Complex technology, large-scale programs run on tight deadlines, making products with almost no margin for error. Result: big potential for delays. As usual, coach-potatoes across the United States complain, and the blame game has already started. It’s America’s favorite pastime (much more fun than fixing our problems).
Other posts about the swine flue epidemic:
(1) What about all the hype, the extreme warnings, about swine flu?, 3 September 2009
(2) Update: about the swine flu epidemic, 9 October 2009
(3) Is the Swine Flu pandemic being used to an excuse to expand government powers (UK edition)?, 14 October 2009
(5) More about the swine flu pandemic: about Cassandras, 26 November 2009
Here are a few examples of this madness, most by people who think vaccines are as easily made as Dixie Cups.
- “Delay Undercuts H1N1 Vaccine Campaign“, Wall Street Journal, 19 October 2009 — About vaccine program delays caused by articles like this one, fanning baseless fears about vaccine safety.
- “The government has failed dramatically in its effort to make the swine flu vaccine widely available”, Paul, Powerline, 26 October 2009 — Paul show little knowledge about vaccines, but knows it’s the government’s fault.
- “The Swine Flu Vaccine Screw-up“, Barbara Ehrenreich, TomDispatch, 3 November 2009 — It’s Big Pharm’a fault!
- And then there are all the outright alarmist articles about thimerosal.
There have been a some in the news media working to sort out the various factors. Such as these two article in the Wall Street Journal. First, this one on 26 October 2009:
Manufacturing problems such as low yields from an initial H1N1 “seed” virus have hobbled plans for an initial delivery of a large number of doses. The seed virus didn’t grow well, which sometimes happens with flu viruses. Novartis AG, which has a contract to supply about 90 million doses to the U.S., said a U.S. request for a greater amount of its vaccine order in single-dose syringes also slowed the process.
Initially in late spring, government officials discussed ordering mostly multidose vials from Novartis, Andrin Oswald, head of the company’s vaccine business, said in an interview. Its primary concern at that point was to get a lot of vaccine quickly, he said. But in September, as more consumers started expressing concerns about thimerosal, a mercury-containing preservative used in multidose vials, the government requested more single-dose syringes, which contain only trace amounts of thimerosal. Officials wanted half of the October deliveries to be packaged in prefilled syringes, he said.
But the Department of Health and Human Services said it hadn’t issued a new order or modified its order to Novartis. “Over the past month HHS has been discussing with the manufacturer ways to make more vaccine available to the U.S. public sooner,” Bruce Gellin, director of the National Vaccine Program Office, said in an email. “These discussions have focused on reducing the number of pre-filled syringes supplied to HHS by Novartis. HHS has never issued or discussed a new delivery order or a modification to an existing delivery order that would increase the number of pre-filled syringes and delay supplies to the U.S. public.”
GlaxoSmithKline PLC, which has a contract to deliver 7.6 million doses, or about 3% of the total U.S. order, hasn’t received regulatory approval yet from the Food and Drug Administration for its vaccine. Glaxo filed its H1N1 vaccine application Sept. 4. The other four manufacturers received licenses for their vaccines in mid-September. Glaxo and the FDA are in discussions about the matter, and a Glaxo spokeswoman said Sunday that the FDA has given Glaxo no reason to believe that it has safety concerns about the vaccine, which is made in the same way as the company’s seasonal flu shots. The FDA declined to comment.
That’s the first level of complexity. To see deeper read “Why You Can’t Get the Swine Flu Vaccine“, Scott Gottlieb (a practicing physician, deputy commissioner of the FDA from 2005-2007), Wall Street Journal, 28 October 2009 — Excerpt (bold emphasis added):
The first fateful policy decision, made last spring, was to forgo vaccine additives — called adjuvants—that activate the immune system and make shots more potent. Adjuvants allow a smaller supply of vaccine stock to be stretched across more doses. These adjuvants are included in H1N1 vaccines world-wide, but not in the U.S.
Why do adjuvants matter? An adjuvanted H1N1 vaccine being used in Europe contains 3.75 micrograms of vaccine stock. The same vaccine in the U.S., without the adjuvant, requires 15 micrograms of vaccine for equal potency. If we used adjuvants, we could have had four times the number of shots with the same raw material.
The second cautious decision was to require that the H1N1 vaccine be a single shot. The government demanded single-dose syringes because they contain smaller amounts of thimerosal than multi-dose vials. This mercury-containing vaccine preservative continues to stir concern it can trigger childhood autism, even though this has been firmly disproven.
The third policy decision was to stick for too long with a proven, but slow process for making flu shots that uses chicken eggs to grow the raw vaccine material. Shots can be made much faster using mammalian cells to grow vaccine, and this process is already being used in Europe. The cell-based vaccines are unlikely to be approved in the U.S. Our precaution when it comes to vaccines means we don’t easily embrace novel technologies, even if the Europeans would part with some of their limited supply.
For more information
For a good summary, I recommend “Blowing the Shot – What we can learn from the shortage of H1N1 vaccine“, Marc Siegel, Slate, 2 November 2009 — A sensible look at the problems making a new vaccine.
Here is a wonderful graphics from the Information is Beautiful website, showing the relative seriousness of swine flu compared to other illnesses — and the power of hand washing to prevent its spread.
Background information:
- “Egg Beaters – Flu vaccine makers look beyond the chicken egg“, Scientific American, 23 February 2004
- “Vaccine Production Is Horribly Outdated. Here Are 3 Ways to Fix It“, Discover, 27 July 2009
Articles about the Swine Flu on the FM website:
- What about all the hype, the extreme warnings, about swine flu?, 3 September 2009
- Update: about the swine flu epidemic, 9 October 2009
- Is the Swine Flu pandemic being used to an excuse to expand government powers – UK edition?, 15 October 2009
Afterword
Please share your comments by posting below. Per the FM site’s Comment Policy, please make them brief (250 word max), civil and relevant to this post. Or email me at fabmaximus at hotmail dot com (note the spam-protected spelling).
FM: “Complex technology, large-scale programs run on tight deadlines, making products with almost no margin for error. Result: big potential for delays.”
This describes, more generally, the vulnerability inherent in the JIT distribution system. Much of the power of John Robb’s critique comes from the current economy’s being so JIT configured.
But we need not necessarily adopt John’s ideas to see that, rather than spending hundreds of billions in Iraq and Afghanistan, we would better secure ourselves by spending the money to make our distribution system more supple, redundant, and decentralized.
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Fabius Maximus replies: I agree with your last paragraph. Note however than many things — like flu vaccines — inherently operate on a just-in-time basis.
Regarding the theory that our nation is less resilient than in past, due fragile systems and JIT logistics — IMO it’s not correct. While our key infrastructure systems have much room for improvement, they are in general far more resilient than in the past. It’s largely a function of increased wealth, as redundency and resiliency tend to be expensive.
We are an urban society, inherently more vulnerable than an rural one. And our population is far above the natural carrying capacity of the land, making us vulnerable to systems collapse. Offsetting this is the extreme power and robust nature of our systems. Failure becomes less likely, but more dangerous. To use a bad analogy, now we’re a 747 — in 1850 we were a hot air balloon.
>Complex technology, large-scale programs run on tight deadlines, making products with almost no margin for error.
Then outsource it to Germany or Japan.
If it’s moderate technology, need lots of funding, can run bit late, making products where 80% is good enough then use used to do it in the US – now you send it to China.
““Over the past month HHS has been discussing with the manufacturer ways to make more vaccine available to the U.S. public sooner,” Bruce Gellin, director of the National Vaccine Program Office, said in an email. “These discussions have focused on reducing the number of pre-filled syringes supplied to HHS by Novartis.”
This is a dead giveaway. Reducing the number of pre-filled syringes versus vials is not something you need to discuss over the past month. You just change the order or the ratio of vials to syringes. Takes about 10 minutes. It’s a manufacturing issue not a “discussion” issue that takes more than a month to resolve and come up with a solution. If HHS really wanted more vials available then we would have more vials versus syringes.
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Fabius Maximus replies: Please re-read more carefully. The vaccines are different; it’s not a matter of just packaging. The single-dose has less thimerosal, which is why they wanted the switch.
Marie Curie and the pitchblende . The sailors watching the Bimini tests . The first polio vaccines . Depleted uranium . And who in 1940 , would have thought asbestos or cigarettes could be so harmful ?
Proceed with caution . You want a botched job thrown together ?
There’s probably a lingering institutional memory of the last time a mass vaccination of the Swine Flu was attempted. Given that the debacle that was the 1976 vaccination debacle is now being used as a cudgel against the current swine flu vaccine program it’s probably correct to take a go slow and test approach.
As for the delay switching to single use injectors and not relying on adjutants. Thank Andrew Wakefield and the rest of the anti-vax crew for that part of it. It is very very hard for me to maintain an appropriate tone when discussing them, so I won’t go further into it.
As a former R&D scientist in big pharma, albeit one absent from the field for almost a decade now, I can attest to the drag the FDA imposes on the R&D and scale-up processes. The FDA has unlimited powers to inspect a given pharmaceutical company, without notice, and cite a firm over QC or other violations, without telling the alleged violator how to come into compliance or setting conditions for passing review. One firm here near Chicago, a very-well regarded Fortune 500 firm, was fined over 100 million dollars by the FDA under just the circumstances above. Open-ended or ill-defined regulations, and heavy-handed inspectors do impose delays on producing vaccines, drugs, medical devices and much else that safeguards our health. Bringing a single new drug to market often costs in excess of a billion dollars, and that was some years ago. I don’t know what it costs now, but I doubt it has dropped in price.
This is not the first time that the government has failed to produce, or kept others from producing, the desired number of vaccines, antitoxins, etc. for a healthcare crisis. As documented by Miller et al. in their book ‘Germs: Biological Weapons and America’s Secret War,” in the long run-up to the 1991 invasion of Iraq, the government failed to secure the necessary doses of anthrax and botulinum vaccines and antitoxins against the bio-chem weapons it was feared that Saddam Huseein would use against US/colation forces. It was found, for example, that the government had licensed only one lab in the entire USA to make vaccine against the two diseases – the Michigan Dept. of Public Health; Ft. Dettrick – the army’s specialist center for medical research, could not get up to speed in time. Upon calling all of the major pharmaceutical companies to ask for help, the Pentagon and DOD were told by them that a quick scale-up would not be possible under FDA regulations, which the government would not waive. Moreover, the army would not indemnify the companies from lawsuits.
The example I have given is not a perfect analogy to the current flu snafu, but there are parallels. The regulatory and legal regimen in place is cumbersome, and ineffiencies in the system are the cost we pay for safety. Safety, effectiveness and speed of manufacture are in constant conflict; you can get all three but only at a very high price, and of course no one wants to spent the money until there is a crisis, and by then it is already past time to take action.
Perfectly safe pharmaceutical products, whether they are drugs, antitoxins or vaccines, do not exist. All products carry some risk for a small number of aypical responders, those allergic to them, those do not follow dosing instructions, or the like. Additional increments toward perfect safety on the cost-benefit curve, eventually buy less and less safety and effectiveness, for ever greater cost, and delay potentially lifesaving agents from getting to the people who need them. Moreover, the FDA rarely allows patients to waive safety guidelines if they are desperate to try a new cancer therapy or something similar.
Biologicals are complex, often very difficult and technique-sensitive to produce, costly and cannot simply be stamped out like widgets on an assembly line. Lead times are long for product development and scale-up, and it cannot be done quickly with the FDA looking over your shoulder at every turn. There are times when every step has to be followed, and improvisation does not work; this is one of those times. You need surge capacity, you have to build it into your system – before there is a crisis.
As someone who works for a company producing vaccines for clinical use, I can second everything Pete said. The degree of regulation (and vagueness of such regulation) is difficult to conceive for someone on the outside. Rigorous validation of methods, validation of the methods used to validate those methods, testing at every level (many of those cell-based tests taking several weeks just to execute), testing of the components used to manufacture, testing of the components used for testing. Monitoring of facilities, environment, utilities, personnel, etc. Studies on scale-up, mock fills, qualifications. Add the attendant storm of documentation with approvals and counter-approvals for every step, and at our scale it’s probably 99% “overhead.” That’s the price we pay for safety, and like Pete said, the cost/benefit curve for further increasing levels of safety is exponential.
Frankly I’m astounded that seasonal flu vaccine can be made at all in the window of time allotted.
And yes, the amount of work (and time) involved in simultaneously changing the formulation, the dose size and the container of a filled drug product would make one’s head spin. The idea that it would be a “10 minute discussion,” is an understandable misconception, but is beyond risible in this industry.
You are now saying Swine Flu is a major crisis ? Wow , I dont know how we survived 1976 – on hot lemon drink .