NOT ONE RCT on Swine Flu or H1N1?! – Outrageous!

16 12 2009

Last week doctorblogs (Annabel Bentley) tweeted: “Outrageous- there isn’t ONE randomised trial on swine flu or #H1N1“

Annabel referred to an article at Trust the Evidence, the excellent blog of the Centre for Evidence-Based Medicine (CEBM) in Oxford, UK.

In the article “Is swine flu the most over-published and over-hyped disease ever?” Carl Heneghan first showed the results of a quick PubMed search using the terms ‘swine flu’ and ‘H1N1’: this yielded 4,475 articles on the subject, with approximately one third (1,437 articles) published in the last 7 months (search: November 27th). Of these 107, largely news articles, were published in the BMJ, followed by the Lancet and NEJM at 35 each.

Top News stories on H1N1 generated appr. 2000 to 4000 news articles each (in Google). Items included outbreak of a new form of ‘swine flu’ which prompted the United States and the World Health Organization to declare a public health emergency (April), Southern Hemisphere being mostly spared in the swine flu epidemic (May), Tamiflu, i.e. the effects of Tamiflu in children in the BMJ (co-authored by Carl) in August and the availability of the vaccine H1N1 vaccine clinics to offer seasonal flu shots in November.

According to Heneghan this must be the most over-hyped disease ever, and he wonders: “are there any other infections out there?”

Finally he ends with: “Do you know what the killer fact is in all of this? There isn’t one randomized trial out there on swine flu or H1N1 – outrageous.”

My first thoughts were: “is H1N1 really so over-published compared to other (infectious) diseases?”, “Is it really surprising that there are no RCTs yet? The H1N1-pandemics just started a few months ago!” and even “are RCT’s really the study designs we urgently need right now?”

Now the severity of the H1N1 flu seems less than feared, it is easy to be wise. Isn’t is logic that there are a lot of “exploratory studies” first: characterization of the virus, establishing the spread of H1N1 around the world, establishing mortality and morbidity, and patterns of vulnerability among the population? It is also understandable that a lot of news articles are published, in the BMJ or in online newspapers. We want to be informed. In the Netherlands we now have a small outbreak of Q-fever, partly because the official approach was slow and underestimated the public health implications of Q-fever. So the public was really underinformed. That is worse than being “overexposed”.

News often spreads like wildfire, that is no news. When I google “US Preventive Services Task Force” (who issued the controversial US breast cancer screening guidelines last month) 2,364 hits still pop up in Google News (over the last month). All papers and other news sources echo the news. 2,000 hits are easily reached.

4,475 PubMed articles on ‘swine flu’ and ‘H1N1’ isn’t really that much. When I quickly search PubMed for the rather “new” disease Q-fever I get 3,752 hits, a search for HPV (Alphapapillomavirus OR papilloma infections OR HPV OR human papilloma virus) gives 19,543 hits (1,330 over the last 9 months), and a quick search for (aids) AND “last 9 months”[edat] yields 4,073 hits!

The number of hits alone doesn’t mean much, certainly not if news, editorials and comments are included. But lets go to the second comment, that there is “not ONE RCT on H1N1.”

Again, is it reasonable to expect ONE RCT published and included in PubMed over a 9 month period? Any serious study takes time from concept to initiation, patient-enrollment, sufficient follow-up, collection of data, writing and submitting the article, peer review, publication, inclusion in PubMed and assignment of MeSH-terms (including the publication type “Randomized Controlled Trial”).

Furthermore RCTs are not always the most feasible or appropriate study designs for answering certain questions. For instance for questions related to harm, etiology, epidemiology, spreading of virus, characteristics, diagnosis and prognosis. RCTs may be most suitable to evaluate the efficacy of treatment or prevention interventions. Thus in case of H1N1 the efficacy of vaccines and of neuraminidase inhibitors to prevent or treat H1N1 flu. However, it may not always be ethical to do so (see below).

I’ve repeated the search, and using prefab “My NCBI filters” for RCTs discussed before I get the following results:

Using the Randomized Controlled Trials limits in PubMed I do get 7 hits, and using broader filters, like the Therapy/Narrow Filter under  Clinical Queries I even find 2 more RCTs that have not yet been indexed by PubMed. With the Cochrane Highly sensitive Filter even more hits are obtained, most of which are “noise”, inherent to the use of a broad filter.

The found RCTs are safety/immunogenicity/stability studies of subunit or split vaccines to H1N1, H3N2, and B influenza strains. This means they are not restricted to H1N1, but this is true for the entire set of H1N1 publications. 40 of the 1443 hits are even animal studies. Thus the total number of articles dealing with H1N1 only -and in humans- is far less than 1443.
By the way, one of the 15 H1N1-hits in PubMed obtained with the SR-filter (see Fig) is a meta-analysis of RCTs in the BMJ, co-authored by Heneghan. It is not about H1N1, but contains the sentence: “Their (neuraminidase inhibitors) effects on the incidence of serious complications, and on the current A/H1N1 influenza strain remain to be determined.”

More important, if studies have been undertaken in this field they are probably not yet published. Thus, the place to look is a clinical trials register, like Clinical trials.gov (http://clinicaltrials.gov/), The International Clinical Registry Platform Search Portal at the WHO (www.who.int/trialsearch) , national or pharmaceutical industry trials registers.

A search for H1N1 OR swine flu in Clinical trials.gov, that offers the best searching functions, yields 132 studies, of which 116 were first recieved this year.

Again, most trials concern the safety and efficacy of H1N1 vaccines and include the testing of vaccines on subgroups, like pregnant women, children with asthma and people with AIDS. 30 trials are phase III.
Narrowing the search to H1N1 OR swine flu | neuraminidase inhibitors OR oseltamivir OR zanamivir (treatment filled in in the filed “Interventions”) yields 8 studies. One of the studies is a phase III trial.

This yield doesn’t seem bad per se. However, numbers of trials don’t mean a lot and a more pertinent issue is, whether the most important and urgent questions are investigated.

Three issues are important with respect to interventions:

  1. Are H1N1 vaccines safe and immunogenic? in subpopulations?
  2. Do H1N1 vaccines lower morbidity and mortality due to the H1N1 flu?
  3. Are neuraminidase inhibitors effective in preventing or treating H1N1 flu?
Question [1] will be answered by current trials.
Older Cochrane Reviews on the seasonal influenza flu (and updates) cast doubt on the efficacy of [2] vaccines (see the [poor*] Atlantic news article) ànd [2] neuraminidase inhibitors in children (Cochrane 2007 and BMJ 2009) ànd adults  (Cochrane 2006, update 2008 and BMJ 2009) against symptoms or complications of the seasonal flu. The possibility has even been raised that seasonal flu shots are linked to swine flu risk.
However, the current H1N1 isn’t a seasonal flu. It is a sudden, new pandemic that requires different actions. Overall H1N1 isn’t as deadly as the regular influenza strains, but it hits certain people harder: very young kids, people with asthma and pregnant women. About the latter group, Amy Tuteur (obstetrician-gynecologist blogging at The Skeptical OB) wrote a guest post at Kevin MD:
(…) the H1N1 influenza has had an unexpectedly devastating impact among pregnant women. According to the CDC, there have been approximately 700 reported cases of H1N1 in pregnant women since April.** Of these, 100 women have required admission to an intensive care unit and 28 have died. In other words, 1 out of every 25 pregnant women who contracted H1N1 died of it. By any standard, that is an appalling death rate. (……)
To put it in perspective, the chance of a pregnant woman dying from H1N1 is greater than the chance of a heart patient dying during triple bypass surgery. That is not a trivial risk.
The H1N1 flu has taken an extraordinary toll among pregnant women. A new vaccine is now available. Because of the nature of the emergency, there has not been time to do any long term studies of the vaccine. Yet pregnant women will need to make a decision as soon as possible on whether to be vaccinated. (Emphasis mine)
…. Given the dramatic threat and the fact that we know of no unusual complications of vaccination, the decision seems clear. Every pregnant woman should get vaccinated as soon as possible.
Thus the anticipated risks must be balanced against the anticipated benefits, Amy urges pregnant women to get vaccinated, even though no one can be sure about side effects ànd about the true efficacy of the vaccine.
For scientific purposes it would be best to perform a double randomized trial with half of a series of pregnant women receiving the vaccine, and the other half a placebo. This would provide the most rigid evidence for the true efficacy and safety of the vaccine.
However it would not be ethical to do so. As “Orac” of Orac Knows explains so well  in his post “Vaccination for H1N1 “swine” flu: Do The Atlantic, Shannon Brownlee, and Jeanne Lenzer matter?” RCTs are only acceptable from an ethical standpoint if we truly do not know whether one treatment is superior to another or a treatment is better than a placebo. There is sufficient reason to believe that vaccination for H1N1 will be more efficacious than “doing nothing”. Leaving a control group unvaccinated will certainly mean that a substantial percentage of pregnant women is going to die. To study the efficacy of the H1N1 among pregnant women observational studies (like cohort studies) are also suitable and more appropriate.
Among the studies found in ClinicalTrials.gov there are a few H1N1 Vaccine Clinical Studies in Pregnant Women, including RCTs. But these RCT’s never compare vaccinated women with a non-vaccinated women. All pregnant women are vaccinated, but the conditions vary.
In one Danish study the arms (study groups) are as follows:
Thus two doses of H1N1 with adjuvant are compared with a higher dose H1N1 without adjuvant. As a control non-pregnant women are vaccinated with the adjuvant H1N1.*** The RCT is performed within a prospective, birth-cohort study recruiting 800 pregnant mothers between Q1- 2009 and Q4-2010. As a natural control women pregnant in the H1N1 season (Q4) will be compared with women outside the season. Please note that the completion date of this study will be 2012, thus we will have to wait a number of years before the study describing the results will be found in PubMed….
To give an impression of the idea behind the study, here is the summary of that trial in the register (not because it is particularly outstanding, but to highlight the underlying thoughts):
“Pregnant women are at particular risk during the imminent H1N1v influenza pandemic. The new H1N1v virus requires urgent political and medical decisions on vaccination strategies in order to minimize severe disease and death from this pandemic. However, there is a lack of evidence to build such decisions upon. A vaccine will be provided in the fourth quarter of 2009, but there is little knowledge on the immunogenicity. Particularly its clinical effectiveness and duration of immunity in pregnant women and their newborn infants is unknown. Therefore, it will be important to study the optimal vaccination regimens with respect to dosing and use of adjuvant to decide future health policies on vaccination of pregnant women. We have a unique possibility to study these aspects of H1N1v infection in pregnant women in our ongoing unselected, prospective, birth-cohort study recruiting 800 pregnant mothers between Q1- 2009 and Q4-2010. Pregnant women from East-Denmark are being enrolled during the 2nd trimester and their infant will undergo a close clinical follow-up. The H1N1v pandemic is expected to reach Denmark Q4-2009. The timing of this enrollment and the imminent pandemic allows for an “experiment of nature” whereby the first half of the mothers completes pregnancy before the H1N1v pandemic. The other half of this cohort will be pregnant while H1N1v is prevalent in the community and will require H1N1v vaccination.The aim of this randomized, controlled, trial is to compare and evaluate the dose-related immune protection conferred by vaccine and adjuvant (Novartis vaccine Focetria) in pregnant women and non-pregnant women. In addition the protocol will assess the passive immunity conferred to the newborn from these vaccine regimes. The study will provide evidence-based guidance for health policies on vaccination for the population of pregnant women during future H1N1v pandemics.”
Although with regard to H1N1-vaccination, appropriate studies are being done, it is feasible that certain measures might not be appropriate on basis of what we know. For instance, pretreating people in the non-risk groups (healthy young adults) with neuraminidase-inhibitors, because they are “indispensable employees”. Perhaps Heneghan, who as you remember is a co-author of the BMJ paper on neuraminidase -inhibitors in children with the seasonal flu, was thinking of this when writing his post.
If Heneghan would have directed his arrows at certain interventions in certain circumstances in certain people he might have had a good point, but now his arrows don’t hit any target. Revere from Effect Measure and Orac from Orac Knows might well have diagnosed him as someone who suffers from “methodolatry,” which is, as Revere puts it, the “profane worship of the randomized clinical trial as the only valid method of investigation.”
Notes
* But see the excellent post of Orac who trashes the Atlantic paper in Flu vaccination: Do The Atlantic, Shannon Brownlee, and Jeanne Lenzer matter? (scienceblogs.com). He also critiques the attitude of the Cochrane author Jefferson, who has a different voice in the media compared to the Cochrane Reviews he co-authors. Here he is far more neutral.
** There is no direct link to the data in the post. I’m not sure whether all pregnant women in the US are routinely tested for H1N1. (if not the percentage of H1N1 deaths among H1N1 infected pregnant women might be overestimated)
***In the US, vaccins given to pregnant women are without adjuvant.
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Twitter goes Viral: Swine Flu Outbreak – Twitter a Dangerous Hype?

30 04 2009

twitter-network-and-virusTwitter has been praised for its actuality and news breaking character. Remember the earthquakes and the two recent airplane crashes (Hudson River, Schiphol). Twitter often was the first to bring the news.

Twitter’s power lies in its simplicity, -the 140 character limit-, its speed and it’s domino-effect. Tweets (twitter messages) can be read by your followers (I have appr. 650). If they find something important, funny or whatever they could “RT” or Retweet (i.e. resend) the message, and their friends could retweet it as well. Via these secondary networks Twitter can go viral (in its replication and spread).

Below a friends of a friend network of a well known twitter personality Robert Scobleizer, as obtained by Twitterfriends. Only the “relevant network” is shown, directed to someone in particular: tweets beginning with @ (followed by the twitter name of your friend). The actual reach of tweets not starting with @ is greater, because they can be read by all followers.

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Apart from following specific tweople one can also search for certain words or (hash)tags via Twitter Search or #hashtags.

Pushed by celebrities, such as Ashton Kutcher and Oprah Winfrey, who recently joined Twitter. Twitter’s traffic was poised to double and the number of tweeting people has steeply increased.

Twitter has been glorified by the stars. They created a real (meaningless) twitter mania.

But what raises high, can drop low.

Several sources dethroned Twitter because of it’s viral role in the recent swine flu outbreak. One of the first and most serious critiques came from a blog (Foreign Policy: Net Effect). It’s title: Twine flu: Twitter’s power to misinform.swine-flu-totThis is a serious allegation. Evgeny Morozov‘s main critiques:

  1. The “swine flu” meme has led to misinformation, fear and panic. Wrong info includes: fear that it “could be germ warfare” or “that one should not eat pork and certainly not from Mexico”.

  2. Unlike a simple Google search Twitter gives too much noise (irrelevant or wrong information).

  3. Messages from trustworthy sources have as much weight as those from uninformed people.

  4. There is very little context you can fit into 140 characters, even less so if all you are doing is watching a stream.

  5. Evgeny also worries about a future misuse of Twitter by cyber-terrorists shaping conversations on serious topics. A number of corporations are already monitoring and partially shaping twitter conversations about particular brands or products.

In addition some posts highlight that most of the Tweets belong to the category “witty or not so witty”. (also see this post)
And after these comments many similar comments were to follow: In fact these comments and critiques were going viral as well: take a look at this Google Search for Twitter Swine Flu and note the negative sound of most of the headlines.
The CNN website quotes Brennon Slattery, a writer for PC World,

“This is a good example of why [Twitter is] headed in that wrong direction, because it’s just propagating fear amongst people as opposed to seeking actual solutions or key information (..). The swine flu thing came really at the crux of a media revolution.”

Is Twitter just a hype and useless as an information source? Is it dangerous when a wide number of people would turn to Twitter in search of information during an emergency? Or have people just found a stick to beat the dog?

I will go to several aspects of the twitter flu coverage as I have encountered it.

Number of tweets

Indeed, as brought forward by Mashable, Tweets about “Swine Flu” are *now* at 10,000 per hour!!

Yesterday, 5 out of 10 twitter buzzwords were connected to Swine Flu:

  • # · Swine Flu
  • # · swineflu
  • # · Mexico
  • # · H1N1
  • # · Pandemic

Searching for information on Twitter
You can imagine that it is hardly useful to keep track of tweets mentioning *swine flu*, nor is searching for these buzzwords or hastags useful, if not combined with other terms or names, like CDC or laikas (just to find what you tweeted yourself).
I keep track of certain words via Tweetdeck in separate columns, accepting a certain “noise”, knowing this will only yield 20-50 tweets per day. It would not come to my mind to just blindly search for swineflu on Twitter.

The official media
It is said that Twitter doesn’t give useful or correct information, and indeed it hasn’t been designed for that (being merely a social Network). In its primitive form it is just online gossip or as The Register (UK) puts it- “it is not a media outlet“. But odd enough, the official media did not behave differently. Cable television programmers went into crisis mode and a look at newspaper front pages and website home pages around the world showed a range of responses, from the almost hysterical to the concerned and more measured (Reuter’s Blog).

Look at this message from AJ Cann, that I retweeted :

laikas: RT @AJCann Totally irresponsible #swineflu journalism in the Dail Mail http://tinyurl.com/cms3km (expand) >>and they say twitter evokes global panic! 9:56 AM Apr 27th from TweetDeck

Is there really no reason to be worried?
Let’s face it. We don’t know an awful lot about this new virus strain. While it is true that the common flue has killed 13,000 people in the US since in a rather unnoticed way, and while there are relatively few swine flu casualties yet, one never knows how this new H1N1 epidemic will evolve. It might just fade away or it could kill millions of people. We just don’t know. It is a new, deadly virus. Not for nothing (as I learn from Twitter), the WHO has just raised the current level of influenza pandemic alert from phase 4 to phase 5. But this is only meant to be prepared and to inform, not to cause panic.
who-message
Via @AJCann (on twitter), I was just alerted to a very refreshing view of Ben Goldacre on the whole situation. Ben, a doctor writing for the Guardian, excelling in critically informing the public about science (and quack) and a real valibrity, was invited all over by the media to be a naysayer on the “aporkalypse”.
Ben on his Blog Bad Science:

By Tuesday, pundit-seekers from the media were suddenly contacting me, a massive nobody, to say that swine flu is all nonsense and hype, like some kind of blind, automated naysaying device. “Will you come and talk about the media overhyping swine flu?” asked Case Notes on Radio 4. No. “We need someone to say it’s all been overhyped,” said BBC Wales.

I assumed they were adhering, robotically, to the “balance” template, but no: he kept at it, even when I protested and explained. “Yeah, but you know, it could be like Sars and bird flu, they didn’t materialise, they were hype.” Simon Jenkins suggested the same thing. It’s not true, I said. They were risks, risks that didn’t materialise, but they were still risks. That’s what a risk is. I’ve never been hit by a car, but it’s not idiotic to think about it. Simon Jenkins won’t be right if nobody dies, he’ll be lucky, like the rest of us. Do people think this flappily in casinos? The terrible truth is yes.

Ben compares it with the story of the boy who cried wolf and he concludes:

(….) because not only have the public lost all faith in the media; not only do so many people assume, now, that they are being misled; but more than that, the media themselves have lost all confidence in their own ability to give us the facts.

How to deal with Twitter Noise?
I do agree that it would be hardly useful to start monitoring all tweets about the flu.Twitter has produced millions of “tweets” about swine flu since this outbreak began a mere week ago and most of it has been nothing but noise.
Suppose you would listen to all radio channels at once: that would be an unbearable noise. Usually you choose a channel, your favorite one, and just listen what comes next. But you may switch to another channel anytime. And for news you might just go to a specific channel that you know is the most informative.
It is exactly the same with Twitter. I don’t follow everyone. Since I use Twitter mostly for my work (medicine, library, science, web 2.0) and not primarily for a chat or wit, I choose the tweople I follow carefully. If they produce too much noise I might unfollow them. They are my human filter to the news.

6a00d8341bfa9853ef0105368fcb5e970c-400wi-darmano

Furthermore among the ones I follow are News or Health Sources, like @CNN Health, sanjayguptaCNN, @BBC Health, @BreakingNews, @health and recently (because of retweets of friends): @WHOnews , @CDCemergency, Reuters_FluNews, Fluheadlines.

Below are some of my tweets starting off Saturday 24th April (see all here) (Black= tweets, green is a commentary). April 24 I was not aware that something really serious was happening, as I live in Europe and considered the swine flu as a local problem.

Once I saw @BreakingNews and @health mentioning real casualties and the WHO calling an emergency meeting, I realized the seriousness of the problem. I was also pointed to @WHOnews and @CDCemergency, the most trustworthy sources to follow.
I also understood that the swine flu might be difficult to contain.

laikas: RT @BreakingNews: BULLETIN — WORLD HEALTH ORGANISATION CALLS EMERGENCY MEETING TO DISCUSS DEADLY SWINE FLU OUTBREAKS IN MEXICO AND THE U.S.2:31 PM Apr 24th from TweetDeck

laikas: RT @health WHO, CDC concerned about possible epidemic following reports of 60+ people killed by new flu strain in Mexico http://bit.ly/d3JsO 6:23 PM Apr 24th from TweetDeck

laikas: RT @TEDchris: Swine flu outbreak. This is how it was SUPPOSED to have been contained. http://is.gd/us6r Worrying. >> WHO protocol 6:56 AM Apr 25th from TweetDeck

This feeling was strengthened by the reporting of flu cases in other continents. Furthermore @allergynotes pointed to a map showing all cases reported thus far. At that time the map was very up to date and clear (not many dots). From the map I learned that a woman in Kansas was infected by her husband who became ill after returning from a conference in Mexico. Then I realized that the “swine flu” was no longer a swine flu but a “human flu”. My tweets about the New Zealand cases and the map were retweeted several times, thus contributing a little to the domino effect.

laikas: RT @BreakingNews: Reports of flu outbreak in New Zealand. 22 students may have been infected after a trip to Mexico. BNO trying to confirm. 3:25 AM Apr 26th from TweetDeck

laikas: RT @dreamingspires: RT @AllergyNotes Map of H1N1 Swine Flu of 2009 http://bit.ly/P2mcc (expand) 4:41 AM Apr 26th from TweetDeck

laikas: Map of H1N1 Swine Flu of 2009 http://bit.ly/P2mcc _ New Zealand added to the map. 4:42 AM Apr 26th from TweetDeck


Direct Link to H1N1 Swine Flu Google Map:

Somewhat later came the informative phase. Long before the official media were giving any useful information, some of my twitterfriends alerted me to their own or other (official) news.

@ajcann already wrote a post on his blog Microbiology Bytes (a blog with the latest news on microbiology) :10 things you should know about swine flu. (April 25th)

laikas: Reading @sciencebase Swine Flu http://bit.ly/y5Xqz 7:47 AM Apr 26th from web

laikas: RT @sanjayguptaCNN: I’ll answer your swine flu Q’s LIVE on CNN at 7:30a ET. call 1-800-807-2620. thanks 4he gr8 tweet Q so far.

laikas: RT @consultdoc: Great swine flu summary via @ubiquity http://bit.ly/DK0xV (expand) Thanks Greg.1:18 PM Apr 26th from TweetDeck

laikas: RT @BreakingNews: The WHO is holding a news conference on swine flu. Michael van Poppel is covering it live @mpoppel. 1:49 PM Apr 26th from TweetDeck

laikas: RT @stejules: RT @mashable HOW TO: Track Swine Flu Online http://tinyurl.com/dh68n8 (expand) (via @tweetmeme) (5:17 PM Apr 26th from TweetDeck

Later the flu spreaded to Israel, Europe and South America.

At that point I became saturated with all information. I just follow the main news and read some good overviews

end-tweet-flu
Conclusion
For me, Twitter was the first and most accurate news source to get informed and updated on the swine flu pandemics. It was reliable, because “my friends” filtered the news for me and because I follow some trustworthy sources and news sites. Indirectly other tweople also pointed me at good and actual information.
And in my turn I kept my followers informed. The news has alarmed me, but I’m not in panic or frightened. I just feel informed and at the moment I can do nothing more than “wait and see”.

It has often been said: Twitter is what you make of it.
But keep in mind the golden rule:

tweet-but-verify

Information on Swine Flu

News and Blogs

Photo Credits:

* wonderful those different names.


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