FDA Injects A Wrinkle into Botox Marketing

By Carrie S. Martin –      

FDA announced on April 30, 2009, that all botulinum toxin products will now require a Risk Evaluation and Mitigation Strategy ("REMS") and safety labeling changes, including a boxed warning, due to the risk of spread of botulinum toxin effects from the site of injection.  The products covered by the new requirements are:  (1) Botox and Botox Cosmetic (botulinum toxin type A); (2) Myobloc (botulinum toxin type B); and (3) Dysport (abobotulinumtoxinA).  Approved botulinum toxins have both therapeutic and cosmetic uses.  For example, Botox, Myobloc, and Dysport are indicated for severe neck muscle spasms (cervical dystonia).  Botox is also indicated for the treatment of severe underarm sweating (primary axillary hyperhidrosis) that is inadequately managed with topical agents, crossed eyes (strabismus), and spasm of the eyelids (belpharospasm).  Botox Cosmetic and Dysport also have cosmetic indications:  the temporary improvement in the appearance of glabellar lines, the frown lines between the eyebrows.

FDA’s announcement came in the form of a response to a Citizen Petition.  The Citizen Petition, filed by Public Citizen in January 2008, asked FDA to do three things:  issue a letter to physicians alerting them to the problems that can arise when the effects of botulinum toxin spread from the site of injection to other parts of the body, require black box warnings on the products’ labels, and require a Medication Guide ("MedGuide") to be dispensed to patients when the drug is injected.  Public Citizen argued that these actions were necessary because of reports in the United States and in the European Union ("EU") indicating that the spread of the toxin’s effects has been associated with serious adverse events ("AEs"). 

Public Citizen justified its request, in part, with results of a search of FDA’s adverse event database ("AERS") for reports between November 1997 and December 2006, when only Botox, Botox Cosmetic, and Myobloc had FDA approval.  Before responding to the Citizen Petition, FDA conducted its own analysis of risks associated with botulinum toxin, including a review of postmarking cases from the AERS database, medical literature, and post-approval clinical trial data.  The Agency determined that the number of AEs was likely higher than Public Citizen’s estimates, and found that the migration of botulinum toxin effects may result in muscle weakness, hoarseness or trouble talking, loss of bladder control, trouble breathing, trouble swallowing, and blurred vision, among other symptoms.  As a result, it determined that safety labeling changes and a REMS would be required for all botulinum toxin products.  FDA further noted that Botox, Myoboc, and Dysport are not interchangeable, because the products differ in potency among different toxin types as well as within a toxin type.  However, FDA declined to distinguish among the products in requiring the labeling changes and REMS because the Agency believed the safety issues were applicable to all three products.

Safety Labeling Changes.  FDA is requiring that all of the holders of the Biologic License Applications ("BLAs") for botulinum toxins strengthen their products’ warnings to include a boxed warning regarding the spread of botulinum toxin effects beyond the site of injection in children and adults.  In addition, labeling must be revised to strengthen current warnings about dysphagia and breathing problems in patients treated for cervical dystonia.  FDA’s authority stems from the new safety labeling changes provision of Food and Drug Administration Amendments Act of 2007 ("FDAAA") (Section 505(o)(4) of the Federal Food, Drug, and Cosmetic Act (FDC Act)) and 21 C.F.R. §§ 201.57(c)(1) and 201.80(a). 

REMS.  In addition, FDA concluded that a REMS will be required under FDAAA (FDC Act § 505-1) to ensure that the benefits of the products outweigh their risks.  The REMS is to include:  a MedGuide, a Communication Plan, including a Dear Health Care Provider letter, and a timetable for assessments.  FDA found that the MedGuide was necessary because botulinum toxin products pose serious and significant public health concerns and that these risks could affect a patient’s decision to use, or continue to use, the products.  Physicians will be required to distribute the MedGuide to their patients at the time the product is injected.  Regarding the Communication Plan, FDA will require that a Dear Health Care Professional letter describing the risks of botulinum toxin effects spreading from the injection site be sent to neurologists, dermatologists, and other relevant specialists and professional staff.  The letters must also explain that botulinum toxin products are not interchangeable. 

FDA responded to the Citizen Petition, which announced the need for safety labeling changes and a REMS, the day after Dysport’s approval, which already includes the boxed warning, other warning statements in its labeling, and the REMS that FDA is requiring.  The other BLA holders are required to submit their proposed labeling changes by May 29, 2009, and a proposed REMS within 30 days of receiving FDA’s notification.  Although a BLA holder usually has 120 days to respond with a proposed REMS, the Agency can shorten that period if it determines that it is required to protect the public health. 

The fact that FDA concluded that safety labeling changes and a REMS are required for botulinum toxin products – based on the science and the reported AEs – may not be surprising.  More interesting are two points:  (1) that FDA made this determination in response to a third-party’s request via a Citizen Petition; and (2) that FDA announced a class-wide REMS and the approval of a class product approval with a REMS simultaneously.  With regards to the first point, FDA’s willingness to require a REMS at the suggestion of someone other than the applicant or the Agency could begin a new era of offensive use of REMS requests by competitor companies.  Regarding the second point, FDAAA includes a schedule for negotiating the language of safety labeling changes and the provisions of a REMS.  Dyport’s approval, however, may restrict the ability of the BLA holders for Botox, Botox Cosmetic, and Myobloc to negotiate their labeling and REMS.  Although it is possible that the BLA holders already informally agreed to language prior to Dysport’s approval, this REMS is still significant for it being the first class-wide REMS to be imposed simultaneously with the announcement of a class product approval for which the REMS details are final.  We will keep a close eye on whether these isolated events evolve into identifiable trends.