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Content, Consistency, and Quality of Black Box Warnings: Time for a ChangeContent, Consistency, and Quality of Black Box Warnings

Tarig Elraiyah, MBBS, MSc; Michael R. Gionfriddo, PharmD; Victor M. Montori, MD, MSc; and Mohammad Hassan Murad, MD, MPH
[+] Article, Author, and Disclosure Information

This article was published online first at www.annals.org on 29 September 2015.


From Mayo Clinic, Rochester, Minnesota.

Disclaimer: The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.

Grant Support: Dr. Gionfriddo was supported by Clinical and Translational Science Award grant number TL1 TR000137 from the National Center for Advancing Translational Sciences.

Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-1097.

Requests for Single Reprints: Mohammad Hassan Murad, MD, MPH, Knowledge and Evaluation Research Unit, Mayo Clinic, 200 First Street SW, Rochester, MN 55905; e-mail, Murad.mohammad@mayo.edu.

Current Author Addresses: Dr. Elraiyah: Mayo Clinic, 200 First Street SW, Rochester, MN 55905.

Dr. Gionfriddo: Mayo Clinic, Plummer 3—CTSA, 200 First Street SW, Rochester, MN 55905.

Dr. Montori: Knowledge and Evaluation Research Unit, Mayo Clinic, Plummer 4-402, 200 First Street SW, Rochester, MN 55905.

Dr. Murad: Knowledge and Evaluation Research Unit, Mayo Clinic, 200 First Street SW, Rochester, MN 55905.

Author Contributions: Conception and design: T. Elraiyah, M.R. Gionfriddo, M.H. Murad.

Analysis and interpretation of the data: T. Elraiyah, M.R. Gionfriddo, V.M. Montori, M.H. Murad.

Drafting of the article: T. Elraiyah, M.R. Gionfriddo, M.H. Murad.

Critical revision of the article for important intellectual content: M.R. Gionfriddo, V.M. Montori, M.H. Murad.

Final approval of the article: T. Elraiyah, M.R. Gionfriddo, V.M. Montori, M.H. Murad.

Administrative, technical, or logistic support: M.H. Murad.

Collection and assembly of data: T. Elraiyah, M.R. Gionfriddo.


Ann Intern Med. 2015;163(11):875-876. doi:10.7326/M15-1097
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Black box warnings have been the subject of controversy, due in part to their opaque connection to the underlying body of evidence. This commentary proposes a new structure for presenting black box warnings that takes into consideration the fundamental principles of evidence-based medicine.

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Improving the Clinical Utility of Boxed Warning Information
Posted on October 19, 2015
Christine M. Cheng, Colleen DeLizza
First Databank
Conflict of Interest: Authors are employed by First Databank, a drug knowledge vendor.
In their study of boxed warnings (BWs), Elraiyah et al (1) propose that adding an evidence profile would improve the utility of these warnings. While knowing the quality of evidence supporting each warning may help prescribers gauge the strength of association between a drug and an adverse reaction, we suggest that what is critical to determining the applicability of the BW to an individual patient is an assessment of the patient’s risk factors for the adverse reaction. As reported by Elraiyah et al, all of the BWs in their review described the at-risk population.
We have reviewed BWs in the labels for more than 3,000 prescription drugs and noted wide variation in content, level of detail and number and type of adverse reactions. Some BWs are based on results from large prospective studies (e.g., estrogen replacement therapy and cardiovascular events). Others are based on case reports (e.g., progressive multifocal leukoencephalopathy and rituximab) or animal data (e.g., teratogenicity and valganciclovir). Despite varying levels of evidence, all have strong recommendations for preventing, mitigating or managing the serious adverse reaction. Even in cases where the evidence is of low-to-moderate quality (e.g., abacavir-induced hypersensitivity and HLA-B*5701 allele), a patient risk assessment is standard of practice.(2)
We agree with Elraiyah et al that an implementation plan is important for facilitating safe use of BW drugs. We have found that the drug label often provides detailed discussions and recommendations for addressing adverse reactions, though the information may be in several different sections of the label and not necessarily contained within the BW itself.(3) The authors’ findings that 96% of the BWs reviewed provided BW-specific practice recommendations is consistent with our observations.
With the increased use of electronic health information systems, we feel that the utility of BWs could be improved by integrating BW-specific information into the electronic clinical workflow. The information should identify the drug, its associated adverse reaction(s) and actions to be taken. These actions should be stratified by the steps of the medication use process, including pre-treatment assessments (e.g., evaluation of patient risk factors) and considerations for prescribing, dispensing, administration, monitoring or patient counseling for the drug. Clinicians could then choose to only view action items relevant to his or her role in the care of the patient. Rigorously maintained BW data could help provide point-of-care guidance for the safe use of BW drugs.


References:

1. Elraiyah T, Gionfriddo MR, Montori VM, Murad MH. Content, Consistency, and Quality of Black Box Warnings: Time for a Change [published online ahead of print September 29, 2015]. Annals of Internal Medicine. doi: 10.7326/M15-1097. PubMed PMID: 26415046.
2. Sousa-Pinto B, Pinto-Ramos J, Correia C, Goncalves-Costa G, Gomes L, Gil-Mata S, et al. Pharmacogenetics of abacavir hypersensitivity: A systematic review and meta-analysis of the association with HLA-B*57:01. J Allergy Clin Immunol. 2015 October;136(4):1092-1094. doi: 10.1016/j.jaci.2015.03.019. PubMed PMID: 25934581.
3. FDA Guidance for Industry. Warnings and Precautions, Contraindications, and Boxed Warning Sections of Labeling for Human Prescription Drug and Biological Products – Content and Format. October 2011. Available from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM075096. Accessed October 8, 2015.
Author's Response
Posted on January 29, 2016
Tarig Elraiyah, MBBS, MSc, M. Hassan Murad, MD, MPH
Mayo Clinic
Conflict of Interest: None Declared
We thank Cheng et al (1) for their interest in our article (2). We are very pleased that their own review of black box warnings is consistent with ours. We wholeheartedly agree that the individual patient baseline risk for adverse effects should be assessed to determine what action to take based on the warning. In fact, this is one of the reasons we called for an implementation guide to accompany such warnings. The guide can include a tool to estimate the risk in each patient (if available). Therefore, we propose that each warning is accompanied by a rating of our certainty in the evidence and an implementation guide. If such elements can be incorporated in the Electronic Medical Record (EMR), that would even facilitate decision-making and make it more streamlined.


References:
1. Cheng CM, DeLizza C. Improving the Clinical Utility of Boxed Warning Information.
2. Elraiyah T, Gionfriddo MR, Montori VM, Murad MH. Content, Consistency, and Quality of Black Box Warnings: Time for a Change [published online ahead of print September 29, 2015]. Annals of Internal Medicine. doi: 10.7326/M15-1097. PubMed PMID: 26415046.
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