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Without evidence of benefit, an intervention should not be presumed to be beneficial or safe.

- Rogue Medic

Is that Aspirin or Acetaminophen? Recall Due to Wrong Drug in Packages

Sun, 30 Jun 2013 08:00:07 -0400 by

 

Last week the FDA (Food and Drug Administration) sent out a safety announcement about a recall of Rugby label Enteric Coated Aspirin Tablets, 81 mg, Lot 13A026.
 


 

The package does not contain 81 mg aspirin, but actually contains 500 mg acetaminophen (Tylenol), which is a much larger dose and is in many other over the counter medicines, such as cough and cold medicines. Almost all of these medicines contain a full adult dose of acetaminophen in addition to whatever the active ingredient is (guaifenesin, dextromethorphan, et cetera).
 

Consumers may be inadvertently taking Acetaminophen 500 mg instead of Enteric Coated Aspirin 81 mg which may cause severe liver damage to those who take other drugs containing acetaminophen, consumers who take 3 or more alcoholic drinks every day, or those who have liver disease. The labeled directions instructs patients to take 4-8 tablets every 4 hours, but not more than 48 tablets in 24 hours. Consumers who take 48 tablets daily of the defective product may be ingesting up to 24,000 mg of Acetaminophen, which is about six times the maximum recommended daily dose of acetaminophen (4,000 mg).[1]

 

Taking more acetaminophen than needed is not safe because of this duplication of doses. The liver may be able to remove the current amount of acetaminophen we are consuming (intentionally and unintentionally), but an extra half gram of acetaminophen may result in a toxic dose.

Some people only take 81 mg enteric coated aspirin on a daily basis for its antiplatelet effects, but the package recommends a lot more.

 

“It’s not an uncommon overdose,” said Dr. Corey Slovis, who heads the department of emergent medicine at Vanderbilt University Medical Center in Tennessee. “We hate Tylenol overdose because they’re the silent overdoses.”

Slovis said patients who overdose on acetaminophen often don’t feel sick right away, unless they’ve taken a massive dose that induces vomiting within six hours. Instead, many patients who overdose on acetaminophen don’t see a doctor for more than two days because they feel fine at first. When they finally get to Slovis, they’re often jaundiced and experiencing the early signs of liver failure.

As such, this kind of overdose could result in liver failure, the need for a transplant or death, Slovis said.[2]

 

The pills are probably larger than the normal aspirin pills, but if you are unfamiliar with the product, you would not recognize the difference. Taking a handful (4-8 tablets every 4 hours, but not more than 48 tablets in 24 hours) of pills at a time is probably not a good idea, regardless of the label instructions.

“Did he take six pills or only five?” Well, to tell you the truth, in all this excitement I kind of lost track myself.[2]

We have trouble counting beyond three.

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Footnotes:

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[1] Advance Pharmaceutical Inc. Issues Voluntary Recall of One Lot of Enteric Coated Aspirin Tablets, 81 mg, Due to Health Risk
Recall – Firm Press Release
FDA
Recall notice

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[2] Aspirin Recalled Over Bottle Mix-Up
Sydney Lupkin (@slupkin)
ABC News
Article

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[3] Dirty Harry (1971)
Quotes
IMDb.com
Quote

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Filed Under: FDA, Heresy, Toxicology

FDA Warning of Zyprexa Deaths – NOT With the Drug used by EMS or in the Emergency Department

Tue, 18 Jun 2013 16:45:09 -0400 by

 

Today the FDA (Food and Drug Administration) sent out a safety announcement about long-acting olanzapine (Zyprexa Relprevv).

This is not the form of olanzapine (Zyprexa) used by EMS or used in the ED (Emergency Department).
 

Post-injection Delirium Sedation Syndrome (PDSS): Patients are at risk for severe drowsiness (including unconsciousness or coma) and/or confusion and disorientation after each injection and must stay at the doctor’s office or clinic for at least 3 hours after the injection is given. ZYPREXA RELPREVV is only prescribed by doctors who are enrolled in the ZYPREXA RELPREVV Patient Care Program to patients who are also enrolled.[1]

 

The affected medication is packaged as Zyprexa Relprevv, the long-acting version of olanzepine.
 

Image credit.[2]
 

We would use olanzapine in its regular formulation, which has been available as a generic since 2011, when Eli lilly’s patent expired.

The patent on Zyprexa Relprevv does not expire until September 30, 2018, so it is only available as an expensive version from Eli Lilly.[3]

What happened?
 

FDA is investigating two unexplained deaths in patients who received an intramuscular injection of the antipsychotic drug Zyprexa Relprevv (olanzapine pamoate). The patients died 3-4 days after receiving an appropriate dose of the drug, well after the 3-hour post-injection monitoring period required under the Zyprexa Relprevv Risk Evaluation and Mitigation Strategy (REMS). Both patients were found to have very high olanzapine blood levels after death.[4]

 

Why 3 hours?
 

Click on images to make them larger.
 

Post-injection delirium/sedation syndrome events and time to initial onset, incapacitation, and hospitalization. The middle line inside the box is the median 50th percentile; left border of the box is the 25th percentile and right borders of the box is the 75th percentile; left whisker is the 10th percentile and right whisker is the 90th percentile.[5]

 

All patients demonstrated symptoms within 5 hours of injection, so onset 3 to 4 days after injection seems unlikely. This medication can only be given in the clinic or doctor’s office, so an extra dose is improbable.

How likely is it that the cause of death is the medication?

It would seem unlikely, except that Both patients were found to have very high olanzapine blood levels after death.

The FDA will investigate this and may find out the cause(s) of death, or may nor find out the cause(s) of death, but it does not appear to be something that affects emergency patients.

These patients may present to EMS, or the ED, from a doctor’s office or clinic and we should be familiar with treatment.

Symptoms appear to be less severe than with an overdose of olanzapine, so management should be just supportive care (assess blood sugar, vital signs, level of consciousness, . . .), only treating what truly needs to be treated (seizures, airway compromise, . . .).
 

As discussed by McDonnell et al. [5], the probable mechanism most likely involves accidental entry of the medication into the blood stream following blood vessel injury during the injection process. The similarity in incidence of olanzapine LAI PDSS (0.07% of injections) to that of Hoigne’s syndrome following accidental intravascular injection of penicillin procaine G (0.08% of injections) [6] suggests that these findings may be approximating the naturally occurring background rate for accidental direct or indirect intravascular injection during any intramuscular injection process.[5]

 

Accidental intravenous, or intra-arterial, injection does not seem to be a possible cause of deaths that happen several days later.

We do not have other information on the patients, such as when they were last seen without any symptoms, what other medications they were taking, what other medical conditions were present, whether there were signs of trauma, . . . , so the only thing to do is wait for more information.

If you carry olanzapine, there is no reason not to keep using it as before.

If this encourages you to switch to ketamine, I do not see any problem with that decision.

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Footnotes:

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[1] Important Safety Information about ZYPREXA® RELPREVV™ (olanzapine) For Extended Release Injectable Suspension
Eli Lilly
zyprexarelprevv.com
Home page.

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[2] ZYPREXA RELPREVV (olanzapine pamoate) kit
[Eli Lilly and Company]
DailyMed
FDA Label

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[3] Generic Zyprexa Relprevv Availability
drugs.com
Information page.

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[4] Zyprexa Relprevv (Olanzapine Pamoate): Drug Safety Communication – FDA Investigating Two Deaths Following Injection
Posted 06/18/2013
FDA
FDA Drug Safety Communication

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[5] Post-injection delirium/sedation syndrome in patients with schizophrenia treated with olanzapine long-acting injection, I: analysis of cases.
Detke HC, McDonnell DP, Brunner E, Zhao F, Sorsaburu S, Stefaniak VJ, Corya SA.
BMC Psychiatry. 2010 Jun 10;10:43. doi: 10.1186/1471-244X-10-43.
PMID: 20537128 [PubMed – indexed for MEDLINE]

Free Full Text from BMC Psychiatry.

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Filed Under: FDA, Heresy, Ketamine, Pharmacology, Toxicology

Let the drug shortages help us make better patient care decisions

Sun, 19 May 2013 08:00:11 -0400 by

Image credit.[1]
–
 

Maryland made smart changes to their protocols because of the drug shortages.[2]

50% dextrose is not as good as 10% dextrose at treating hypoglycemia.[3],[4],[5]

Switching to 10% dextrose is an obvious solution, but not used by everyone.
 

Sedgwick County EMS workers administer about 80 doses of the stuff (50% dextrose) a month, but the county has only received 30 pre-filled doses so far this year through its normal vendor, Braithwaite said.[6]

 

We have research that shows that 10% dextrose is a better choice for EMS, but we continue to use the inferior treatment.

We have trouble obtaining the inferior treatment, but we refuse to change to the better treatment.

Is there a state law that prevents the use of different concentrations of dextrose?

If so, go to the government, explain the problem, and get the law changed. If that does not work, go to the press and point out that the failure to act by the legislature is endangering patients.
 

“We’re now looking at compounding of those medications,” he said.

But that’s an expensive alternative. A pre-filled dose of dextrose costs $6.99. A vial costs $1.81. Pre-filled doses are preferred, Hadley said, because there is one less step for emergency personnel.

Compound dextrose costs $14 per dose and has a much shorter shelf life, 90 days compared with two years.[6]

 

50 ml of 50% dextrose contains 25 grams of dextrose.

A 250 ml bag of 10% dextrose contains 25 grams of dextrose.

The cost of the bag of 10% dextrose is about $2.50, which is much less than the $7 cost of and amp of 50% dextrose.

Is there a difference in shelf life? If they are giving 80 doses a month, how much does that matter?

The only advantage to the 50% dextrose is familiarity, which is due to our failure to change to a better treatment when it becomes the right thing to do.

The drug shortages do not affect 10% dextrose.

Isn’t it time we cut costs, improved safety, improved care, and eliminated 50% dextrose?

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Footnotes:

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[1] Images in emergency medicine. Dextrose extravasation causing skin necrosis.
Levy SB, Rosh AJ.
Ann Emerg Med. 2006 Sep;48(3):236, 239. Epub 2006 Feb 17. No abstract available.
PMID: 16934641 [PubMed – indexed for MEDLINE]

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[2] Drug shortages leading to better EMS protocols
Fri, 19 Oct 2012
Rogue Medic
Article

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[3] Dextrose 10% or 50%: EMS Research Episode 10
Tue, 05 Jul 2011
Rogue Medic
Article

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[4] Dextrose 10% or 50% in the treatment of hypoglycaemia out of hospital? A randomised controlled trial.
Moore C, Woollard M.
Emerg Med J. 2005 Jul;22(7):512-5.
PMID: 15983093 [PubMed – indexed for MEDLINE]

Free Full Text from PubMed Central

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[5] A review of the efficacy of 10% dextrose as an alternative to high concentration glucose in the treatment of out-of-hospital hypoglycaemia
Ziad Nehme, Daniel Cudini
2009; Volume 7 : Issue 3; Article Number: 990341
Journal of Emergency Primary Health Care
Free Full Text with link to PDF Download

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[6] Sedgwick County EMS warns of national drug shortages
By Deb Gruver
The Wichita Eagle
Published Tuesday, May 14, 2013, at 8:41 p.m
Article

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Filed Under: Dextrose, Drug Shortages, FDA, Heresy, Risk Management

Bad Pharma – Can we trust drug companies to provide accurate information about their products? Part III

Sat, 02 Mar 2013 22:45:30 -0500 by
 

 

We have a problem with the way drug companies do business. Dr. Ben Goldacre regularly criticizes the misbehavior and nonsensical claims of alternative medicine and other bad science at his blog Bad Science and in his book Bad Science. He included some criticism of the misbehavior of drug companies, as well. Now he has written a book that is more specifically critical of the drug companies – Bad Pharma.

The whining by the representatives of the drug companies is just as ludicrous as that of the placebo pushers of alternative medicine. In Forbes, John LaMattina writes that a two page section of a 449 page book misrepresents the pharmaceutical industry.
 

I agree that one of the big challenges that the industry faces is the need to be more transparent about its work and I have written about this both on this blog and in Devalued & Distrusted. However, Goldacre’s cherry-picking of data to fit his arguments is inappropriate and infuriating to those who know something about the pharmaceutical industry.[1]

 

If Goldacre’s cherry-picking of data to fit his arguments is inappropriate, is LaMattina’s cherry-picking of only a portion of two pages of a 449 page book appropriate?

The pharmaceutical industry has been getting better at reporting trials, but the improvements are in things that they should have been doing all along.

A sensationalistic way of presenting this might be to ask if a serial killer cutting back on killing is a good person, because he is working at getting better.

Yes, the drug companies do make drugs that sometimes kill, but they are not the same as serial killers, since they make drugs that do a lot of good, too.

One of the reasons people are harmed by medications is that they do not have full information about the effects of the medications. An important part of this is selective publishing. Dr. Goldacre does not need to use this example to make a case that drug companies engage in selective publishing. There is plenty of evidence that drug companies .
 

The authors have been unable to obtain the full set of clinical study reports or obtain verification of data from the manufacturer of oseltamivir (Roche) despite five requests between June 2010 and February 2011. No substantial comments were made by Roche on the protocol of our Cochrane Review which has been publicly available since December 2010.[2]

 

Is this a surprise?

No.

Is Dr. Goldacre misrepresenting the misbehavior of drug companies?

No.
 

We expect full clinical study reports containing study protocol, reporting analysis plan, statistical analysis plan and individual patient data to clarify outstanding issues. These full clinical study reports are at present unavailable to us.[2]

 

Listen to Dr. Goldacre discussing the book and the ways it is misrepresented by the media and the drug companies.[3]

Maybe Dr. Goldacre’s next book should have a specific focus on alternative medicine – Bad Placebo.

It is disappointing that we are so interested in taking something – anything new, but not interested in knowing if any of these new drugs are safe or if the drugs do what they are supposed to do – help people heal.
 

The desire to take medicine is perhaps the greatest feature which distinguishes man from animals. – William Osler.
 

If we point out the imperfections in medicine, in order to try to improve medicine, we end up being criticized as being opposed to medicine . This is idiotic.

There is a lot of room for medicine to improve, but ignoring the problems is very bad medicine.
 


 
http://www.alltrials.net/
An initiative of Bad Science, Sense About Science, BMJ, James Lind Initiative and Centre for Evidence-based Medicine.

There is still a long way to go.

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Footnotes:

–

[1] Bad Pharma? Maybe. But Goldacre’s Selective Use of Data Is Wrong
2/14/2013 @ 8:20AM
John LaMattina
Forbes
Article

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[2] Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children.
Jefferson T, Jones MA, Doshi P, Del Mar CB, Heneghan CJ, Hama R, Thompson MJ.
Cochrane Database Syst Rev. 2012 Jan 18;1:CD008965. doi: 10.1002/14651858.CD008965.pub3. Review.
PMID: 22258996 [PubMed – indexed for MEDLINE]

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[3] #201 Bad Pharma
February 22, 2013
Skeptically Speaking
Podcast page.

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Filed Under: Ethics, FDA, Heresy, Pharmacology

Methodology of tPA Studies – Comment from Joshua

Wed, 30 Jan 2013 08:00:00 -0500 by
 

In response to my criticism of the ACEP (American College of Emergency Physicians) polict statement on Genentech’s r-tPA (recombinant tissue Plasminogen Activator) – alteplase (Activase®),[1] Joshua responded with these comments on what I cited/quoted. I think this is a first for me. –
 

First of all, IST-3 is a very large trial, involving more than 3000 subjects. Nortin Hadler, in his book Rethinking Aging, wisely suggests that whenever a very large trial is required to show statistical benefit, it means that the purported benefit cannot be clinically important.19 [2]

I disagree. When we are unable isolate a single variable (in this case administration of tPA) a large scale study may be the only way to identify outcomes attributable to the intervention (good or bad). The further from treatment to identifiable outcome and the more variables that can’t be (or simply are not) accounted for the larger the sample size should be.

 

There are several reasons I did not use that quote. I would have used an earlier book[3] as the source of that idea.

You do raise an important point. If few variables have been controlled for, are we measuring what we think we are measuring?

You appear to be making one of the same arguments that Dr. Lyden made. That enough data makes the flawed methods irrelevant.

I do not agree with that.

Dr. Lyden wrote –
 

The study leadership invoke a concept known as “large simple” trials, meaning trials that seek power by simplifying protocols and reducing data collection to a bare minimum in hopes of enhanced recruitment. Large simple trials may be an answer to the continuing difficulty getting clinical trials finished on budget and in time.[4]

 

And –
 

When reorganized, the trial became an unblinded trial with a design that sounds rigorous: “prospective, randomized, open, blinded end point” (PROBE). The investigators have written that their end point is blinded because a centralized researcher, unaware of the patient’s treatment group, contacts the patient or family member 6 months after stroke and attempts to derive a modified Rankin Scale from a questionnaire or telephone call.[4]

 

While this does make things more simple, it does not appear to be capable of producing blinded data, but it may blind some people to the fatal flaws of the study methods.
 

If we have only one variable that is the same among thousands of patients, then we might draw some conclusions, but only tentatively. There could easily be other variables which are not universally present and are not being controlled for, yet may have much greater influence on the outcomes. We would not know what is being measured.

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There’s a lot more that goes into the treatment of stroke patient than just whether or not they received fibrinolytic therapy. How many patients received rehabilitative care? How many were treated for hypertension and if so with what? How was patient weight calculated with an administration dose that’s weight dependent? If you only have 100 patients 1 or 2 nurses screwing up their drug calculations (of course that never happens and it ALWAYS gets reported ;-)) is a difference of 1-2% when evaluating final outcomes. What about 10 patients receiving anti hypertensive therapy in a sample size of 100? If 8 out of those ten patients have a negative outcome what’s to say that the combination of therapies and not TPA itself is responsible for this 8% increase in patients with increased neurological deficit at the 90 day mark? The larger the sample size the more you can negate the weight of these variables. While it’s not unreasonable to assume that 1 or 2 nurses may inadvertently administer an incorrect dose assuming that 100-200 nurses in a sample size of 1000 would do the same would suggest that tPA is the last thing we should be worried about when evaluating our patient’s outcomes.

 

The variability in competence and variability in methods are some of the problems that become more difficult to address in larger studies, but they may reflect the diversity in treatment that exists across the country, or around the world.
 

The substantial increased rate of symptomatic intracerebral hemorrhage among tPA-treated patients has tempered enthusiasm for the rapid adoption of tPA as routine care, in part because of the concern that treatment may be less safe in routine clinical practice than in the highly monitored setting of a clinical trial.[5]

 

This raises a serious problem.

In theory, there is no difference between theory and practice. But in practice, there is.
― Yogi Berra

If tPA works tolerably only during studies, but does a lot damage in use outside of controlled studies, is tPA too dangerous to use outside of controlled trials?

–
 

Three out of eight guideline writers directly involved with the pharmaceutical manufacturer. As far as indirect support, however, if they wanted to be more transparent, Dr. Edlow, Dr. Jagoda, Dr. Stead, Dr. Wears, and Dr. Decker also ought to have disclosed their association with the Foundation for Education and Research in Neurologic Emergencies – supported by multitudinous pharmaceutical manufacturers, including Genentech.

If you’re irritated that pharmaceutical manufacturers are helping write our clinical guidelines, make your voice heard.[3] [6]

Why are we suprised that pharmacuetical manufacturers are helping write our clinical guidelines?
(http://www.manhattan-institute.org/html/fda_05.htm)(http://www.sciencebasedmedicine.org/index.php/what-does-a-new-drug-cost/ <– read both parts)

It takes a lot of money to conduct phase 2 and 3 drug trials, though as the second article points out the actual cost is probably significantly skewed intentionally. But even at a conservate estimate of $43.4 million that's a lot of money to be gambling. So it's no wonder that they want the best chance at a possible outcome and hire people to make it happen.

 

Genentech should not have any control over who writes policy statements.

It is not a surprise that a drug company would attempt to influence policy statements, but it should not be so easy for any drug company to succeed.
 

–
 

More so than full financial disclosure (because given the cost there's only one entity that can afford it so it's usually safe to assume who's paying to make it happen) I'd like to see a better explanation of how patients are treated in their entirety. Give me ALL the data and not just what you want me to see or what magical mathematical formula you think justifies what you've written in your abstract and let me be the one to interpret it. It's kind of like EPI in cardiac arrest. We may find that the drug is not beneficial for everyone but should instead be reserved for a particular subset of patients.

 

The quality of the research that is published does leave a lot to be desired. How much would it cost to add an on-line data file supplement, or several file supplements, of the raw data to the paper?

Not much.

How much do some of the researchers want to hide this information?

Probably very much.

Along with requiring registering the study with ClinicalTrials.gov, this is something that should be simple to achieve high compliance on. The reality is only about half of trials were registered prior to enrolling patients.[7] Improvements in research quality take time, even though they seem as if they should be no-brainers.

One of the big problems with NINDS was the refusal of the NINDS investigators to release the raw data.[8],[9]

The biggest problem may be the expectation that we will successfully develop drugs in laboratories, when this is not the way we have historically come up with useful drugs.

We would like a drug better than warfarin (Coumadin), but the designer drugs do not seem to be better. The designer anti-clotting drugs only seem to improve surrogate endpoints over warfarin, but we spend a lot on them and that may increase dramatically.

A lot of patients studied, but no important difference in outcomes. Sometimes, when a very large trial is required to show statistical benefit, it means that the purported benefit cannot be is not clinically important.
 

Image credit.

Where is Waldo?

Is Waldo’s location clinically significant?

Click on the image to make the image larger, but making it larger won’t make Waldo any more clinically significant. 😉

There he is.
 

Image credit.
 

“Spinal immobilization” is one area where the results will require huge numbers, the number of affected patients will be tiny, but the importance of the outcomes will be very important clinically.

The sad thing is that so many people do not want to know how much harm we may be causing or if we could improve care.

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Footnotes:

–

[1] Can we trust drug companies to provide accurate information about their products? Part II
Mon, 28 Jan 2013
Rogue Medic
Article

–

[2] How is more negative evidence being used to support claims of benefit: The curious case of the third international stroke trial (IST-3).
Hoffman JR, Cooper RJ.
Emerg Med Australas. 2012 Oct;24(5):473-6. doi: 10.1111/j.1742-6723.2012.01604.x. No abstract available.
PMID: 23039286 [PubMed – in process]

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[3] Fiction And Fantasy In Medical Research: The large scale randomised trial
By James Penston
Published by London Press, 2003
ISBN 0954463617, 9780954463618
144 pages
GoogleBooks link

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[4] In anticipation of International Stroke Trial-3 (IST-3).
Lyden PD.
Stroke. 2012 Jun;43(6):1691-4. Epub 2012 May 3. No abstract available.
PMID: 22556196 [PubMed – indexed for MEDLINE]

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[5] Clinical Policy: Use of Intravenous tPA for the Management of Acute Ischemic Stroke in the Emergency Department.
This clinical policy is the result of a collaborative project of the American College of Emergency Physicians and the American Academy of Neurology.
Ann Emerg Med. 2013 Feb;61(2):225-43. doi: 10.1016/j.annemergmed.2012.11.005. No abstract available.
PMID: 23331647 [PubMed – in process]

Free Full Text Download in PDF format from Elsevier.

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[6] New ACEP tPA Clinical Policy
Wednesday, January 23, 2013
EM Literature of Note
Article

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[7] Characteristics of clinical trials registered in ClinicalTrials.gov, 2007-2010.
Califf RM, Zarin DA, Kramer JM, Sherman RE, Aberle LH, Tasneem A.
JAMA. 2012 May 2;307(17):1838-47. doi: 10.1001/jama.2012.3424.
PMID: 22550198 [PubMed – indexed for MEDLINE]

Free Full Text from JAMA.

The proportion of trials registered before beginning participant enrollment increased over the 2 time periods: from 33% (9041/27 667) in October 2004–September 2007 to 48% (19 347/40 333) in October 2007–September 2010.

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[8] Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group.
[No authors listed]
N Engl J Med. 1995 Dec 14;333(24):1581-7.
PMID: 7477192 [PubMed – indexed for MEDLINE]

Free Full Text from New England Journal of Medicine.

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[9] The raw data of the NINDS trial should be made public
Dr. Jeffrey Mann
BMJ
Rapid response letter

Unfortunately, it has been years since Dr. Mann discontinued his EM Guidemaps site, where he posted the raw data that the NINDS investigators finally sent him in 2003, and I no longer have a copy of what he posted.

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Filed Under: Ethics, FDA, Heresy, Pharmacology, Research, tPA

Can we trust drug companies to provide accurate information about their products? Part II

Mon, 28 Jan 2013 08:00:23 -0500 by
 

I am continuing to look at the problems with drug companies promoting drugs for uses that have not been approved by the FDA (Food and Drug Administration.The Second Circuit Court panel’s ruling allows drug company representatives to discuss/promote off-label use of their drugs.[1] A friend sent an email including the following –
 

This has nothing to do with the discussion of off-label uses in other forums. It has to to with making sure that drug representatives, with huge financial interest in the sale of their drug, both personal and institutional, cannot just make $#!+ up to sell their drug.

 

Unfortunately, the drug companies can just make $#!+ up to sell their drug. Even with drugs used as approved by the FDA.

Look at Genentech’s r-tPA (recombinant tissue Plasminogen Activator) – alteplase (Activase®).
 

Note: Within any time window, once the decision is made to administer IV tPA, the patient should be treated as rapidly as possible. As of this writing, tPA for acute ischemic stroke in the 3- to 4.5-hour window is not FDA approved.[2]

 

Who needs to get their drug reps to encourage the off-label use of a drug, when they can get doctors funded by drug companies to write practice guidelines that recommend off-label use?
 

Does the research support aggressive use for suspected acute ischemic stroke?

A. Within 90 minutes of symptom onset.

B. Within 180 minutes of symptom onset.

C. Within 270 minutes of symptom onset.

D. Within 360 minutes of symptom onset.

E. As long as we massage the data, we can give a fibrinolytic to whomever we want whenever we want.
 

Image credit.
 

ACEP (American College of Emergency Physicians) just had a policy statement on tPA for acute ischemic stroke written by a bunch of doctors who receive money from the drug companies affected by policy statement.

How much attention was paid to the criticism of the fatal flaws of some of these studies?

Little to none, based on the citations.

Only one paper by Dr. Jerome Hoffman is cited. Nothing by Dr. Jeff Mann is cited.

Dr. Mann’s papers –
 

Truths about the NINDS study: setting the record straight.
Mann J.
West J Med. 2002 May;176(3):192-4. No abstract available.
PMID: 12016245 [PubMed – indexed for MEDLINE]
 

tPA for acute stroke: balancing baseline imbalances.
Mann J.
CMAJ. 2002 Jun 25;166(13):1651-2; author reply 1652-3. No abstract available.
PMID: 12126317 [PubMed – indexed for MEDLINE]
 

NINDS Reanalysis Committee’s reanalysis of the NINDS trial.
Mann J.
Stroke. 2005 Feb;36(2):230-1; author reply 230-1. Epub 2005 Jan 6. No abstract available.
PMID: 15637327 [PubMed – indexed for MEDLINE]
 

Sex-based differences in response to recombinant tissue plasminogen activator in acute ischemic stroke.
Mann J.
Stroke. 2005 May;36(5):929; author reply 929. No abstract available.
PMID: 15867164 [PubMed – indexed for MEDLINE]
 

Emergency physician survey: recombinant tissue plasminogen activator for stroke.
Mann J.
Ann Emerg Med. 2006 Oct;48(4):476; author reply 477. No abstract available.
PMID: 16997689 [PubMed – indexed for MEDLINE]
 
 

Dr. Hoffman’s papers –
 

Predicted impact of intravenous thrombolysis. Another trial is needed.
Hoffman JR.
BMJ. 2000 Apr 8;320(7240):1007. No abstract available.
PMID: 10809554 [PubMed – indexed for MEDLINE]
 

Should physicians give tPA to patients with acute ischemic stroke? Against: and just what is the emperor of stroke wearing?
Hoffman JR.
West J Med. 2000 Sep;173(3):149-50. No abstract available.
PMID: 10986160 [PubMed – indexed for MEDLINE]
 

Thrombolytic therapy for acute ischemic stroke – Tissue plasminogen activator for acute ischemic stroke: Is the CAEP Position Statement too negative?
Hoffman JR.
CJEM. 2001 Jul;3(3):183-5. No abstract available.
PMID: 17610781 [PubMed]
 

Annals supplement on the American Heart Association proceedings.
Hoffman JR.
Ann Emerg Med. 2001 Nov;38(5):605. No abstract available.
PMID: 11679880 [PubMed – indexed for MEDLINE]
 

Alteplase for stroke. Why were these authors of the commentaries chosen?
Hoffman JR.
BMJ. 2002 Jun 29;324(7353):1581; author reply 1581. No abstract available.
PMID: 12092608 [PubMed – indexed for MEDLINE]
 

Tissue plasminogen activator (tPA) for acute ischaemic stroke: why so much has been made of so little.
Hoffman JR.
Med J Aust. 2003 Oct 6;179(7):333-4. No abstract available.
PMID: 14503891 [PubMed – indexed for MEDLINE]
 

Stroke thrombolysis: we need new data, not more reviews.
Hoffman JR, Cooper RJ.
Lancet Neurol. 2005 Apr;4(4):204-5. No abstract available.
PMID: 15778096 [PubMed – indexed for MEDLINE]
 

Thrombolysis for stroke: policy should be based on science, and not on politics, money or fear of malpractice.
Hoffman JR.
Emerg Med Australas. 2006 Jun;18(3):215-8. No abstract available.
PMID: 16712529 [PubMed – indexed for MEDLINE]
 

A graphic reanalysis of the NINDS Trial.
Hoffman JR, Schriger DL.
Ann Emerg Med. 2009 Sep;54(3):329-36, 336.e1-35. doi: 10.1016/j.annemergmed.2009.03.019. Epub 2009 May 23.
PMID: 19464756 [PubMed – indexed for MEDLINE]

RESULTS:
Final outcomes were highly dependent on stroke severity. In many graphs, the small difference between groups favored tissue plasminogen activator, particularly when baseline NIHSS score was between roughly 5 and 22. These differences diminish or disappear when 90-day change in NIHSS is graphed. Our graphs fail to support the time-is-brain hypothesis.

^ This is the only paper by Dr. Hoffman that is cited.
 

How is more negative evidence being used to support claims of benefit: The curious case of the third international stroke trial (IST-3).
Hoffman JR, Cooper RJ.
Emerg Med Australas. 2012 Oct;24(5):473-6. doi: 10.1111/j.1742-6723.2012.01604.x. No abstract available.
PMID: 23039286 [PubMed – in process]

The author of this commentary – and by extension the editors of Stroke who approved it – ultimately concludes that despite its many flaws, there is much to learn from IST-3.2 We agree . . . although given that the actual results of IST-3 uniformly failed to show benefit, even in the face of severe bias, we believe the lessons are precisely the opposite of those being trumpeted by the study’s own authors.1

 

the actual results of IST-3 uniformly failed to show benefit, even in the face of severe bias,

That is the problem. Bias.

When examining treatments where people can honestly come to opposite conclusions about the efficacy of a treatment, we do need to consider the effect of bias on the part of those who strongly endorse treatments based on such ambiguous evidence.

Is it also possible that there is bias on the part of those critical of the treatment? Absolutely, but . . .
 

Our bias should be toward intervening only when we have good evidence that our treatments will help.
 

Our bias should be toward not doing harm. Ignorance of the effects of our treatments is not a valid excuse for pushing a treatment.

Treatment for the sake of treatment benefits the person pushing the treatment – and only up until there is inescapable proof that the treatment is harmful.

That is the way medicine develops. We give treatments, based on wishful thinking and inadequate evidence. We find out that the treatments are more harmful than we thought. We abandon those dangerous treatments and make excuses for the harm.

Then we discourage recommend other treatments without good evidence – as if optimism is adequate justification for harming patients.
 

Since the papers I listed are not original research, but analysis of existing research, should the papers be excluded from this review?

Absolutely not.

Negative commentary is essential for pointing out the dangers of treatments.

When we are aggressive with any treatment, we need to be even more familiar with the dangers than the potential benefits.

–

Look at some of the rationalization employed to explain away the diversity of results. Diversity can be just the random variation of an ineffective treatment.
 

Compared with the ECASS III tPA-treated arm, the proportion with good outcome was somewhat lower and the proportion with mortality was somewhat higher, probably because patients in the SITS-ISTR registry had higher initial stroke severity and more medical comorbidities than the patients enrolled in the ECASS III trial.[2]

 

Probably?

If we begin with the bias that tPA is beneficial, that does make sense, but these are experienced researchers who should realize that it is critically important to minimize the influence of bias.

All of these authors receive money from the drug companies that will benefit from these guidelines. While money is not the only bias we should be concerned about, it should be fully disclosed and was not in this paper. Dr. Ryan Radecki wrote about this –
 

Three out of eight guideline writers directly involved with the pharmaceutical manufacturer. As far as indirect support, however, if they wanted to be more transparent, Dr. Edlow, Dr. Jagoda, Dr. Stead, Dr. Wears, and Dr. Decker also ought to have disclosed their association with the Foundation for Education and Research in Neurologic Emergencies – supported by multitudinous pharmaceutical manufacturers, including Genentech.

If you’re irritated that pharmaceutical manufacturers are helping write our clinical guidelines, make your voice heard.[3]

 

Being FDA approved is not the criterion for what is a good treatment. I probably write more criticizing FDA approved uses of drugs, than criticizing off-label uses of drugs.

–

Footnotes:

–

[1] Advertising unapproved uses of drugs is free speech, which is what the FDA has been trying to say
Wed, 05 Dec 2012
Rogue Medic
Article

–

[2] Clinical Policy: Use of Intravenous tPA for the Management of Acute Ischemic Stroke in the Emergency Department.
This clinical policy is the result of a collaborative project of the American College of Emergency Physicians and the American Academy of Neurology.
Ann Emerg Med. 2013 Feb;61(2):225-43. doi: 10.1016/j.annemergmed.2012.11.005. No abstract available.
PMID: 23331647 [PubMed – in process]

Free Full Text Download in PDF format from Elsevier.

–

[3] New ACEP tPA Clinical Policy
Wednesday, January 23, 2013
EM Literature of Note
Article

.

Filed Under: Ethics, FDA, Heresy, Pharmacology, tPA

Can we trust drug companies to provide accurate information about their products? Part I

Sun, 09 Dec 2012 08:00:32 -0500 by
 

A friend sent the following email in response to what I wrote about the Circuit Court panel’s ruling allowing drug company representatives to discuss/promote off-label use of their drugs.[1] This is going to be in several parts, because there are many factors to consider. We probably agree on almost all of them, but we disagree on the right way to handle them.
 

This ruling on off-label promotion is actually potentially harmful to rational marketing and promotion of drugs, and many of us see it as a really bad ruling.

 

Everything is potentially harmful. What we need are better regulations. Not less. Not more. Better.

If this encourages fraud, that helps the drug companies and the tort lawyers, not patients.

This should stimulate some important discussion of how we learn about drugs (and medical devices).

Does this ruling make fraud more legal?
 

This has nothing to do with the discussion of off-label uses in other forums. It has to to with making sure that drug representatives, with huge financial interest in the sale of their drug, both personal and institutional, cannot just make $#!+ up to sell their drug.

 

Does this permit anyone to make false claims?

No.

Does this permit anyone to make misleading claims?

That is going to be the difficult part to prevent.

What is misleading?
 

Epinephrine (Adrenaline) is promoted in many misleading ways for cardiac arrest, even though the people recommending the use of epinephrine are not making any money off of epinephrine and do not appear to be trying to deceive. There is no evidence of better outcomes with epinephrine.[2]

Epinephrine has been shown to get more pulses back, but a lot more patients die in the hospital, or on the way to the hospital.

Is a few hours, or days, intubated and in a coma, with no awareness of anything, but discharged to the morgue, a good outcome?

I do not know of any evidence demonstrating any appropriate use of epinephrine in cardiac arrest.
 

Kayexalate is just as routine for hyperkalemia as epinephrine is for cardiac arrest. As with epinephrine, there is no valid evidence of improved outcomes with Kayexalate.[3] When I mentioned that Kayexalate does not work (at one of the top university hospitals in the world), I was told – We’ve seen it work.

We don’t need drug companies to deceive us. We lie to ourselves, when we say – We’ve seen it work.
 

Much of the same can be said for alternative medicine. Some of the pushers of alternative medicine believe their hocus pokus works. Valid evidence to support their claims does not exist. Therefore the FDA (Food and Drug Administration) does not permit alternative medicine pushers to make medical claims because they are not medicines.

Joe Mercola is perhaps the biggest alternative medicine pusher, who has repeatedly violated the law, but continues to be allowed to sell his snake oil.[4],[5],[6]

Maybe he believes in the nonsense he is making millions of dollars selling to the unsuspecting public.

If he has fooled himself, does that make his products in any way beneficial or make them any less dangerous?

Of course not.

He cannot peddle his snake oil as medicine. He has to use the Quack Miranda Warning –
 

“These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.”[7]

 

This is the Required to Stay Out Of Jail warning used by frauds to convince a jury that their claims should not be taken seriously by any intelligent individual.

But scam artists convince us to ignore our intelligence and to trust them.
 


 

A lot of people still fall for these scams. Maybe they believe Dr. Mercola when he claims that there is some grand conspiracy by doctors, governments, and drug companies to silence him. Bernie Madoff probably made the same claims about his scams.[8]

The reasoning appears to be that there are examples of fraud by the drug companies, therefore anything else must be better. Choosing the complete fraud of alternative medicine over the occasional fraud of drug companies is a mistake.

Yes, the drug companies do a lot of bad things, but the way to stop that is to expose the misbehavior, not to prevent the drug companies from discussing off-label use of their drugs.

These laws are weak.

These laws prevent only some people (drug representatives) from providing this information.

These laws assume that doctors do not get their information from anywhere else.

Yes, there are plenty of gullible doctors, who will blindly accept what the drug representatives tell them.

I do not see these laws making the gullible doctors less gullible, or less dangerous.

We don’t need drug companies to deceive us. We lie to ourselves, when we say – We’ve seen it work.

The problem is that too many of us do not understand how to tell the difference between dangerous wishful thinking and medicine that really works.

To be continued in Part II.

–

Footnotes:

–

[1] Advertising unapproved uses of drugs is free speech, which is what the FDA has been trying to say
Rogue Medic
Wed, 5 Dec 2012
Article

–

[2] What is Evidence-Based Medicine?
Rogue Medic
Tue, 06 Nov 2012
Article

–

[3] Bonus – Is Kayexalate Useless?
by EMCRIT
March 22, 2011
Podcast page

–

[4] FDA Warning Letter to Dr. Mercola
February 16, 2005
Ref. No. CL-04-HFS-810-134
FDA
Warning letter download in PDF format from FDA

Plain text version of this warning letter at Casewatch.org

–

[5] FDA Warning Letter to Dr. Mercola
September 21, 2006
CHI-7-06
FDA
Warning letter in plain text from FDA

Plain text version of this warning letter at Casewatch.org

–

[6] FDA Warning Letter to Dr. Mercola
March 22, 2011
Meditherm Inc. 3/22/11
FDA
Warning letter in plain text from FDA

Plain text version of this warning letter at Casewatch.org

–

[7] Quack Miranda Warning
PalMD
White Coat Underground
Article

–

[8] Bernard Madoff
Wikipedia
Article

.

Filed Under: 'Alternative' Medicine, Ethics, FDA, Heresy, Pharmacology

Advertising unapproved uses of drugs is free speech, which is what the FDA has been trying to say

Wed, 05 Dec 2012 10:00:15 -0500 by
 

Off-label drug use is very common.

This is a ruling a ruling that only affects New York, Connecticut, and Vermont,[1] but may be reviewed by the full Second Circuit Court and by the Supreme Court. That won’t stop it from having an effect nationally. What power does the FDA (Food and Drug Administration) have to regulate what drug representatives may say about uses of drugs that are not FDA approved uses, but are completely legal uses for the doctors they are talking to?

The FDA rules do prohibit drug representatives from discussing uses of drugs that are not FDA approved.

The FDA rules do not doctors from prescribing drugs for uses that are not FDA approved.

This is off-label drug use.

The NAEMSP (National Association of EMS Physicians) has a position paper on off-label drug use.
 

If EMS medical directors use a product for an indication not in the approved or cleared labeling, they have the responsibility to be well informed about the product, to base its use on firm scientific rationale and on sound medical evidence, and to maintain awareness of the product’s use and effects[2]

 

This should be true for any medical treatment.

The most important part of the article on the ruling is this quote –
 

Gerald Masoudi, a former chief counsel of the F.D.A., said the ruling made a distinction between truthful discussion of off-label uses of drugs, many of which are considered legitimate by the medical community, and those that are misleading or false. He noted that “anyone on the planet” could discuss off-label uses of drugs, except for pharmaceutical companies.

“It’s very significant,” he said, “because it’s going to make F.D.A., in its promotion cases, focus on the kinds of speech that are more likely to harm consumers, such as false or misleading marketing versus something that is not approved.”[3]

 

Will that be the case?

That is the way it should work, but the politics of regulation may not be ready for such a reasonable approach.

The FDA should focus on whether the communication is honest and complete, rather than whether taboo topics are mentioned.

 

Then there are the several different flavors of off-label.

1. The label does not mention the particular use, or dose, or population as being approved. Intranasal and intraosseous medication administration are just some of the reasons that EMS drug use can be off-label drug use.

2. The label mentions the use, but points out problems with the use. Haloperidol given intravenously, or in larger doses, is an example.[4]

3. The label has a black box warning. Droperidol is an example.[5]

There are FDA approved drugs that have the same problems, but without the formal warnings. According to the small print of the FDA label, amiodarone has greater problems with QT prolongation and torsades than haloperidol or droperidol, but there is no warning.[6]

While amiodarone does not have any of these warnings, the documented rates of QT prolongation and torsades appear to be greater with amiodarone than with droperidol. Droperidol receives the kiss of death, while amiodarone receives recommendations from the AHA (American Heart Association).[7]

In what way does such an inconsistent approach benefit patients?

Off-label use has also led to many problems, but that is more than can be covered today.
 

Image credit.[8]
 

This decision has not yet been covered on The Volokh Conspiracy, which can be expected to provide excellent insight to the way the law works and what decisions mean for everyone else.

–

Footnotes:

–

[1] United States Court of Appeals
Wikipedia
Article

–

[2] Off-Label Use of Medical Products
NAEMSP Position Statement
Position Statement in PDF format at NAEMSP.org

–

[3] Ruling Is Victory for Drug Companies in Promoting Medicine for Other Uses
By Katie Thomas
Published: December 3, 2012
NY Times
Article

–

[4] Information for Healthcare Professionals: Haloperidol (marketed as Haldol, Haldol Decanoate and Haldol Lactate)
Postmarket Drug Safety Information for Patients and Providers
Page Last Updated: 09/29/2009
FDA letter

There is a black box warning for haloperidol, but there is no mention of this in the black box warning. This is mentioned elsewhere in all capital letters.

FDA ALERT [9/2007]: This Alert highlights revisions to the labeling for haloperidol (marketed as Haldol, Haldol Decanoate and Haldol Lactate). The updated labeling includes WARNINGS stating that Torsades de Pointes and QT prolongation have been observed in patients receiving haloperidol, especially when the drug is administered intravenously or in higher doses than recommended. Haloperidol is not approved for intravenous use.

–

[5] DROPERIDOL injection, solution
[Hospira, Inc.]
DailyMed
FDA label

Here is the first paragraph of the black box warning on the label.

WARNING
Cases of QT prolongation and/or torsade de pointes have been reported in patients receiving droperidol at doses at or below recommended doses. Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal.

–

[6] AMIODARONE HYDROCHLORIDE injection, solution
[Hospira, Inc.]
DailyMed
FDA label

–

[7] Where are the Black Box Warnings on These Drugs – II
Rogue Medic
Sun, 11 Dec 2011
Article

–

[8] Boost for Off-Label Drug Use – FDA Would Let Firms Keep Doctors Informed On Unapproved Methods
By Anna Wilde Mathews and Avery Johnson
Wall Street Journal
Article

.

Filed Under: Critical Judgment, FDA, Heresy, Legal Medicine, Pharmacology
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