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Editorials |

A Hemorrhage of Off-Label Use FREE

Jerry Avorn, MD; and Aaron Kesselheim, MD, JD, MPH
[+] Article and Author Information

From Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02120.


Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-0550.

Requests for Single Reprints: Jerry Avorn, MD, Brigham and Women's Hospital, Division of Pharmacoepidemiology and Pharmacoeconomics, 1620 Tremont Street, Suite 3030, Boston, MA 02120; e-mail, javorn@medsoc.harvard.edu.

Current Author Addresses: Drs. Avorn and Kesselheim: Brigham and Women's Hospital, Division of Pharmacoepidemiology and Pharmacoeconomics, 1620 Tremont Street, Suite 3030, Boston, MA 02120.


Ann Intern Med. 2011;154(8):566-567. doi:10.7326/0003-4819-154-8-201104190-00010
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For 2 millennia, medicine was guided by the principles of logic. One discerned the cause of a given condition and then applied a treatment that would be expected to correct the underlying disease process. As long as the cause, pathophysiology, and therapeutic mechanism all made sense, it was not thought necessary to look too hard at how well anything worked. This internally consistent approach to health care gave us purgatives, bleeding, mutilative surgeries, and a host of herbal and pharmaceutical treatments that fit perfectly with prevailing views of disease etiology. However, most therapies were ineffective, caused serious side effects, or both. The emergence of modern medicine from its dark ages began in earnest in the middle of the 20th century, when we began to subject treatments to randomized, controlled trials to find out whether they actually did any good. A large proportion did not (1). In 1962, the U.S. Food and Drug Administration (FDA) was first given authority to require the radical criterion of trial-documented efficacy before a drug could be granted marketing approval (2).

Armed with this powerful intellectual tool, medicine has made impressive headway in the past 50 years in separating the therapeutic wheat from the chaff of quackery. Countless lives were saved because we got better at distinguishing treatments that worked from those that did not or that harmed patients (3). New laws and policies backed the scientific superiority of the randomized, controlled trial with regulatory clout that made it the law of the land, at least for drug approval. Yet other factors weighed against this movement. First, physicians crave autonomy, as evidenced by the sometimes slow uptake of recommendations from those trials about what we should and should not do (4). Second, pharmaceutical manufacturers found that substantial profits could be made by selling their products to a population much larger than the limited group of patients for whom high-quality and FDA-reviewed efficacy data actually exist. Off-label marketing campaigns flourished in the 1990s and early 2000s, with several companies promoting drugs for uses for which there was neither FDA approval nor credible evidence of efficacy (5).

Of course, a drug may have reasonable evidence supporting its use in particular clinical situations even if the FDA has not defined these as approved indications, perhaps because a manufacturer has not formally applied for that designation. For example, propranolol was initially approved for tachyarrhythmias, and its use as an antihypertensive and antianginal agent was at first “off-label.” At present, rosuvastatin (Crestor, AstraZeneca, Wilmington, Delaware) is the only statin that is approved by the FDA for some patients with high C-reactive protein and normal low-density lipoprotein cholesterol levels, although many researchers in this area believe that other statins may have similar efficacy for this purpose. Thus, off-label prescribing can run the gamut from adequately data-driven to truly implausible and potentially harmful. The latter case is illustrated by gabapentin (Neurontin, Pfizer, New York, New York), whose manufacturer agreed in 2004 to pay the government $430 million to settle charges of improper off-label marketing. Its promotional campaigns had been so successful that by 2004, an estimated 90% of Neurontin sales were for off-label uses (6), including many indications with little convincing evidence of efficacy. A recent review of off-label prescribing among office-based physicians found that a sobering 73% of off-label prescribing had little or no scientific support (7).

This brings us to the case of recombinant factor VIIa (rFVIIa) (NovoSeven, Novo Nordisk, Bagsværd, Denmark), the recombinant procoagulant originally approved in 1999 solely for the management of patients with hemophilia, especially those who had developed inhibitors to factor VIII. However, not many persons have hemophilia and even fewer have inhibitors to factor VIII; in fact, there is so little hemophilia in the marketplace that rFVIIa was approved as an orphan drug under a legislative program designed to incentivize drug development for patients with rare diseases. That law provides manufacturers with numerous financial benefits, including tax breaks for research and 7 years of guaranteed market exclusivity after approval.

However, in this issue, Logan and colleagues (8) show that use of rFVIIa in hospitalized patients without hemophilia grew more than 140-fold from 2000 to 2008 (8). By the end of that period, its approved indication for hemophilia comprised only 3% of its in-hospital use, with 97% of its use for off-label indications, including cardiovascular surgery, trauma, intracerebral hemorrhage, and other purposes. One explanation may derive from the understandable desire of surgeons and neurologists to protect their patients from excessive bleeding, and such use has the Galenic justification of appearing logical on its face: “The patient is bleeding! Administer a procoagulant!”

It is not yet clear whether improper promotion of the product contributed to this rapid expansion of use. The manufacturer has denied such practices (9), although it is under investigation by the U.S. Department of Defense (10), which was reported to be looking into “financial arrangements between the [army] and Novo Nordisk” related to use of NovoSeven in overseas combat operations (11). There is reason to wonder how the use of an obscure recombinant coagulation factor marketed exclusively to hematologists came to be used so widely by cardiac surgeons, neurologists, and trauma specialists. Further investigation may cast additional light on this question (12).

Is such off-label use nonetheless warranted by solid trial evidence? Yank and coworkers (13) address this topic in this issue. In this study, investigators systematically reviewed the literature on the efficacy and safety of rFVIIa used for a variety of unapproved indications. They identified all available reports that addressed this issue and found 64 worthy of review. Only 16 were randomized, controlled trials; the others were observational studies (n = 26) that compared the treatment with another approach or had no comparator group (n = 22). Overall, Yank and coworkers found no evidence that rFVIIa reduced mortality for any off-label use; however, it did increase the risk for thromboembolism. Their findings are compatible with other recent studies (1415).

So here we have rapidly increasing use of a treatment that does not benefit patients and increases the risk for dangerous thrombotic events—and which the investigators estimate to cost $10 000 per dose. Allowing physician autonomy to choose medications is appealing, but not when it results in unhelpful, dangerous, and costly decisions.

With such compelling data in place about the runaway use, uselessness, and risk for this expensive treatment, what can be done to reduce it? First, if evidence should emerge that the manufacturer played a role in building a market for the unauthorized and increasingly implausible prescribing of its product, both civil and criminal responses will probably be brought to bear, as has occurred for many other instances of corporate-sponsored drug misuse (16). Second, rFVIIa is used in hospitals, which should be providing organizational oversight to protect patients, as well as the institutions' own pharmacy budgets. In hospitals where such use continues, existing quality assurance, patient safety, and risk-management groups will surely want to look hard at these practices. Although off-label prescribing by physicians is not illegal, physicians who persist in such use in the face of clear evidence of inutility and harm could be subject to civil action by the affected patients or their heirs.

There is some good news. Both of these studies were made possible by funding from the Agency for Healthcare Research and Quality, which is devoting increasing resources to support such comprehensive assessments of both utilization and of efficacy and safety—the sine qua non of a data-driven health care enterprise (17). The study by Logan and colleagues (8) represents rigorous use of emerging data sets of medication use, and the study by Yank and coworkers (13) is a good example of a solid systematic review, a once-arcane approach that is assuming greater maturity and utility as we begin to think more clearly about the inputs and outcomes of our often out-of-control health care system. These studies provide rigorous, unbiased assessments of both utilization patterns and clinical evidence that can serve as a model for the many other issues of rational therapy decisions that physicians, patients, and policymakers face.

References

Marks HM.  The Progress of Experiment: Science and Therapeutic Reform in the United States, 1900-1990. Cambridge, UK: Cambridge Univ Pr; 2000.
 
Carpenter D.  Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA. Princeton: Princeton Univ Pr; 2010.
 
Avorn J.  Powerful Medicines: The Benefits, Risks, and Costs of Prescription Drugs. New York: Knopf; 2005.
 
Lenfant C.  Shattuck lecture—clinical research to clinical practice—lost in translation? N Engl J Med. 2003; 349:868-74.
PubMed
CrossRef
 
Kesselheim AS, Mello MM, Studdert DM.  Strategies and practices in off-label marketing of pharmaceuticals: a retrospective analysis of whistleblower complaints. PLoS Med. 2011;8. [Forthcoming].
 
Schmit J.  Drugmaker admitted fraud, but sales flourish. USA Today. 17 August 2004.
 
Radley DC, Finkelstein SN, Stafford RS.  Off-label prescribing among office-based physicians. Arch Intern Med. 2006; 166:1021-6.
PubMed
 
Logan AC, Yank V, Stafford RS.  Off-label use of recombinant factor VIIa in U.S. hospitals: analysis of hospital records. Ann Intern Med. 2011; 154:516-22.
 
Sample I.  Blood-clotting drug given to wounded soldiers can cause heart attacks. Guardian. 15 November 2010.
 
Novo Nordisk.  2010 Annual Report. Accessedhttp://annualreport2010.novonordisk.com/web-media/pdfs/Novo-Nordisk-AR-2010-en.pdfon 7 March 2011.
 
Little R.  Federal agents probing army's use of trauma drug. Baltimore Sun. 16 May 2010.
 
Kesselheim AS, Avorn J.  The role of litigation in defining drug risks. JAMA. 2007; 297:308-11.
PubMed
 
Yank V, Tuohy CV, Logan AC, Bravata DM, Staudenmayer K, Eisenhut R. et al.  Systematic review: benefits and harms of in-hospital use of recombinant factor VIIa for off-label indications. Ann Intern Med. 2011; 154:529-40.
 
Stanworth SJ, Birchall J, Doree CJ, Hyde C.  Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia. Cochrane Database Syst Rev. 2007; CD005011.
PubMed
 
Levi M, Levy JH, Andersen HF, Truloff D.  Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med. 2010; 363:1791-800.
PubMed
 
Almashat S, Preston C, Waterman T, Wolfe S.  Rapidly increasing criminal and civil monetary penalties against the pharmaceutical industry: 1991 to 2010. 16 December 2010. Accessed atwww.citizen.org/hrg1924on 7 March 2011.
 
Eden J, Wheatley B, McNeil B, Sox H.  Knowing What Works in Health Care: A Roadmap for the Nation. Washington, DC: National Academies Pr; 2008.
 

Figures

Tables

References

Marks HM.  The Progress of Experiment: Science and Therapeutic Reform in the United States, 1900-1990. Cambridge, UK: Cambridge Univ Pr; 2000.
 
Carpenter D.  Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA. Princeton: Princeton Univ Pr; 2010.
 
Avorn J.  Powerful Medicines: The Benefits, Risks, and Costs of Prescription Drugs. New York: Knopf; 2005.
 
Lenfant C.  Shattuck lecture—clinical research to clinical practice—lost in translation? N Engl J Med. 2003; 349:868-74.
PubMed
CrossRef
 
Kesselheim AS, Mello MM, Studdert DM.  Strategies and practices in off-label marketing of pharmaceuticals: a retrospective analysis of whistleblower complaints. PLoS Med. 2011;8. [Forthcoming].
 
Schmit J.  Drugmaker admitted fraud, but sales flourish. USA Today. 17 August 2004.
 
Radley DC, Finkelstein SN, Stafford RS.  Off-label prescribing among office-based physicians. Arch Intern Med. 2006; 166:1021-6.
PubMed
 
Logan AC, Yank V, Stafford RS.  Off-label use of recombinant factor VIIa in U.S. hospitals: analysis of hospital records. Ann Intern Med. 2011; 154:516-22.
 
Sample I.  Blood-clotting drug given to wounded soldiers can cause heart attacks. Guardian. 15 November 2010.
 
Novo Nordisk.  2010 Annual Report. Accessedhttp://annualreport2010.novonordisk.com/web-media/pdfs/Novo-Nordisk-AR-2010-en.pdfon 7 March 2011.
 
Little R.  Federal agents probing army's use of trauma drug. Baltimore Sun. 16 May 2010.
 
Kesselheim AS, Avorn J.  The role of litigation in defining drug risks. JAMA. 2007; 297:308-11.
PubMed
 
Yank V, Tuohy CV, Logan AC, Bravata DM, Staudenmayer K, Eisenhut R. et al.  Systematic review: benefits and harms of in-hospital use of recombinant factor VIIa for off-label indications. Ann Intern Med. 2011; 154:529-40.
 
Stanworth SJ, Birchall J, Doree CJ, Hyde C.  Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia. Cochrane Database Syst Rev. 2007; CD005011.
PubMed
 
Levi M, Levy JH, Andersen HF, Truloff D.  Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med. 2010; 363:1791-800.
PubMed
 
Almashat S, Preston C, Waterman T, Wolfe S.  Rapidly increasing criminal and civil monetary penalties against the pharmaceutical industry: 1991 to 2010. 16 December 2010. Accessed atwww.citizen.org/hrg1924on 7 March 2011.
 
Eden J, Wheatley B, McNeil B, Sox H.  Knowing What Works in Health Care: A Roadmap for the Nation. Washington, DC: National Academies Pr; 2008.
 

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The off-label use of recombinant activated factor VII
Posted on April 29, 2011
Keyvan Karkouti
University of Toronto and Emory University School of Medicine
Conflict of Interest: None Declared

To the Editor;

Commenting on recent systematic reviews of the off-label use of recombinant activated factor VII (rFVIIa),(1) Dr. Avorn raises concern about the "rapidly increasing use of a treatment that does not benefit patients and increases the risk for dangerous thrombotic events - and which ... costs $10,000 per dose." This concern, however, fails to consider the clinical context in which clinicians choose to administer rFVIIa, which is refractory blood loss.

When presented with a patient who continues to bleed despite administration of all available therapies, clinicians have only two choices: they can keep administering the standard interventions that have failed to work in that patient, or they can administer a novel therapy like rFVIIa. Based on the increasing in-hospital off-label usage of rFVIIa,(2) clinicians seem to be choosing the second option. What would compel them to make this "unhelpful, dangerous, and costly" decision?(1)

Perhaps they recognize that: a) unless they gain control of the blood loss in a timely manner, patients will fare poorly; b) standard interventions - which, incidentally, have also not been shown to benefit patients, have inherent risks, and are expensive - are unlikely to gain control of the blood loss in a timely manner; c) based on an expanding body of observational data,(3) and some randomized trial data in bleeding patients,(4) rFVIIa is likely to reduce the blood loss; d) the efficacy and safety data from most existing randomized trials do not apply because they did not study patients with refractory blood loss; e) even if the safety data from existing randomized trials do apply, which indicate that rFVIIa doubles the risk of thrombotic complications,(5) this risk is likely dwarfed by the risk of allowing blood loss to continue unabated; f) and applicable data from placebo-controlled randomized trials will not be forthcoming because of feasibility issues (e.g., difficulty in obtaining informed consent in a timely manner, ethical concern of administering a placebo to patients with refractory blood loss, and lacking standardized alternative therapies).

We believe that comments on the off-label use of rFVIIa that do not consider the clinical context in which the drug is being used may be flawed. All procoagulant agents have the risk for potential adverse responses, but their individualized risk-benefit profile is largely dependant on the clinical context.

Keyvan Karkouti Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada

Jerrold H Levy Emory University School of Medicine, Atlanta, Georgia

Potential Conflicts of Interest: Both authors have conulted for and have received research funding from Novo Nordisk

Reference List

(1) Avorn J, Kesselheim A. A hemorrhage of off-label use. Ann Intern Med 2011; 154:566-567.

(2) Logan AC, Yank V, Stafford RS. Off-Label Use of Recombinant Factor VIIa in U.S. Hospitals: Analysis of Hospital Records. Ann Intern Med 2011; 154:516-522.

(3) Karkouti K, Beattie WS, Arellano R, Aye T, Bussieres JS, Callum JL et al. Comprehensive Canadian Review of the Off-Label Use of Recombinant Activated Factor VII in Cardiac Surgery. Circulation 2008; 118:331-338.

(4) Gill R, Herbertson M, Vuylsteke A, Olsen PS, von HC, Mythen M et al. Safety and efficacy of recombinant activated factor VII: a randomized placebo-controlled trial in the setting of bleeding after cardiac surgery. Circulation 2009; 120:21-27.

(5) Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med 2010; 363:1791-1800.

Conflict of Interest:

Both authors have consulted for and have received research funding from Novo Nordisk.

Author's Response
Posted on May 26, 2011
Jerry Avorn
No Affiliation
Conflict of Interest: None Declared

To the editor:

We sympathize with the plight of the physician described by Karkouti and Levy, trying to emergently manage a patient with refractory, life- threatening bleeding. However, in the review by Yank et al. that demonstrated that recombinant activated Factor VII (rFVIIa) confers little or no benefit along with a significant elevation of risk of thrombotic events, the vast majority of patients studied were given this product under just such emergent conditions. The same was found in another recent comprehensive review of the literature, of which Dr. Levy was a co- author, and this conclusion was highlighted in an accompanying editorial comment. The cited randomized trial by Gill et al. did report a reduction in bleeding-related events, but it also found a striking increase in death, stroke, and gut infarction in patients given rFVIIa, though the trial was under-powered to measure these rates with precision.

Management of active blood loss is a stressful and challenging clinical crisis, yet these patients still deserve treatment based on the most comprehensive available evidence. Physicians in emergency settings face an understandable desire to take some action in the face of a deteriorating situation. But this perceived need should not justify administering agents that are harmful and ineffective. Emergent care of the bleeding patient should not follow a flawed algorithm that states, in effect, "We must do something. This is something. Therefore, we must do it."

Even in urgent situations, if the bulk of available data suggests that an intervention will not benefit the patient and will increase the risk of an important harm, then such therapeutic activism is not in the patient's interest, however understandable and well-intentioned it may be. Science-based care requires the treating physician to rise above the "availability heuristic" --the tendency to base decisions on the events which are most apparent at the time (diminution of bleeding) rather than on more complete risk-benefit information. In this case, that would have to include treatment-induced complications that occur after the bleeding has stopped, such as myocardial infarctions, strokes, or other thrombotic events precipitated by a hypercoagulable state generated by rVIIa.

Systematic reviews of all available evidence provide the best available prediction of the outcome of a given treatment in a particular clinical situation. The danger of invoking the need for an "individualized risk-benefit profile" is that this approach, if not guided by data, can be used to justify anecdotally-based decisionmaking that does not take full account of all that is known about actual benefits and harms.

Jerry Avorn, M.D.

Aaron S. Kesselheim, M.D., J.D., M.P.H.

References

1. Yank V, Tuohy CV, Logan AC, Bravata DM, Staudenmayer K, Eisenhut R, et al. Systematic review: benefits and harms of in-hospital use of recombinant Factor VIIa for off-label indications. Ann Intern Med. 2011;154(8):529-40.

2. Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated Factor VII in randomized clinical trials. N Engl J Med. 2010;363:1791-1800.

3. Aledort LM. Off-label use of recombinant activated Factor VII - safe or not safe? New Engl J Med. 2010;363:1853-4.

4. Elstein AS. Heuristics and biases: selected errors in clinical reasoning. Acad Med. 1999;74:791-94.

5. Berg A and Morton S, eds. Finding what works in health care: standards for systematic reviews. Washington, D.C.: National Academic Press, 2011.

Conflict of Interest:

None declared

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