Bird Flu Preparedness: Medicine

by hilzoy

This is (hopefully) the first in a series of posts on our government's response to the threat of pandemic avian influenza. It focusses on what medications can be used to deal with bird flu, what we have done to stockpile these medications, and whether, as a result, we can expect them to be widely available. (Short answer: no.)

There are two main ways to deal with avian influenza: vaccines, which protect us from getting it, and antivirals, which can either be given prophylactically, to protect people who are not yet infected, or to treat avian influenza once someone has it. I'll deal with them separately.

Vaccines: To its great credit, the US has commissioned two companies to begin work on a vaccine against the H5N1 strain of avian flu -- the strain that has people worried. One of these companies -- Sanofi Pasteur -- has tested its vaccine, with positive results. (Revere of Effect Measure has some concerns about these results here.) However, there are some very serious problems with the idea that we will be able to rely on vaccines to any significant extent in an avian flu pandemic. These problems are: first, it's not clear that we have the right vaccine; second, it will take months to produce it; and third, we don't have nearly enough capacity to produce enough vaccine for everyone in any case. Taking these in turn:

First: the strain used to create these vaccines is from 2004. The virus has been evolving since then, and will continue to evolve. For this reason, it's not clear that the vaccine we are now testing will work against any strain of avian flu that actually shows up here. (See here for more.) If we don't have the right strain, we will need to develop a new vaccine from scratch, and that will take time -- at least six months.

Second: the actual process of growing vaccines is long and cumbersome. The LA Times cites the Department of Health and Human Services as saying that it would take six to eight months to produce vaccine -- six to eight months during which the pandemic would be raging.

Third, the world doesn't have anything like enough vaccine manufacturing capacity to meet the need. According to the Economist:

"[The world's] entire capacity for flu-vaccine production is only 300m shots a year (each containing 15 micrograms of the active ingredient known as antigen). Yet in the case of superflu, several billion people would need vaccination—and they may need two shots at higher doses."

And about those higher doses: as the Economist noted, normal flu vaccines deliver 15 micrograms of antigen. According to the study that showed results from a vaccine against H5N1, it takes two shots with 90 micrograms each to produce (what we hope is) an immune response capable of conferring protection against the virus. Since that's twelve times the normal amount of antigen per person, and since producing antigen is what limits our capacity to produce vaccines, our global flu vaccine capacity, if devoted entirely to producing avian flu vaccine, would be able to produce only enough vaccine for 25 million people. In the world.

As far as the US is concerned, Nature reports: "If the entire US vaccine production system, which can produce 180 million seasonal flu vaccines, was devoted entirely to making pandemic vaccine at this concentration, it could make enough for 15 million people: barely 5% of the US population."

And that's assuming that any vaccine produced in the US is used in the US. Most people I've read assume that this is true: that if a pandemic strikes, countries with the capacity to produce vaccines will use those vaccines for their own populations. Quoting the Economist again:

"Most of the world's flu vaccine is produced in nine countries: Australia, Britain, Canada, France, Germany, Italy, Japan, the Netherlands and the United States. Europe produces 70% of the vaccines. And Europe's vaccine producers are worried. Without international agreements now, they say there is a high risk of inadequate, inequitable and delayed supplies of vaccines. Among public-health officials and vaccine manufacturers, there is a widespread assumption that, during an outbreak, countries with production facilities would declare a national emergency and limit or ban the export of vaccine to other countries. That might be good for people living in the nine countries on the list, but it would leave the rest of the world without any vaccine at all."

Bottom line: it's wonderful that we're working on a vaccine. Efforts to ramp up our vaccine production capacity, and to develop quicker ways of manufacturing vaccines, will have lots of benefits down the road. But don't count on vaccines to protect you if an avian flu pandemic hits.

Antiviral drugs: There seem to be two antiviral drugs to which H5N1 is not resistant: Tamiflu and Relenza. To quote the Fluwiki, "Most attention has been given to Tamiflu because it is a tablet, which is easy to administer consistently. Relenza, on the other hand, is more difficult to administer because proper use of a dry-powder inhaler requires some skill. It can also provoke an asthmatic attack." (Yuck.) They can be given either to protect someone who is infected, or to treat someone who has been infected; in this case, however, they must be given within 48 hours of infection, and the earlier the better. Neither cures avian flu; they just ameliorate its effects, making the actual illness weaker and shorter.

The good news is that the government has decided to stockpile Tamiflu. The bad news is that it only made this decision very recently. From the NYT:

"As concern about a flu pandemic sweeps official Washington, Congress and the Bush administration are considering spending billions to buy the influenza drug Tamiflu. But after months of delay, the United States will now have to wait in line to get the pills.

Had the administration placed a large order just a few months ago, Roche, Tamiflu's maker, could have delivered much of the supply by next year, according to sources close to the negotiations in both government and industry. As the months passed, however, other countries placed orders that largely exhausted Roche's production capacity this year and next.

Democrats on Capitol Hill are complaining that the delay has put Americans in jeopardy. "The administration has just drug its feet through this whole process," said Senator Tom Harkin, Democrat of Iowa, who has pressed for legislation to buy more courses of Tamiflu. A course includes enough pills for a full treatment. Senator Barack Obama, Democrat of Illinois, said in an interview that Michael O. Leavitt, the secretary of health and human services, told senators in a closed-door briefing last week that the administration would soon place an order to raise the government's Tamiflu stockpile to 81 million courses - up from 12 million to 13 million courses expected by the end of 2006. Mr. Obama has long been urging the government to buy more Tamiflu.

"Secretary Leavitt admitted that they are currently in negotiations with Roche to try to rapidly build up those stockpiles," Mr. Obama said. "But we're behind countries like Great Britain, France and Japan, and it's probably going to cost us a lot more money than it would have to catch up." (...)

Dr. Irwin Redlener, director of the National Center for Disaster Preparedness at Columbia University, is among those who have been insisting for months that the government buy more Tamiflu. But he said the Bush administration largely ignored his and others' warnings. "And now that they're finally worked up about it, the store is closed," Dr. Redlener said, referring to Roche's supply problems. "The U.S. is now in line behind much of the rest of the world."

Terence Hurley, a Roche spokesman, said that 40 countries had ordered Tamiflu to fill medical stockpiles in case of a pandemic. Many countries in Europe - including France, Britain, Finland, Norway and Switzerland - have ordered enough to treat 20 percent to 40 percent of their populations. The American stockpile would treat less than 2 percent of the population. (...)

The government and industry officials, however, said that Roche had committed to delivering seven million courses to the United States next year and would not be able to deliver substantially more until 2007."

Bottom line: if an avian flu pandemic strikes in the next two years, I wouldn't count on the US having enough Tamiflu to protect more than a small proportion of the population.

***

As I said, I think we deserve credit for our work on vaccines. But our failure to move more quickly on Tamiflu is inexplicable. H5N1 has been getting more and more ominous for about two years now. During those two years, public health people have been saying that we do not have the resources to protect people, and urging the government to stockpile antivirals. The fact that we are only now doing so is something we should be ashamed of. If a pandemic strikes, it will cost people their lives.

The FluWiki's page on Medical therapy has a good discussion of this topic, including how to treat symptoms, and secondary infections. It's very much worth a look.

Comments

[dutchmarbel]

The 20-40% is not just to protect specific groups, but also to be able to create buffer zones around places where it hits, to contain the virus.

The Tamiflu alikes might not help thant much btw. So not having enough might be less bad than you think.

[hilzoy]

dutchmarbel: yes, I saw that. But it turned out to be a mistake:

"It appears a misunderstanding, not a mutation, is behind recent reports suggesting the H5N1 avian flu strain is developing resistance to the drug Tamiflu.

The professor of pharmacology from Hong Kong University quoted as warning of an emerging resistant strain of the virus says he was citing old data, not new evidence, when he gave an interview last week. (...)

When the reports quoting Chui started to circulate, flu experts around the world sent out urgent e-mails trying to find out who had found new evidence of resistance. The flu community keeps close tabs on the efficacy of these important drugs, known as neuraminidase inhibitors.

They came up with a puzzling blank.

Except for that one partially resistant H5N1 isolate from Vietnam, no researchers have reported new discoveries of Tamiflu-resistant viruses isolated from human cases of H5N1, both the WHO and Tamiflu's manufacturer, Hoffman-La Roche confirm.

"There is a network of laboratories that has been set up to follow antiviral resistance among influenza strains," says Michael Perdue, a scientist in the WHO's global influenza program.

"One of the first things they look at (when they get new viral isolates) is the antiviral sensitivity and resistance. And the papers that have been published thus far have shown all the strains to be sensitive."

That doesn't mean there might not be evidence of resistance out there, being kept under wraps by researchers pushing them through the publication pipeline of medical journals.

Still, Perdue thinks word might have gotten around.

"There's no hard and fast rule. But generally people let WHO know information like that. And we have not heard.""

[dutchmarbel]

Ah, I see. Not a bad thing that we ordered a few million than ;)

[hilzoy]

No. You are lucky enough to live in a well-governed country.

[hilzoy]

And if only my great-grandfather had not had to leave the Netherlands, one step ahead of the law, after defrauding widows and orphans and losing both their shirts and his, I might live there too...

You all were probably lucky he left, though.

[dutchmarbel]

Sounds like the proper Dutch attitude in that time ;)

I think that all countries with national healthcare and worker protection have an advantege with the flu:It is easier to stay home when you are ill and go to the doctor to get a diagnose and/or medication.

We are small though, so easier overwhelmed. Also, the Netherlands *is* a travel hub so lots of people are travelling through the country which makes isolation harder.

Pre-Katrina I would have said that the US has the advantage that the rest of the country can compensate if there is an outbreak in a specific area. Now, I'm not so sure.

BTW: you recommend that people get a flu shot as a precaution. Are *those* available enough now?

[Tim]

Actually, every nation in the world with the ability should be turning out oseltamivir in mass quantities. They should be paying Roche to release their data so that everyone could set up facilties. Buying the stuff from one vendor just isn't going to cut it.

[Jackmormon]

Tim's point seems important to me. If a pandemic should take hold, would governments really sit around, respecting intellectual property rights and previous contracts?

And even as I think that they shouldn't, my dialectal self wonders why, if private companies are even almost able to meet the demand, their property rights shouldn't be protected. It is surely in the interest of the state to buy out medical patents that are or might be vitally important to the national interest, but, oy, that might get expensive.

I'd be interested to hear a more traditionally conservative side of this argument. The historiography of epidemics has almost always favored the centralized government argument, but since I exist in this world today, and the avian flu crisis remains only a possibility, I'm still open to the property-rights argument, if it can be done well.

(As someone who's spent months in the stacks reading up on cholera, however, my inclination is towards seizing the IP in the name of national security, and, should the worst present itself, seizing whatever facilities are convenient for producing anti-viral medication or vaccines. Politically unpalatable, I know, but pandemics are, well, scary.)

[jwo]

I find myself often wondering how in the world we ended up with such an incompetent administration at such a critical time in our country's history!!!!

[liberal japonicus]

I think it is important to imagine how a pandemic would play out to get a better purchase on the question of IP. If the pandemic occurs, the disruption to the world economy would occur regardless of the manufacture of vaccines. One could make an argument that a quick resolution would be less painful, but the businesses that would be hurt would still be in very bad shape. Thus, you wouldn't have a push by them to seize IP. You would have a lot of pushback by the drug companies (I am now thinking of the thread that had discussion socialized medicine and the advancement of medical research). In addition, if the rate of death (probably less than the Spanish flu's rate of 1-4% because secondary complications will be taken care of?) would not, I sadly believe, generate the necessary political will to take steps, especially since those who die would again more likely be the poor and uninsured (I do note that the Hong Kong bird flu seems to have a 30% mortality rate, which may be enough to generate political will) There will be no property seizure until the pandemic is upon us, and at that point, the bell can't be unrung.

[hilzoy]

Probably von can speak more informatively to this, but I think that there is now an exemption to pharmaceutical patents in the case of public health emergencies. It may be only for poor countries, though: in any case, the context in which I've heard of it has been HIV in sub-Saharan Africa (how to get AIDS cocktails to people in countries where the annual per capita spending on health care is $5? And thus where there is absolutely no chance whatsoever that they or their governments will be able to pay full price? Suppose one could make a cheap knockoff and somehow sell it only there: would that be OK? Etc.) I suspect the arguments would be less convincing if made by the US. And it's unclear to me why Roche couldn't just ramp up production, and whether, if it can't, there's any reason to think that someone else could.

Or, in brief: the problem here isn't the lack of a market, or the lack of someone with IP willing to manufacture the drug. Whatever it is, then, it's not clear that voiding a patent (or whatever) would solve it.

[Jackmormon]

It's just that I'm remembering how, during WWII, the Richard, CA shipyards were supposedly able to turn out an armorclad warship in a single week.

If at some point we really are in a pandemic, I would hope that the government could really mobilize nationally. I would hope that seizing IP wouldn't come too late, and I would hope that commandeering laboratories wouldn't come too late. I would also hope that such extreme measures would never be invoked except in the case of grave emergency--and I'm really glad I'm not in a position to make such calls.

The problem is, as I see it, that the best preventative measures presume a nationalization of health care that is currently unthinkable in the US, and that the best responsive measures available today involve militarily enforced quarantines. Somewhere between we must be able to seize IP and labs to mitigate harm to the nation, right?

To Hilzoy: I think that if one voided Roche's patent and commendered laboratories in the name of national security, one might be able to produce huge amounts of anti-virals or vaccine. This would require a real state of emergency, yes, and a real trust in the central authority.

Von? IP lawyer? Advice, here?

[dutchmarbel]

If the situation around anthrax is an indication it will not need that much to override patents in case of a threat.

[Sebastian Holsclaw]

I know it sounds crazy, but you could always pay for the drug.

[dutchmarbel]

It is not about payment Sebastian, it is about availability of the product. Production cannot keep up with demand.

[Tim]

It's not even Roche's drug. They license it from the guys who developed it. What is their IP is the production method. Considering that the Chinese are apparently already making a cheaper version it might even benefit Roche do go along with making their process public.

[liberal japonicus]

Of interest is this from the NYTimes

A major Indian drug company announced yesterday that it would start making a generic version of Tamiflu, the anti-influenza drug that is in critically short supply in the face of a possible epidemic of avian flu.

"Right or wrong, we're going to commercialize and make oseltamivir," said Dr. Yusuf K. Hamied, chairman of Cipla of Bombay, using the drug's generic name and acknowledging that he might face a fight in the Indian courts with Roche, the Swiss pharmaceutical giant that holds the patent.

Although generic manufacturers cannot legally sell the patented drug in the West, all national patent laws, including those of the United States, allow governments to cancel patents during emergencies and either buy generics or force patent holders to license their formulas to rivals.