COMMENTARY Commentary on Impact of Postreconstitution Room Temperature Storage on the Efficacy of IncobotulinumtoxinA Treatment of Dynamic Lateral Canthus Lines The purpose of this study was to test a restriction placed by the package insert of incobotulinumtoxinA (Xeomin) on the product’s use in the clinical setting.1 The authors outline in their introduction that the ideal storage temperature of both free and reconstituted botulinum toxin A of various formulations has been studied, as currently the manufacturers’ recommendations that require refrigerated storage and prompt discarding of unused toxin lead to unnecessary waste.2–4 The authors cite recent studies that prove that botulinum A in its reconstituted form remains clinically effective after 6 weeks of refrigeration. They add that it is now common practice for physicians to store reconstituted botulinum toxin in a refrigerator for up to a week, because these studies have failed to show decreased efficacy or increased risk of contamination or infection. Because the new incobotulinumtoxinA does not require refrigerated storage before reconstitution, the authors challenged the recommendation detailed in the package insert that it be refrigerated after reconstitution. As they expected, they found no difference in the efficacy of the freshly reconstituted product when they compared it with the product that had been stored after reconstitution at room temperature. So will the manufacturer change their recommendation to reflect common, safe, and cost-effective practice? Unlikely. Changing the package insert requires further trials, resubmission to the Food and Drug Administration (FDA), and significant cost to the manufacturer. What is the relationship between the package insert and standard of care in medicine?5 The pharmaceutical company composes the package insert as a response to FDA regulation. The information is required for the manufacturer to market, advertise, and
promote a medication. It is not information intended for creating a standard of care but rather to inform the consumer of the risks of taking the medication and limit the manufacturer’s liability for a medication. The importance of this intent cannot be underestimated. Pharmaceutical companies are in the business of selling their products and limiting their own liabilities in relation to those products. They are not in the business of establishing standard of care for physicians using the products. This is a critical distinction. The Federal Food, Drug, and Cosmetic act (legislation behind the package insert requirements) does not restrict the manner in which a physician can prescribe an FDAapproved medication, and the FDA itself recognizes that appropriate use of a medication may not be reflected by the package insert but rather by experience and reports in the medical literature.5,6 In the complicated environment of modern medicine, who establishes standard of care? There are many stakeholders, but do the constituencies have an equal voice and does the balance of power make sense? Federal regulators such as the FDA and the Joint Commission have a strong voice. Most recently, the Joint Commission mandated that no medications (used in their accredited settings) be used in any way not congruent with the package insert. Although it is likely that their intent was to standardize care and improve patient safety, the effect was to make it very difficult to use botulinum toxin in the hospital environment as the waste would make the cost prohibitive. Many academic physicians had to fight their internal regulatory authorities for the right to continue to use this FDAapproved medication in a manner that was clearly supported by their experience and the medical literature. On
The author has indicated no significant interest with commercial supporters. © 2015 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved. ISSN: 1076-0512 Dermatol Surg 2015;41:718–719 DOI: 10.1097/DSS.0000000000000338
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© 2015 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
COMMENTARY
the Web site for Joint Commission, they state that they strive for standards that “have a strong evidence base. . . have a strong relationship to patient outcomes and clinical care. . . have benefits that outweigh the costs. . . support a healthcare priority that impacts quality and safety. . ..”7 The impact of the changes made by regulatory bodies is often not studied to measure the effectiveness in improving care by some appropriate metric, nor is it evaluated for the impact on the cost of care. Package inserts and federal regulations do not create standards of care. Good clinical research can provide a basis for ethical physicians, professional societies, hospital administrators, patient advocates, and federal regulators to formulate standards of care in a dynamic environment in which there is reassessment and a reasonable method to amend the standards. Utopia.
References 1. Soares DJ, Dejospeh LM, Zuliani GF, Liebertz DJ, Vivek-Sagar PM. Impact of postreconstitution room temperature storage on the efficacy of
incobotulinumtoxina treatment of dynamic lateral canthus lines. Dermatol Surg 2015;41:712–7. 2. Hexsel DM, De Almeida AT, Rutowitsch M, De Castro IA, et al. Multicenter, double-blind study of the efficacy of injections with botulinum toxin type A reconstituted up to six consecutive weeks before application. Dermatol Surg 2003;29:523–9. 3. Lizarralde M, Gutierrez SH, Venegas A. Clinical efficacy of botulinum toxin type A reconstituted and refrigerated 1 week before its application in external canthus dynamic lines. Dermatol Surg 2007;33: 1328–33. 4. Hexsel D, Rutuwitsch M, de Castro LCM, do Prado DZ, et al. Blind multicenter study of the efficacy and safety of injections of a commercial preparation of botulinum toxin type A reconstituted up to 15 days before injection. Dermatol Surg 2009;35:933–40. 5. Thornton RG. Package inserts and the standard of care. Proc (Bayl Univ Med Cent) 2003;16:502–4. 6. FDA Drug Bulletin. Available at: http://www.jointcommission.org/. Accessed April 1, 2015. 1982;12:4–5. 7. Joint Commission Website, Facts about Joint Commission Standards. March 25, 2014. Accessed January 11, 2015.
Naomi Lawrence, MD Division of Dermatology Department of Medicine Cooper Medical School of Rowan University Marlton, New Jersey
41:6:JUNE 2015
719
© 2015 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Copyright of Dermatologic Surgery is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
promote a medication. It is not information intended for creating a standard of care but rather to inform the consumer of the risks of taking the medication and limit the manufacturer’s liability for a medication. The importance of this intent cannot be underestimated. Pharmaceutical companies are in the business of selling their products and limiting their own liabilities in relation to those products. They are not in the business of establishing standard of care for physicians using the products. This is a critical distinction. The Federal Food, Drug, and Cosmetic act (legislation behind the package insert requirements) does not restrict the manner in which a physician can prescribe an FDAapproved medication, and the FDA itself recognizes that appropriate use of a medication may not be reflected by the package insert but rather by experience and reports in the medical literature.5,6 In the complicated environment of modern medicine, who establishes standard of care? There are many stakeholders, but do the constituencies have an equal voice and does the balance of power make sense? Federal regulators such as the FDA and the Joint Commission have a strong voice. Most recently, the Joint Commission mandated that no medications (used in their accredited settings) be used in any way not congruent with the package insert. Although it is likely that their intent was to standardize care and improve patient safety, the effect was to make it very difficult to use botulinum toxin in the hospital environment as the waste would make the cost prohibitive. Many academic physicians had to fight their internal regulatory authorities for the right to continue to use this FDAapproved medication in a manner that was clearly supported by their experience and the medical literature. On
The author has indicated no significant interest with commercial supporters. © 2015 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved. ISSN: 1076-0512 Dermatol Surg 2015;41:718–719 DOI: 10.1097/DSS.0000000000000338
·
·
718
© 2015 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
COMMENTARY
the Web site for Joint Commission, they state that they strive for standards that “have a strong evidence base. . . have a strong relationship to patient outcomes and clinical care. . . have benefits that outweigh the costs. . . support a healthcare priority that impacts quality and safety. . ..”7 The impact of the changes made by regulatory bodies is often not studied to measure the effectiveness in improving care by some appropriate metric, nor is it evaluated for the impact on the cost of care. Package inserts and federal regulations do not create standards of care. Good clinical research can provide a basis for ethical physicians, professional societies, hospital administrators, patient advocates, and federal regulators to formulate standards of care in a dynamic environment in which there is reassessment and a reasonable method to amend the standards. Utopia.
References 1. Soares DJ, Dejospeh LM, Zuliani GF, Liebertz DJ, Vivek-Sagar PM. Impact of postreconstitution room temperature storage on the efficacy of
incobotulinumtoxina treatment of dynamic lateral canthus lines. Dermatol Surg 2015;41:712–7. 2. Hexsel DM, De Almeida AT, Rutowitsch M, De Castro IA, et al. Multicenter, double-blind study of the efficacy of injections with botulinum toxin type A reconstituted up to six consecutive weeks before application. Dermatol Surg 2003;29:523–9. 3. Lizarralde M, Gutierrez SH, Venegas A. Clinical efficacy of botulinum toxin type A reconstituted and refrigerated 1 week before its application in external canthus dynamic lines. Dermatol Surg 2007;33: 1328–33. 4. Hexsel D, Rutuwitsch M, de Castro LCM, do Prado DZ, et al. Blind multicenter study of the efficacy and safety of injections of a commercial preparation of botulinum toxin type A reconstituted up to 15 days before injection. Dermatol Surg 2009;35:933–40. 5. Thornton RG. Package inserts and the standard of care. Proc (Bayl Univ Med Cent) 2003;16:502–4. 6. FDA Drug Bulletin. Available at: http://www.jointcommission.org/. Accessed April 1, 2015. 1982;12:4–5. 7. Joint Commission Website, Facts about Joint Commission Standards. March 25, 2014. Accessed January 11, 2015.
Naomi Lawrence, MD Division of Dermatology Department of Medicine Cooper Medical School of Rowan University Marlton, New Jersey
41:6:JUNE 2015
719
© 2015 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Copyright of Dermatologic Surgery is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
