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Original Investigation | Health Care Reform

Association of Off-label Drug Use and Adverse Drug Events in an Adult Population

Tewodros Eguale, MD, PhD1,2,3,4; David L. Buckeridge, MD, PhD1,2; Aman Verma, PhD1; Nancy E. Winslade, PharmD2; Andrea Benedetti, PhD1; James A. Hanley, PhD1,5; Robyn Tamblyn, PhD1,2
[+] Author Affiliations
1Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada
2Department of Medicine, McGill University, Montreal, Quebec, Canada
3Division of General Medicine and Primary Care, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
4Department of Social and Administrative Pharmacy, Schoool of Pharmacy, MCPHS University, Boston, Massachusetts
5Department of Mathematics and Statistics, McGill University, Montreal, Quebec, Canada
JAMA Intern Med. 2016;176(1):55-63. doi:10.1001/jamainternmed.2015.6058.
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Importance  Off-label use of prescription drugs has been identified as an important contributor to preventable adverse drug events (ADEs) in children. Despite concerns regarding adverse outcomes, to date, no systematic investigation of the effects of off-label drug use in adult populations has been performed.

Objective  To monitor and evaluate off-label use of prescription drugs and its effect on ADEs in an adult population.

Design, Setting, and Participants  A cohort of 46 021 patients who received 151 305 incident prescribed drugs was assembled from primary care clinics in Quebec, Canada, using the Medical Office of the XXIst Century electronic health record, which supports documentation of treatment indications and treatment outcomes. Prescriptions dispensed from January 1, 2005, through December 30, 2009, were followed up from the date of the prescription to the date the drug use was discontinued, the end of treatment, or the end of follow-up (December 30, 2010). Data were analyzed from January 5, 2012, to March 15, 2015.

Exposures  Off-label prescription drug use with and without strong scientific evidence.

Main Outcomes and Measures  Adverse drug events in off-label use with and without strong scientific evidence. Analysis used multivariate marginal Cox proportional hazards regression for clustered data with the drug as the unit of analysis.

Results  A total of 3484 ADEs were found in the 46 021 study patients, with an incidence rate of 13.2 per 10 000 person-months. The rate of ADEs for off-label use (19.7 per 10 000 person-months) was higher than that for on-label use (12.5 per 10 000 person-months) (adjusted hazard ratio [AHR], 1.44; 95% CI, 1.30-1.60). Off-label use lacking strong scientific evidence had a higher ADE rate (21.7 per 10 000 person-months) compared with on-label use (AHR, 1.54; 95% CI, 1.37-1.72). However, off-label use with strong scientific evidence had the same risk for ADEs as on-label use (AHR, 1.10; 95% CI, 0.88-1.38). The risks for ADEs were higher for drugs approved from 1981 to 1995 (14.4 per 10 000 person-months; AHR, 1.62; 95% CI, 1.45-1.80) and for those used by women (14.3 per 10 000 person-months; AHR, 1.17; 95% CI, 1.06-1.28), patients receiving 5 to 7 drugs (12.1 per 10 000 person-months; AHR, 3.23; 95% CI, 2.66-3.92), and patients receiving cardiovascular drugs (15.9 per 10 000 person-months; AHR, 3.30; 95% CI, 2.67-4.08) and anti-infectives (66.2 per 10 000 person-months; AHR, 6.33; 95% CI, 4.58-8.76). Patients with a 1-unit increase in the continuity of care index had a 19% increase in ADEs (AHR, 1.19; 95% CI, 1.12-1.26).

Conclusions and Relevance  Off-label use of prescription drugs is associated with ADEs. Caution should be exercised in prescribing drugs for off-label uses that lack strong scientific evidence. Future electronic health records should be designed to enable postmarket surveillance of treatment indications and treatment outcomes to monitor the safety of on- and off-label uses of drugs.

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Figure 1.
Documentation in the Medical Office of the XXIst Century Electronic Health Record (MOXXI EHR)

If a medication (eg, gabapentin) is discontinued, the physician must choose a reason for discontinuing use of the drug. If the reason selected is an adverse drug event, the reaction is documented. TID indicates 3 times per day.

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Figure 2.
Cumulative Hazard Ratios (HRs) of Adverse Drug Events (ADEs) According to On-label and Off-label Use

The comparison has not been adjusted for drug and patient characteristics (HR, 1.48; 95% CI, 1.35-1.64). After adjustment for such variables on multivariate analysis and taking into account the correlation within the patient, the difference between the 2 groups was statistically significant (adjusted HR, 1.44; 95% CI, 1.30-1.60; P < .001).

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Figure 3.
Cumulative Hazard Ratios (HRs) of Adverse Drug Events (ADEs) According to On-label and Off-label Use With and Without Strong Scientific Evidence

The comparison has not been adjusted for drug and patient characteristics. The unadjusted HRs (95% CI) for off-label use with and without strong scientific evidence were 1.04 (0.84-1.30) and 1.62 (1.45-1.80), respectively. After adjustment for such variables on multivariate analysis and taking into account the correlation within the patient, the adjusted HR (95% CI) for off-label use with and without strong scientific evidence were 1.10 (0.88-1.38; P = .40) and 1.54 (1.37-1.72; P < .001), respectively.

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Submit a Comment
This study renders the FDA superfluous
Posted on January 12, 2016
David L Keller MD
none
Conflict of Interest: None Declared
LIbertarians have long chafed at the extreme expense and delay caused by the process of FDA approval of a drug for a new indication. This landmark study demonstrates that on-label (FDA-approved) prescribing is no safer than off-label (FDA-unapproved) prescribing, provided the latter is backed by strong evidence. The take-home message of this study is not that we need to crack down on off-label prescribing, but that we need to crack down on unscientific prescribing. Electronic health records should be programmed to discourage unscientific prescribing, not off-label prescribing. Let's keep our terms straight.
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