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

- Rogue Medic

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


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]

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]



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.


[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

[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



  1. “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.”

    I disagree. When you’re 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’s a lot more that goes into the treatment of stroke patient than just whether or not they recieved fibrinolytic therapy. How many patients received rehabiliatative care? How many were treated for hypertension and if so with what? How was patient weight calculated with an adminstration 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.

    “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]”

    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.

    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.