Is Boehringer Providing Proper Informed Consent?
24 CommentsBy Ed Silverman // June 15th, 2011 // 10:18 am
Earlier today, we wrote how a new meta-analysis in BMJ found that Spiriva, a medication used to treat chronic obstructive pulmonary disease, may raise the risk of an early death by 52 percent. The results have generated considerable attention since a mist version is sold in 55 countries, although not in the US. However, the FDA last year decided Spiriva does not increase the risk of heart attack or stroke.
Meanwhile, Boehringer Ingelheim which, along with Pfizer, markets Spiriva, is conducting a study in 17,000 patients that compares two different versions - a mist that is delivered with the Respimat inhaler and a powder that is delivered with a Handihaler device. The study is designed to verify safety and efficacy (read the earlier post, including the links to BMJ, here), although a separate editorial in BMJ argues the device is safer than the inhaler.
And so, the researchers whose analysis was published in BMJ are raising yet another issue - they say Boehringer is not providing proper informed consent to the 17,000 study participants. In their view, Boehringer has failed to warn about the risks, even though the drugmaker should be fluent in the ins and outs of the clinical trials that were the subject of the BMJ meta-analysis.
“There are two issues,” co-author Curt Furberg, a professor at the Wake Forest University School of Medicine, tells us. “One, if you read informed consent, they don’t warn about the risks. The company obviously knew about what we published but they don’t say a word about an increased risk of mortality. That’s inadequate.
“The other is the trial is a comparison of two drugs that are harmful and and the primary outcome is harm. The issue is can you set a trial ethically and have a primary outcome being harm and ask which drug is most harmful? The answer is no, you can’t do that. To set up a trial to determine what is harmful is against recommendations by the Institute of Medicine. They should not test two drugs to see which one is most harmful.”
This is the section of the informed consent form that he finds objectionable: “There is some evidence that tiotropium Respimat may do more than tiotropium HandiHaler in reducing the number and severity of COPD exacerbations, although some trials have shown a higher number of deaths with tiotropium Respimat (2.2% of Respimat treated patients compared to 1.7% of patients in the other treatment group), which were mainly in patients who were known to have a heart rhythm problem. The higher numbers in the tiotropium Respimat group have not been considered related to tiotropium.”
“Look at that last line: ‘higher numbers have not been considered.’ I, personally, as a clinical trial ethicist find this line to be deceptive,” Sonal Singh, an assistant professor at the Johns Hopkins University School of Medicine, tells us. “We already have conclusive proof of a higher mortality rate. Why do we need 17,000 randomized patients to find that out?”
Meanwhile, the researchers note that numerous regulatory agencies, including the FDA, have already approved the trial, which they intend to protest. If you would like to read the entire informed consent form, you can do so here. We have contacted Boehringer for a response and will update you accordingly.
safety pic thx to militaryhealth on flickr
ol cranky
I fear that the ICFs from many trials are far from up to snuff. Some companies outsource to a vendor who has contract staff not directly involved with the trial writing their consents; some companies split up the consent development and the review of the site specific consent and the quality of the document and the review have fallen significantly. It’s amazing what an IRB will approve if someone from the sponsor (someone directly involved in the trial, who understands the study design, etc.) doesn’t review the draft well enough to recognize some glaring errors and refuse to approve the document or just accepts the document as written because they don’t understand the document and/or the protocol and, oh well, the IRB approved it so it must be OK. This is all part and parcel to the dumbing down of clinical research in which demonstrable clinical understanding and hands on clin ops experience was necessary before you got a “manager” title.
Barbie
Ed, you may have wanted to mention that is the same Sonal Singh who released an early meta-analysis regarding anticholnergics (Inhaled Anticholinergics and Risk of Major Adverse Cardiovascular Events in Patients With Chronic Obstructive Pulmonary Disease) that was widely refuted by the medical community and the fda. To the Editor: The meta-analysis by Dr Singh and colleagues1 appears to demonstrate an increased risk of cardiovascular death, myocardial infarction, or stroke events in patients using inhaled anticholinergics. I believe that this study incorporates errors in article identification and data extraction.
At least 1 article that meets the authors’ search criteria for long-acting anticholinergics and recorded cardiovascular events was not included.2 The event data in Casaburi et al3 showed no difference between tiotropium and controls (7 deaths in each group and serious adverse event rates of 18% in the tiotropium group vs 21% in the control group). However, Singh et al reported 12 vs 3 events, respectively. The study by Wedzicha et al4 apparently showed 36 events in the tiotropium group and 26 events in the control group when nervous system, vascular, and cardiac disorders were combined, whereas Singh et al reported 23 vs 13 events, respectively. Reanalysis of the data in the study by Singh et al with these changes might shift the risk ratios toward 1, which would indicate no significant cardiovascular event difference between tiotropium and other agents. This likelihood is substantiated by the results of the UPLIFT trial.
Bruce Wayne
Dear Barbie,
We all know abot reclassifcation of deaths from Vioxx and Merck don’t we? Its an industry wide problem that both Merck and Lilly have been found to have engaged in for years in pharma.
BI has been covering the isues with their anticholinergics for years ever since the NIH Lung Health Study showed more people died on ipratropium than those taking nothing so how do you explain that? Three separate analyses done all showing cardiac death and stroke seems all too coincidental. Oh and it was confirmed it yet another huge analysis. So in the end, their is a risk from Atrovent in 3 separate looks which are Lung Health Study, Singh’s analysis, and yet another.
Now there is an appearance of risk with yet another anticholinergic. At what point do you acknowledge it? When its your Dad or Mom who dies? I am serious about this question. At what point does life risk matter?
There is lots of smoke here and there would logically be a fire somewhere. Take a long ook at the concerns about the product when it was submitted to the FDA. Their were lots of risks inherently concerning many even at a less risky profile in patient population. The company involved is not talking which is really peculiar but not so odd if you look at past behavior.
They have lots to lose by talking.
Go back to modeling Barbie.
Stay away from science as its not your strong suit.
Bruce
Sonal Singh
The UK regulators have already put a warning on the increased risk of death with Spiriva
http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON099869
A recent Canadian study also reported an 16 % increased risk of death with Spiriva compared to LABA
http://www.annals.org/content/154/9/583.abstract?sid=e0cff83e-d495-4055-8d95-651076ca7331
Another clinical trial programme of indacaterol reported an more than 60 % statistically increased risk of cardiovascular and cerebrovascular events with Spiriva.
Worth H, Chung KF, Felser JM, Hu H, Rueegg P. Cardio- and cerebrovascular safety of indacaterol vs formoterol, salmeterol,
tiotropium and placebo in COPD.Respir Med. 2011 Apr;105(4):571-9. Epub 2011 Jan 11.
We updated our JAMA analysis and found similar results of increased risk of MI, stroke and CV death in JAMA in 2009.
As for The UPLIFT study, it did not count death in 1500 participants that were withdrawn, dismissed approximately 2/3rd of investigator reported cardiovascular events, and did not record EKGs, or count sudden deaths as CV deaths, hence didn’t see a risk and needs to be reexamined.
These recent findings have been shared with the FDA. If the market is any guide the view is different from that of the poster.
http://www.fnno.com/video/trading/331-pfizer-slips-after-researchers-find-mist-inhaler-may-increas-business
Barbie
Ed, so sexist comments are okay how are we on racism, b wayne you are a sad little man
Bruce Wayne
Barbie,
You really don’t deserve a response. What pharma outfit do you model for and drop drugs off to offices for anyway? You are way too sensitive. I guess you want my comments screened because you know I am right and want them “restricted”. You in favor of book burning too? I am entitled to my own opinion. Who said I was a man anyway…you really assume too much.
“Bruce”
Sonal Singh
I wish there were solutions and not only problems with anticholinergics for patients with COPD. This issue of anticholinergics increasing heart rhythm problems was was first brought to light in 1995.Unfortunately in this case the mechanism of the drug–causing sudden cardiac death precludes us from any easy solutions. Unfortunately basic clinical pharmacology still holds water.
Barbie
Not in pharma at all, just a student, as for you Bruce, I can only assume you are a never was, someone who hoped for more in life and instead became an internet toll.
Dr Singh do you think the increase in cardiac death could be tied to increase SABA use in stead of the antichlinergics? I know spiriva caused a reduction in use of SABA’s but ipratropium would have a large amount of SABA use resulting increased tachcardia.
Lana Keeton
Barbie, What part of dead don’t you understand? You want to bury the truth in a bunch of words. Dead is dead. Bruce Wayne is not sexist. He is just honest. You should find another job that doesn’t include pushing drugs that kill people. And no, your statistics don’t tell the whole story of how many people are dead who are not even in those studies. Or the doctors who prescribe these medications to people who don’t even need them. This is serious and you should put in perspective that you are messing with peoples lives. Like dead or alive.
Bruce Wayne
Thanks Lana for echoing common sense. Dr Singh has been yelling into a room full of FDA people and no one is listening. It’s frightening how utterly ignorant they are right now. Not funny, but its a deadly problem …this deafness.
Its a pandemic issue for FDA…look how long it took them to get around to Actos bladder cancer as an example.
Bruce
Sonal Singh
Barbie: The interaction is possible with SABAs/LABAs and Bateman et al did look at this in one of the respimat studies. Remember the mist inhaler has tiotropium and is conclusively linked to death. The risk with atrovent may be higher because usally short acting drugs result in higher dose. The other more relevant interaction is between anticholinergics and those who continue to smoke as there is some preliminary biological evidence to suggest this
Respiration. 2011 May 10. [Epub ahead of print]
Bronchodilation and Smoking Interaction in COPD: A Cohort Pilot Study to Assess
Cardiovascular Risk. van Dijk WD, Lenders JW, Holtman J, Grootens J, Akkermans R, Heijdra Y, van Weel C, Schermer TR.
Unfortunately, someone should be asking these questions and trying to answer them?
It is unclear if any company or agency is willing to even ask these important questions, let alone answer them?
Bruce Wayne
Singh,
They are burying the truth. It has been there for over a decade plus. The ones raising the alarm have been called heretics. The risks are apparent and frankly patients are not being warned. Most COPD patients continue to smoke and this is a known fact, so it is not an unknown enhancement of risk factors. Just being around a smoker could potentially enhance risks.
The other risk is with the nebulized solution forms which no one has looked at and also the Combination inhaler. The risks are magnified due to the way they were promoted. Dosing dilemmas and death rise exponentially.
kerry_zaputz
Bruce Wayne: with all due respect, you are a complete idiot. (And I mean that in the nicest possible way). Your indictment of the FDA and “how long it took them to get around to Actos bladder cancer” is evidence of your naivete and ignorance. The POTENTIAL link between Actos and bladder cancer is far weaker than the link between uncontrolled type 2 diabetes and death. Actos is an effective treatment for diabetes; a disease which causes significantly greater morbidity and mortality than bladder cancer (which is higher in diabetes regardless of tx). I, for one, am tired of the FDA over-reacting to remote and manageable risks of Rx drugs by pulling them from the market. Ask your friends with arthritis if they would accept the minimally increased risk of CV events with Vioxx to have effective pain relief. Don’t be late for your AP class, Bruce.
Sonal Singh
Bruce: OK with being a heretic as long as it is for my patients good.
Some other alternatives that we considered based on the counter arguments
1. Maybe it is that placebo lowered mortality by 33%? Any takers ( reminds me of few years ago and another drug Vioxx etc) If so we should all take it.
2. Maybe its the device ( placebo arm also had the same device– devices dont kill people drugs do)
3. Recent press release argues that mortality rates in the trial are similar to other COPD trials. We neeed to compare Tiotropium and placebo diference in death not the overall death to other studies.
And lest someone get the wrong idea that I am one of those KOLs up for grabs by the other inhaler manufacturers as is the prevalent trend of the times. here is our recent paper on Advair and fractures from Thorax.
http://thorax.bmj.com/content/early/2011/05/20/thx.2011.160028.abstract
Sixteen RCTs (14 fluticasone, 2 budesonide) with 17 513 participants, and seven observational studies (n=69 000 participants) were included in the meta-analysis. ICSs were associated with a significantly increased risk of fractures (Peto OR 1.27; 95% CI 1.01 to 1.58; p=0.04; I2=0%) in the RCTs. In the observational studies, ICS exposure was associated with a significantly increased risk of fractures (OR 1.21; 95% CI 1.12 to 1.32; p<0.001; I2=37%), with each 500 μg increase in beclomethasone dose equivalents associated with a 9% increased risk of fractures, OR 1.09 (95% CI 1.06 to 1.12; p<0.001).
Conclusion
Conclusion Among patients with COPD, long-term exposure to fluticasone and budesonide is consistently associated with a modest but statistically significant increased likelihood of fractures.
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There are other ways of making money–like seeing patients
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If you eliminated the impossible, all that remains is the truth.
Bruce Wayne
My attack on the feds delay regarding identifying Bladder Cancer issues with Actos is due to multiple factors and least of it is even discussed as yet. The FDA has been slow trigger on some but no trigger on others.
Singh is making a valid point here. The risk of anticholinergics are presently and routinely ignored by the largest privately held naufacturer in the world. If there were more competing companies, more would be discussed. Its about Share of Voice.
The danger is ever present. Don’t rely on the manufacturers or promotors to speak the truth as they are told to say “its inconclusive”. I have been there. “Don’t talk to the media or you will get fired” was the other threat.
Walter
Singh, its an interesting paper, but I think you do the field a disservice by overstating your conclusions here far beyond what is supported by your data.
Your claims here of having conclusively established an increased risk of death contrast with what the description in the peer reviewed article:
“Our analysis has limitations, which mainly reflect the quality of reported data. Differences exist in the populations studied, doses of tiotropium using the mist inhaler, and length of follow-up. The estimates are imprecise owing to the fairly low event rates. We could not examine cause specific mortality in great depth because of the lack of details in the reported data. Similarly, cardiovascular death was not a prespecified outcome, and the analysis relies on post hoc classification and adjudication. We did not have access to individual patient data to allow analyses of time to event.”
In all fairness, these “other alternatives” should have been mentioned above, in addition to the straw man alternative explanations you presented.
Similarly, you support your position above by stating that “The UK regulators have already put a warning on the increased risk of death with Spiriva”, thereby implying that these regulators have reached conclusions similar to your own. The actual “warning” looks like this;
“There were differences between the Respimat and HandiHaler study populations at baseline, including smoking status, gender, and disease severity, and the causes of death varied across studies. The underlying reasons for the apparent difference in the risk of all-cause mortality between the HandiHaler and Respimat devices are unclear, and may be a chance finding.”
Caveats and limitations on conclusions in scientific publications are not just formalities. Recognizing the limits of your data is an intrinsic part of the scientific process, and to one’s integrity as a researcher.
Sonal Singh
I was remiss in not discussing these limitations. But thankfully, as you suggest, all of them are in the paper for people to read and make up their own mind. Additional limitations include that relative risk of 52% translates into an NNH of only 1 in 124 deaths which may be a small absolute risk at individual level.
The examples provided were not straw-men but actual examples presented and we elaborate on them in the paper.
Conclusiveness is based on a “public health” approach after examination of the studies and not purely a statistical approach and takes into account prior concerns with this class ( including Lung Health Study), biological plausbility of sudden cardia death, dose-response, and consistency. This signifies that while the exact level of harm may be imprecise we do not need another “randomised experiment” of 17,000 COPD patients to determine if Spiriva mist is more harmful than Spiriva handihaler. The regulatory agencies and IRBs need to update the consent form and notify participants. Only informed participants can decide to continue in a trial that aims to provide this very high arbitrary threshold for “conclusive” proof of increased death with mist inhaler.
Bruce Wayne
Singh is raising the alarm because others in high places are not speaking the truth because of the factors you do not know.
I applaud his courage and what he speaks is worthy of consideration. Those who close their eyes and ignore the facts are making a serious mistake. Common sense is not so common anymore.
Bruce Wayne
Kerry,
Do you understand the mechanism by which this drug could be causing these issues and risks? Please answer this before you cast aspersions upon those who are scietists and have medical knowledge. This is a forum for discussion. You have not presented anything to indicate that you are more than a mole for the industry or someone protecting their paycheck….
I am offended by your tone, but I was told to never argue with someone who is misinformed or something like that. You get my drift.
kerry_zaputz
What’s a “scietists”? Follow up question: what pearls of wisdom have you imparted upon the readers to demonstrate your medical pedigree? I, for one, have seen no evidence of any scientific or medical knowledge in your posts. You sound like a disgruntled former rep.
Bruce Wayne
Kerry, actually you now have found your purpose in life. Be an editor or more specifically a spellchecker. As far as who I am-none of your business and I know who Singh is and have read his publishings and understand them unlike you. Why are you taking such a personal stake in what is said here? Are you a stakeholder in one of these industry giants ? Bet so. You have nothing to say other than “burn her at the stake”. Now go return to “fox news channel”, where you get the whole “truth”. You need to remove the Palin 2008 sticker off your car too. Its kinda embarassingn huh?
Salient point
Bruce-Twice in this thread alone you have directed attacks at other commenters based on what you believe their profession to be. If this is how you’re going to approach communicating on this forum, it is actually other commenters’ “business” to know the specifics of your own background.
Salient point
Yes this is very sophomoric & not even particularly amusing.
For the record, by “background” I meant profession, expertise, etc.
Bruce Wayne
Salient,
I am in expert in the field of medicine and published.