts of FDA/NIH meeting on adjuvants.  Look up what Jesse Goodman says, starting from page 19 of day 1.  He's the director of CBER, the office inside the FDA in charge of regulating vaccines.  Bear in mind that any official speaking in public has to be very diplomatic, so you have to read slowly to discern what he is saying.  Find out the latest thinking within the FDA (and the NIH) on adjuvants, which is what vaccine companies are up against.  

Here are a couple of quotes:

So at FDA, we are asked to make some difficult judgments ranging from clinical trial judgments to approval judgments to where to put resources in terms of trying to stimulate product development. And it comes down to, in this area, enhanced immunity versus inflammation, adverse events, and potentially autoimmunity.  

And I like to remind people, particularly when many people here are maybe engaged mostly in laboratory investigation, that these products ultimately interface with humans who are your children, our children, our country's children, the world's children.

So what are some of these potential concerns we want to keep in mind?  As I mentioned, you could get an antigen-specific or nonspecific increase in potency of immune and inflammatory stimulation.  

We typically see, for effective adjuvants, increased immunogenicity, an FDA term for feverishness, sore arm at the site, which we typically see with non-adjuvanted vaccines but often see more in the presence of an adjuvant.

I want to point out it is very unclear whether these ever correlate with more severe adverse events.  You know occasionally they do.  But we have not found, to date -- (unclear) but the flip side is it would be difficult to find, for example, that increased local reactogenicity or feverishness down the road increases the commonality of some of the more severe adverse events that we might be concerned about such as neurologic events.  

There just aren't those data.

The toxicology of vaccines, not to mention the toxicology of adjuvants has been a really neglected area. And, you know, we've tended to only recently pay attention to this. And we've had just tools of conventional toxicology, which largely focus on drug effects on organs.  And, of course, when you are talking about immunotoxicology, there are not a lot of good models. I think there is a huge opportunity for the scientific community to develop better nonclinical or non-human models and even human studies that could tell us about the safety of novel vaccines and adjuvants.

The fact is, adjuvants work.  They absolutely do, if you want effective vaccines.  There's no doubt about that. The problem has always been the toxicity.  We (or scientists) just haven't been able to solve those problems yet. Also, among scientists, adjuvants are called "the immunologist's dirty secret".  Try googling that phrase and see what you get.  

So, it's a complex story.  I'm sure the desire to save lives plays a big role, cos again, as I said, vaccines DO work.  Adjuvants DO work. How and whether we have the scientific knowledge and the regulatory structure, oversight, and transparency to adequately balance risk vs benefit, is the problem that IMHO still needs a lot of work, in order to make sure we have better, more effective, and safer vaccines.  



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
sorry, there's a typo
We typically see, for effective adjuvants, increased immunogenicity, an FDA term for feverishness,

should read

We typically see, for effective adjuvants, increased reactogenicity, an FDA term for feverishness,

DUH!!



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
They have completely backed themselves into a corner
with promises of a vaccine by early fall.  Once it becomes clear it won't work quite that smoothly there will be poltical hell to pay.  Either it won't be effective, the strain will change, it won't be safe, there won't be enough, or some combination of the four.  They are wasting time when people could be doing more to prep - even to get two weeks worth of food, water and extra meds in case they have to stay home to tend sick children.  There is still time to do this.  Instead, they keep saying - "there will be a shot for that."  Guess what?  There won't.

All I know is there ain't no way I'm rolling up my sleve for a vax that gets rushed through that fast.  


I suspect many people would agree with you
All I know is there ain't no way I'm rolling up my sleve for a vax that gets rushed through that fast.  

Which was why I felt it important to bring this to people's attention.  



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
I'm sorry to say this
but here's the difference between the US and the EU.  I just received email notification that there will be an urgent teleconference tomorrow of the NBSB, discussing precisely these issues and inviting the public to voice their opinions.  I've put up a new diary for it.  http://www.newfluwiki2.com/dia...

Read the experts opinions.  The difference in approach cannot be more stark... Sigh...  



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


Baxter
From what I've read, the Baxter vaccine uses no adjuvant, or at least CELVAPAN, the mock-up licence, did not include one.

The CELVAPAN EMEA licensure supports fast track approval of a pandemic vaccine containing the A/H1N1 virus strain. Baxter will submit the A/H1N1 vaccine for approval upon completion of initial manufacturing runs.

http://tinyurl.com/lntn8y

"CELVAPAN combines innovative science and breakthrough production technology with the aim of protecting people against an H5N1 pandemic flu infection," said Hartmut J. Ehrlich, MD. "This is an immunogenic vaccine without the need for an adjuvant to boost the immune response."

http://www.medicalnewstoday.co...

Adding an adjuvant at this stage, would invalidate the licence. Is that correct?

Therefore, if it gets approval in five days, it will be an unadjuvanted vaccine. What is your opinion of its safety profile in that case?


yes that is correct
the Baxter vaccine uses no adjuvant.  It is a inactivated whole virus vaccine grown in cell culture.  Whole virus vaccines tend to be more immunogenic, and as often happens, they also tend to cause more reactions.  Older flu vaccines used to be whole virus, but they were discontinued in the (I think) 70s because of the reactogenicity.  

The other thing is this vaccine is grown in Vero cells, a mammalian cell line.  Although this cell line is considered safer than other mammalian cell lines in terms of tumorigenicity (ie the potential for inducing tumors), mammalian cell lines in general are prone to contamination.  One famous episode of vaccine contamination was the contamination of the polio vaccine by SV40, a monkey virus that is potentially carcinogenic.  There's more about this contamination from wikipedia http://en.wikipedia.org/wiki/P...

At the moment, I don't have an opinion about the safety of this vaccine, other than concerns about contamination (and Baxter does not have a good track record, as we know) and the small number of subjects (about 800, see above) in clinical trials used to support the mock-up dossier application.  I'll be reading more about this and will post if I find more information.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
but whether or not an adjuvant is used
the dose ranging issue remains, particularly since this is a new vaccine, ie we don't have any clinical experience with it, as we would have with the inactivated subunit vaccines.  That said, I would speculate that the dose issue may be less of a problem than in an adjuvanted vaccine.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
Thanks
I didn't know about "tumorigenicity". Goodness, as if there wasn't enough to worry about! I guess I'll hit google with that next.

welcome to my world LOL
that's how I"ve been learning.  One thing leading to another!  Enjoy!



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
here are a couple of documents for the UK
Swine flu vaccine development presentation at HPA board meeting, June 24, 2009

H1N1 Swine Flu Vaccine, from the Parliamentary Office, May, 2009

Pandemic influenza and swine flu, briefing document provided to MPs, June 25, 2009.

Here's what I gather.  The UK had 'sleeping contracts' signed previously, with Baxter (72 million doses) and GSK (60 million).  These contracts were supposed to kick in when WHO announced Phase 6.  On May 15, the UK government placed orders for 90 million doses (combined, no breakdown by company).  When the WHO announced the phase change, on June 11, these orders were superceded by the sleeping contracts, which means the UK government has, in effect, placed orders for 132 million doses of vaccines.

The delivery of these vaccines will depend on "the number of other countries which have also activated contracts and the relative scale of those contracts".




All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


something that I don't understand
this is from the presentation made at the HPA Board Meeting on June 24, which was 2 weeks after the WHO had already announced a change to Phase 6.  

3.16 On the basis of these encouraging results, the UK government entered some time ago into 'sleeping contract' agreements with both Baxter and GSK to procure influenza vaccine for the entire UK population (2 doses) in the event of a pandemic. These contracts are somewhat complex in that they can only be activated after WHO has
declared pandemic alert level 6, and that the rate of vaccine delivery to any one country will depend on the number of other countries which have also activated contracts and the relative scale of those contracts.

3.17 Given the uncertainty about whether or not WHO would declare pandemic alert level 6,the UK elected more than three weeks ago to place a contract with GSK and Baxter for 90 million doses of A(H1N1)v vaccine under what might be described as 'pre-pandemic' conditions. If WHO moves to Phase 6, activation of the sleeping contracts would supersede these arrangements.

3.18 The regulatory framework for licensing these vaccines is complex and is not yet completely clear. The EMEA has developed a fast track procedure for licensing pandemic vaccines under WHO Phase 6 conditions. This is based on manufacturers submitting in advance of a pandemic, a 'mock-up' dossier that describes in detail the pandemic vaccine that they would make, backed up by clinical experience and data with a version of the vaccine based on an existing strain. Several manufacturers (including GSK and Baxter) have had mock-up dossiers approved using data from their experience with H5 vaccine candidates.

3.19 If Phase 6 is not declared the licensing route for the swine influenza vaccines is much less clear. It would be impossible to deliver the kind of full information package that would normally have to accompany a new vaccine in the time available. This is well recognized by regulators and discussion is ongoing about possible solutions.

The presenter was, according to the document, Stephen Inglis of the National Institute for Biological Standards and Control (NIBSC).  I don't know who he is, but it sounds like he's a real senior scientist.  Did he not know that the WHO had already raised the Pandemic alert phase to 6, 2 weeks before his presentation?  

That seems rather unlikely.  It could be that this was a pre-prepared document, and they just uploaded it.  If that's the case, I find it very disturbing, the sloppiness of their work.  Like even with TWO WEEKS of notice, he or his office still couldn't be bothered to give an updated version of this document to be placed in the public domain??

And what exactly DID they talk about, at that June 24 meeting anyway, if this document is NOT an accurate account of the discussion??

It would be very disturbing if he REALLY did make those kinds of statements at that meeting, AND the document still ended up on the official website...



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
I was kinda hoping
the HPA document would give us some idea of how they would be approaching the vaccination issue.  But with the above snafu, I don't know how much of that document reflects real thinking within the UK government.  I most sincerely hope it does NOT!!

Which is worse, something that makes you mad?  Or finding yourself not even getting mad cos this kind of incompetence and bureaucratic sclerosis is entirely within expectations???

I don't know whether to rant or to sigh....  



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
Completely uninformed guess
Susan: I suspect that the bad state of the incumbent party and PM Brown drives them to be seen to be doing something. Add in the plausible assertions of regulatory cspture where industry to some extent influences gov't officials who are supposed to regulate/oversee/use pharmaceuticals and you get a rush to use vaccines on a flu that may or may not justify taking the chances they are apparently willing to run. The toughest choice will be with kids who are at risk if they go to school and face a lifetime of immune reaction if things go poorly. Informed consent is needed. Many will choose to take even a well disclosed risk. How high a percentage of vaccinated kids is needed to get herd immunity in schools?  

[ Parent ]
actually these are not either/or choices
The toughest choice will be with kids who are at risk if they go to school and face a lifetime of immune reaction if things go poorly

Right now the highest AR are in kids, but not the highest CFR.  In addition, the UK has a substantial stockpile of tamiflu.  As long as you can get the meds to those who need it, the VAST majority of people, kids included, who get infected will make a full recovery.

I respect that others may have different risk perception than myself, and I'm not persuading anyone about anything, but if you really want my honest opinion, I'd say, vaccines should be saved for HCWs and the MOST essential of critical infrastructure workers, pregnant women, and those with underlying health conditions etc.  After that, anyone else who want to get vaccinated.  

For kids, I think we should aim at reducing infection rates by partial or full school closure, as suggested by ACM, protecting the most medically vulnerable (and putting them in front of the queue for vaccines) while making sure the system of getting tamiflu to patients works.  

Again, even in 1918, 98% of those infected survived, and that was in the days BEFORE antivirals.

Not everyone needs, or will want, a vaccine.  The government should think through this rationally, rather than just going on autopilot.  Just cos the orders are placed, doesn't mean you have to vaccinate.

In addition, adjuvanted vaccines like the GSK one, is supplied in separate vials.  The adjuvant is only mixed with the antigen just before use.  So it's entirely feasible for the UK to go the US route, to vaccinate fewer people but with a safer vaccine.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
Well, this may all be moot
Fights over swine flu vaccine doses loom, could provoke battles among govts, broken contracts

http://www.cbc.ca/cp/health/09...

LONDON - An ugly scramble is brewing over the swine flu vaccine - and when it becomes available, Britain, the United States and other nations could find that the contracts they signed with pharmaceutical companies are easily broken.

Experts warn that during a global epidemic, which the world is in now, governments may be under tremendous pressure to protect their own citizens first before allowing companies to ship doses of vaccine out of the country.

That does not bode well for many countries, including the United States, which makes only 20 per cent of the flu vaccines it uses, or Britain, where all of its flu vaccines are produced abroad.

"This isn't rocket science," said Michael Osterholm, director of the Center for Infectious Diseases Research and Policy at the University of Minnesota. "If there is severe disease, countries will want to hang onto the vaccine for their own citizens."

Experts say politicians would not be able to withstand the pressure.

"The consequences of shipping vaccine to another country when your own people don't have it would be devastating," added David Fedson, a retired vaccine industry executive.

[snip]

Countries with flu vaccine plants might decide to seize all vaccines and ban their export, thus breaking the pharmaceutical contracts promising other countries vaccine supplies. These private contracts are not binding international law between two countries, according to Fidler.

He said most vaccine contracts include a clause allowing them to be broken under extraordinary circumstances, such as a health emergency. That would leave the countries who had brokered such deals not only without vaccine, but without legal recourse.

"There's nothing in international law that helps you resolve this, it's just a political nightmare happening in the midst of an epidemiological nightmare," Fidler said.  



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


Force Majeure vs National Power
The main point of the article is indisputable.  

But a quibble is in order.

Force Majeure clauses described at the end of the article are intended to excuse non-performance in the event of unanticipated events, typically characterized as beyond the control of the non-performing party (sometimes quaintly referred to as Acts of God.)

Saying that such a clause would operate in a contract specifically negotiated for a pandemic vaccine to excuse the mft's breach of the contract in the event of a pandemic is like saying your fire insurance is nullified in the event of a fire.  

Much more likely is that the country inside which the vaccine is made would excericise it's emergency police powers to just take the vaccine and distribute it however it sees fit.

The article accurately conveys the bottom line: contract performance under this type of scenario becomes a product of power (economic/political/military) not law.  

In which case the issues discussed in BB's recent diary may be of greater interest to the US Pandemic Planners and advisory boards.
http://www.newfluwiki2.com/sho...

ITW(Joel J)
Courage is resistance to fear, mastery of fear - not absence of fear.
- Mark Twain
 


[ Parent ]
Hmm, it could work both ways
The manufacturers supplying UK vaccines, GSK and Baxter, do not have plants in the UK.  However, Novartis and MedImmune do.  Right now they are suppliers for the US.  I wonder whether we'll see a chain reaction, if the UK can't get its vaccines from other countries, will it also stop all export of vaccines?  

According to this CBO report released late 2008, out of the different companies that the US has placed an order with, only Sanofi has US production facilities.  Only 26.4% of vaccines that the US is expecting, is made by Sanofi.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
The 1% thing
That document says that adverse events with the mock-up vaccine would likely be detectable when they occur with 1% of test subjects.  Now, remember that the mock-up has to undergo a 6 month safety follow as part of its clinical trials.  In addition to this, the vaccine manufacturer has to submit a post-marketing pharmacovigilance plan.  The 1% guideline you're referring to is a rough estimate regarding the ability to detect adverse events in the mock-up vaccine and has nothing to do with the actual detecting of adverse events once the pandemic vaccine is being distributed.

Hopefully, the postmarketing vigilance plan would be able to detect adverse events at a rate lower than 1%.


Umm, there's a saying here on this forum
Hopefully, the postmarketing vigilance plan would be able to detect adverse events at a rate lower than 1%.

coined by others, not me, ;-D that "hope is not a plan".  

And, it makes my case, that the public, and their kids, would be the guinea pigs  



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
Why based on H5N1?
"would a vaccine now made for H1N1 be considered 'similar other than in strain content' from the H5 vaccines used to support the mock-up dossier approval?"

Why do you say that the answer to this is yes?  There's nothing I can find in the EMEA guidelines that indicates that the mock-up vaccine for an H1N1 pandemic would be an H5N1 strain.

"Bear in mind that this protocol was developed with H5N1 in mind.  All 3 vaccines were approved based on the H5N1 virus"

You need to back up.
Which protocol?  The pharmacovigilance guidelines?  The pandemic mock-up dossier guideline?  I'm not sure what you're talking about.

Which 3 vaccines?

I'm still not sure why you think that the mock-ups vaccines will be H5N1 vaccines.  I really think you need to make your reasoning for this more explicit, because I don't see anything in the EMEA's guidelines that suggest such a thing.

Two suggestions for improving the process to the EMEA:

1)  Require that the mock-up virus be as close as possible to the pandemic virus.

2)  Make the requirements for the pharmacovigilance plan that has to be submitted as intensive as possible.


you're not sure what I'm talking about?
OK, it's very easy.  Take a look at the CHMP ASSESSMENT REPORT FOR Pandemrix.  What does it say right there on the front page?  
Common Name:
Pandemic influenza vaccine (H5N1) (split virion, inactivated, adjuvanted) A/VietNam/1194/2004 NIBRG-14

Submission of the dossier
The applicant GlaxoSmithKline Biologicals S.A. submitted on 2 February 2007 an application for Marketing Authorisation to the European Medicines Agency (EMEA) for Pandemrix, through the centralised procedure falling within the Article 3(1) and point 1 of Annex of Regulation (EC) No
726/2004 .

The legal basis for this application refers to:

A - Centralised / Article 8(3) / New active substance.
Article 8.3 of Directive 2001/83/EC, as amended - complete and independent application

The application submitted is a complete dossier: composed of administrative information, complete quality data, non-clinical and clinical data based on applicants' own tests and studies and/or bibliographic literature substituting/supporting certain test(s) or study(ies)

The applicant applied for the following indication: Prophylaxis of influenza in an officially declared pandemic situation.

So, correct me if I'm wrong, does this not say that GSK submitted data based on H5N1?  IF this data is now going to be used to support recommendation for licensure of the vaccine for novel H1N1 virus without further clinical trials, would it not be correct to say that data generated from trials based on the H5 virus, is now being used to support the use of a vaccine against H1N1?

That's the basic question.  I'm sorry you find it so confusing.  I'm sure you didn't mean to make your comments similarly confusing to readers as well.  



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
experts warn against fast tracking vaccine
http://news.bbc.co.uk/2/hi/uk_...

Professor Hugh Pennington, of Aberdeen University, warned against fast-tracking a vaccine, before all the data has been properly analysed.

[snip]

He said, "Once the initial tests have been done I think there is a possibility - laid out in the pandemic plan - that we could use emergency procedures just to rush it through before all the test results have been analysed and completed.

"I'd be concerned about that because the pandemic plan was looking really at a virus that was much higher mortality than the one we're seeing now, the one we're seeing now is basically no different in that respect from seasonal flu."

Vaccine for swine flu may be unsafe warns WHO

More than 132million doses have been ordered with the first batch due to arrive next month.

However, Dr Keiji Fukuda, the WHO's flu chief, today warned about the potential dangers of the untested vaccine: "There are certain areas where you simply do not try to make any economies. One of the things which cannot be compromised is the safety of vaccines."

The European Medicines Agency, the drug regulatory body for the EU, is accelerating the approval process for the vaccine, allowing firms to bypass large-scale human trials and instead test a vaccine based on bird flu.

Countries including Britain, Greece, France and Sweden plan to start using it as soon as it is cleared.

The Department of Health said it was "extremely irresponsible" to suggest Britain would use an unsafe vaccine. A spokesman said: "Over 40,000 doses of the vaccine which the swine flu vaccines are based on have been given without any safety concerns."





All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


Let's see, which do you think is more "extremely irresponsible"?
Suggesting that Britain might use an unsafe vaccine and warning against it?  

Or actually using an unsafe vaccine?



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
no different than seasonal flu?
Re:"...the one (flu virus-H1N1) we're seeing now is basically no different in that respect from seasonal flu..."

I thought it was considered a 1957-ish impact-type panflu-didn't WHO say that some time back?

It is better to look ahead and prepare than to look back and regret.


[ Parent ]
the issue is order of magnitude
comparing the current H1N1 to H5N1.  Whatever we think the CFR for H1N1 is, it still is 2 logs lower than that of H5.  That is the point.  I think.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
Magnitude..
Understand the difference between H5N1 and H1N1, but it appeared he was saying that seasonal flu=H1N1 impact.

Just thought it had been anticipated to be a 1957'ish model.

It is better to look ahead and prepare than to look back and regret.


[ Parent ]
for me the key point he was making
was that we need to be cautious, and not use the 'big guns' that we initially planned to use for H5N1, in this H1N1 pandemic.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
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