Wednesday, March 16, 2005

Tamiflu: Dylan's retort, part II

Here is the second part of reader "Dylan's" comments on the Tamiflu post (part I, here). For readability I am not "block-quoting" reducing font size as I usually do for quotes. Instead his remarks are in plain font and full width, mine will be in block quotes and reduced font. Dylan's intention is to provoke discussion. In that spirit I have engaged him in a dialog. Whatever you think of his arguments, which are substantive, he has done us a service. He has my thanks.

Dylan continues:

Now for Tamiflu. I'd like to keep this short, but that's not possible. I have not read the research paper written by Ms. Ward and her associates of Roche, but even so I will state my objections to their findings which clearly strongly support the case for Tamiflu. Since Roche makes the drug, this should surprise no one.

Number one: Research conducted by "in-house" researchers is always suspect. That doesn't mean that the research in this case is in any way "tainted, or "fraudulent;" it simply means that all research is directed towards a particular end, and that end may exclude possible avenues that are not entirely consistent with the desired outcome of the research in question. Tobacco companies, for instance, conducted research for years that found no connection between cigarette smoking and lung cancer. Drug companies (all of them, I suspect) pushing antidepressants conducted many studies that failed to find a relationship between antidepressants and adolescent suicide rates (they finally got caught flat-out lying on this one). Ever hear of Agent Orange? I could go on with this line of reasoning, but I think this will suffice.
I think some comment is needed here. Clearly I agree with the thrust of your remarks regarding conflict of interest to the piont where I felt it necessary to call attention to it in my post because of the ethically challenged history of the drug companies. However there are two points I want to make. The first is that the drug companies are often the only source of information about these drugs, at least initially. That information has to be judiciously evaluated but we shouldn't throw it out because of the source. It is a lot like going to a new car dealer and getting information about the different models from the salesperson. They know about the cars and it is normal to ask them questions. It is also normal (and prudent) to think critically about what they say, compare it to other sources of information and try to "triangulate" to get a fix on the most accurate data. Data that is uncomfortable for the company is not usually falsified but rather suppressed or spun in a way that requires an informed reader to "read between the lines." I tried to do that with their paper, to the extent I was able. But as I said, caveats are in order.

The second point is perhaps more important. Conflicts of interest are not the only sources of incorrectly presented or perceived data. We all have a tendency to latch on to things that accord with our prior beliefs and to discount things that don't. This can easily lead us astray. There is also a reflex tendency to defend our own prior judgments or statements, as I did when reader Gaudia objected to my casual characterization of Roche's Tamiflu storage indications as "room temperature." Nothing much rested on this matter and I could easily have let it go. I didn't, instead dredging up a statement from The National Library of Medicine's Medline Plus database to show they also characterized Tamiflu storage as "room temperature." My point here is it isn't only economic incentives that can modify our perceptions, how we express things and how we react to others. The avian flu issue calls forth strong emotions for many reasons. In my case it relates less to my personal safety than what it says about the state of the profession in which I have spent my life. Others will have different reasons, but the emotions will be there need to be taken into account. Sermon over.
Number two: Research that is not thoroughly comprehensive -- especially when it could have been -- is necessarily inconclusive, premature, and completely suspect, at best.
I must respectfully disagree. No research is "thoroughly comprehensive," whatever that might mean. All research is in some sense inconclusive and premature. This does not imply it is "completely suspect." I'll take this as a momentary lapse into hyperbole on your part. It isn't needed for your argument.
Isolates of H5N1 that produce pantropic, and neurotropic infections that are atypical -- when compared with the symptoms produced by pneumotropic isolates that would been used in this research -- could not have been part of the research conducted in this study because knowledge of their existence was not available before this research was published. I'm sticking my neck way out here, but I'm almost certain that this is the case because the publication date of the research matches almost precisely the date that the existence of these particular isolates was first made public. Now, I don't want to be too harsh here, but if I had a piece of research that was nearly complete and that strongly supported my position, I might find it very awkward to have to reevaluate things by introducing variables that are very likely to skew the findings in a manner that does not support my position. I would get that paper right out the door, before this ever became an issue. And no one could really fault me for it.
As you point out, at the time the manuscript was written and submitted there was likely no concrete knowledge of neurotropic forms of H5N1. The context here was the usual influenza pandemic disease, which is devastating enough. But even if there were some suspicion or even some evidence, in my view delaying publication until such time as it could be incorporated into this paper (and even now there is not enough information to allow publication of that material) would have been very unfortunate and might even be considered irresponsible considering the wealth of information the authors already had. Whether they presented that information fully and fairly is another question which we will never know or know only at some future time. Withholding what they did know, however, would have opened them to justifiable criticism. Remember that H5N1 is not the only strain out there and we could easily have a pandemic with a pneumotropic strain. This was a review article to inform the scientific community. I believe it accomplished that.
In Vietnam right now there are strains of H5N1 that are pneumotropic but may segue into neurotropic expression as the disease progresses; and there are strains that express first in a neurotropic, or pantropic pattern (sometimes with complete absence of any upper respiratory involvement, where neurotropic strains are concerned). I have seen nothing anywhere that suggests that Tamiflu can have any effect whatsoever on an H5N1 infection of a pantropic or neurotropic nature. Dedicated pneumotropic strains would fit well with research constructed to test the efficacy of Tamiflu, with regard to them alone. The hemaglutinin in a strain of this sort would be constrained to interaction with receptors in the epithelial cells of the upper respiratory tract only. In the lab at least, neuraminidase inhibitors could prove to be very effective against a strain of this sort. I have reservations where Tamiflu's efficacy in the field is concerned, though. The record is not entirely clear, but it is in no way conclusively supportive of Tamiflu.
In my view this is unwarrantedly pessimistic. There are good reasons to think oseltamivir will work against any influenza virus that requires neuraminidase to release the budding virus from its receptor, i.e., all of them that we know of so far, including those with tropisms other than the lung. Moreover data shows that viral shedding is substantially reduced, which one might expect, given the mechanism. In short, I do not see the rationale for saying Tamiflu won't work on neurotropic or pantropic strains.This may or may not turn out to be true, but the same can be said for virtually any therapeutic modality. Indications so far suggest it will work with H5N1 strains. That's all we know at present. But if it isn't effective in some strains, the authors of this study can hardly be blamed for that.
Dylan continues the line of argument that Tamiflu might be of doubtful efficacy in an H5N1 pandemic. That will be in the next, and concluding, post.