Guidance for Industry 

Upper Facial Lines: 

Developing Botulinum Toxin 

Drug Products 

 
 
 
 
 
 
DRAFT GUIDANCE
 
 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 90 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance. Submit electronic comments to http://www.regulations.gov.  Submit written 
comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, rm. 1061, Rockville, MD  20852. All comments should be identified with 
the docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document contact Cristina Attinello at 301-796-3986.   
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER)
  
 
August 2014 

Clinical/Medical 

16228dft.doc  
 
08/04/14   
Guidance for Industry 

Upper Facial Lines: 

Developing Botulinum Toxin 

Drug Products 

 
 
 
Additional copies are available from: 

 
Office of Communications, Division  of Drug Information 

Center for Drug Evaluation  and Research 

Food and  Drug Administration 
 
10903 New Hampshire Ave., Bldg. 51, rm. 2201 

Silver Spring, MD   20993-0002 

Tel:  301-796-3400; Fax: 301-847-8714; E-mail:  druginfo@fda.hhs.gov 

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER)
  
 
August 2014 

Clinical/Medical 

   
TABLE OF CONTENTS 
 
 
I.   INTRODUCTION............................................................................................................. 1
  
II.   BACKGROUND ............................................................................................................... 2
  
III.   DEVELOPMENT PROGRAM ....................................................................................... 2
  
A.   General Drug Development Considerations ................................................................................ 2
  
1.  Early Phase Clinical Development Considerations ......................................................................... 2 
 
2.  Drug Development Population ........................................................................................................ 3
  
3.  Efficacy Considerations................................................................................................................... 3
  
4.  Safety Considerations ...................................................................................................................... 4
  
B.   Phase 3 Efficacy Trial Considerations ......................................................................................... 5 
 
1.  Trial Design ..................................................................................................................................... 5
  
2.  Trial Population ............................................................................................................................... 5
  
3.  Inclusion and Exclusion Criteria ..................................................................................................... 5
  
4.  Concomitant Treatments.................................................................................................................. 6
  
5.  Randomization, Stratification, and Blinding .................................................................................... 6
  
6.  Specific Populations......................................................................................................................... 7
  
7.  Dose Selection .................................................................................................................................. 7
  
8.  Choice of Comparators .................................................................................................................... 7
  
9.  Efficacy Endpoints  ........................................................................................................................... 7
  
a.   Assessment measures................................................................................................................ 7
  
b.   Endpoints .................................................................................................................................. 9
  
10.   Trial Procedures and Timing of Assessments ............................................................................. 9 
 
11.   Endpoint Adjudication ............................................................................................................... 10 
 
12.   Statistical Considerations.......................................................................................................... 10 
 
13.   Accelerated Approval (Subpart H) Considerations................................................................... 11 
 
14.   Risk-Benefit Considerations ...................................................................................................... 11 
 
C.   Other Considerations ................................................................................................................... 11 
 
1.  Risk Management Considerations ................................................................................................. 11 
 
2.  Pharmacokinetic/Pharmacodynamic Considerations .................................................................... 11 
 
3.  Special Investigation Considerations ............................................................................................ 11 
 
4.  Labeling Considerations................................................................................................................ 12 
 
APPENDIX A .............................................................................................................................. 13
  
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation  
1 
Guidance for Industry  
1 
Upper Facial Lines:  
2 
Developing Botulinum Toxin Drug Products  
3 
4   
5   
6   
7   
8  This draft guidance, when finalized, will represent the Food and Drug Administrations (FDAs) current 
9  thinking on this topic.  It does not create or confer any rights for or  on any  person and does not operate to 
10  bind FDA or the public.  You can use an alternative approach if the approach satisfies the requirements of 
11  the applicable statutes and regulations. If  you want to discuss an alternative approach, contact the FDA 
12  staff responsible for implementing this guidance.  If you cannot identify the appropriate FDA staff, call 
13  the appropriate number listed on the title page of this guidance.  
14   
15   
16   
17   
18  I.  INTRODUCTION  
19   
20  The purpose of this guidance is to assist sponsors in the clinical development of therapeutic 
21  biological products, specifically botulinum toxins, for the temporary improvement in the appearance 
22  of upper facial lines, such as glabellar lines or lateral canthal lines (LCLs).  This guidance addresses 
23  the FDAs current thinking regarding the overall development program and clinical trial designs of 
24  botulinum toxin drug products to support approval for an upper facial lines indication.  The 
25  information presented is intended to help sponsors plan clinical trials, design clinical protocols, and 
26  implement and appropriately monitor the conduct of clinical trials. This draft guidance is intended 
27  to serve as a focus for continued discussions among the Division of Dermatology and Dental 
28  Products, pharmaceutical sponsors, the academic community, and the public.2  Development 
29  plans should be discussed with the review division before embarking on trials to ensure that the 
30  clinical trial design meets defined objectives. 
31   
32  This guidance does not contain discussion of the general issues of statistical analysis or clinical 
33  trial design. Those topics are addressed in the ICH guidances for industry E9  Statistical 
34  Principles for Clinical Trials and E10 Choice of Control Group and Related Issues in Clinical 
35  Trials, respectively.3  
36   
                                                 
1 This  guidance has been  prepared by the Division of  Dermatology and Dental Products in  the Center for  Drug  
Evaluation and Research (CDER) at the Food and Drug Administration.  
 
2 In addition to consulting  guidances, sponsors are encouraged to contact the division to  discuss specific issues that 
arise during the development of botulinum toxin drug  products.  
 
3  We  update  guidances periodically.  To make sure you  have the most recent version of a guidance, check the FDA  
Drugs guidance Web page  at  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
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  Contains Nonbinding Recommendations 
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37  This guidance does not contain a discussion of nonclinical or chemistry, manufacturing, and 
38  controls (CMC) issues.  For information concerning nonclinical and/or CMC issues, see the ICH 
39  guidance for industry M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical 
40  Trials and Marketing Authorization for Pharmaceuticals and the guidance for industry For the 
41  Submission of Chemistry, Manufacturing, and Controls Information for a Therapeutic 
42  Recombinant DNA-Derived Product or a Monoclonal Antibody Product for In Vivo Use. 
43   
44  FDAs guidance documents, including this guidance, do not establish legally enforceable 
45  responsibilities. Instead, guidances describe the Agencys current thinking on a topic and should 
46  be viewed only as recommendations, unless specific regulatory or statutory requirements are 
47  cited. The use of the word should in Agency guidances means that something is suggested or 
48  recommended, but not required.  
49   
50   
51  II.  BACKGROUND 
52   
53  Upper facial lines, also known as hyperdynamic lines or lines of facial expression, develop in the 
54  skin of anatomic areas (e.g., glabella, lateral canthal area) overlying specific musculature (e.g., 
55  corrugator, procerus, orbicularis oculi).  
56   
57  There is an increase in demand for aesthetic procedures to treat the progressive development of 
58  facial lines that are associated with the aging process.  Injection of botulinum toxin to improve 
59  the appearance of facial lines is one of the most common aesthetic procedures performed.4  
60   
61  Several botulinum toxin drug products for the temporary improvement in the appearance of 
62  glabellar lines have received FDA approval, including onabotulinumtoxinA (2002), 
63  abobotulinumtoxinA (2009), and incobotulinumtoxinA (2011).   
64   
65   
66  III.  DEVELOPMENT PROGRAM 
67   
68  A.  General Drug Development Considerations 
69   
70  1.  Early Phase Clinical Development Considerations  
71   
72  Trials to identify an appropriate (safe and effective) dose are an important component of phase 2 
73  development for a botulinum toxin drug product.  A dose-response trial conducted during the 
74  early phase of clinical development (e.g., phase 2 clinical trials) to assess safety and efficacy at a 
75  range of doses can help ensure that suboptimal doses or excessive doses (beyond those that add 
76  to efficacy) are not used and may identify some  dose-related side effects.  For additional 
77  information on the FDAs current thinking regarding dose response, see the ICH guidance for 
78  industry E4 Dose-Response Information to Support Drug Registration and the guidances for 
79  industry Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products  
                                                 
4 Sadick, N, 2004, The Cosmetic Use of Botulinum Toxin Type B in the Upper Face, Clinics in Dermatology, 22;29-
33.  
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80  and Exposure-Response Relationships  Study Design, Data Analysis, and Regulatory 
81  Applications.    
82   
83  For topical drug products, sponsors should address unique concerns such as inadvertent injection, 
84  unintended mucosal exposure, and unintended transfer of the drug product.  A delivery system  
85  designed to reduce the risk of inadvertent injection should be considered early in the 
86  development process.  
87   
88  2.  Drug Development Population  
89   
90  The trial population should be representative of the target population for which the drug product 
91  is intended for use in clinical practice (e.g., reflective of the age, race, and sex of the population 
92  that will be using it for an improvement in upper facial lines in the United States).  The inclusion 
93  and exclusion criteria should be sufficiently broad to allow enrollment of a population that will 
94  be representative of that anticipated with proposed labeling (e.g., representative of real-world 
95  use). 
96   
97  Sponsors are required to submit pediatric study plans no later than 60 days after an end-of-phase 
98  2 meeting.5  Because upper facial lines are uncommon in the pediatric population, the sponsor 
99  may request a waiver for the requirement to submit a pediatric assessment in the pediatric study 
100  plan. 
101   
102  If a sponsor plans to conduct clinical trials outside the United States, the sponsor should consider 
103  factors that may affect the acceptability of such data for drug product approval in the United 
104  States. Sufficient information should be provided to demonstrate that data from clinical trials 
105  conducted outside the United States are applicable to and will predict the clinical outcomes in 
106  U.S. patients (see 21 CFR 314.106).  We also refer the sponsor to the ICH guidance for industry 
107  E5 Ethnic Factors in the Acceptability of Foreign Clinical Data and the guidance for industry 
108  Collection of Race and Ethnicity Data in Clinical Trials. 
109   
110  3.  Efficacy Considerations  
111   
112  In general, two adequate and well-controlled trials are needed to establish safety and efficacy of 
113  a drug product that seeks an indication for the temporary improvement of upper facial lines.  The 
114  sponsor is referred to the guidance for industry Providing Clinical Evidence of Effectiveness for 
115  Human Drug and Biological Products. 
116   
117  We recommend using both investigator-assessed and patient-reported outcome assessment tools 
118  to support the primary efficacy endpoint.  We  encourage the use of well-defined, valid, and 
119  reliable patient-reported outcome measures to assess the subjects perspective related to drug 
120  product effectiveness. 
121   
                                                 
5 See the Pediatric Research Equity Act (Public Law  108-155; section  505B(e)(2)(A) of the Federal Food, Drug, and  
Cosmetic Act; 21 U.S.C. 355B) as amended by the Food and Drug  Administration Safety and Innovation Act 
(Public Law  112-144). 
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122  See section III.B.9., Efficacy Endpoints, for a detailed discussion of endpoints and endpoint 
123  assessments.  
124   
125  4.  Safety Considerations 
126   
127  The protocol should specify the methods to be used to obtain safety data during the course of the 
128  clinical trials. Generally, both adverse event information and safety laboratory data should be 
129  collected during clinical trials.  All subjects should be evaluated for safety at the time of each 
130  trial visit or assessment, regardless of whether the investigational drug product has been 
131  discontinued.  All adverse events should be followed until resolution, even if time on clinical 
132  trial would otherwise have been completed.  
133   
134  Botulinum toxin drug products present a unique set of safety concerns related to the potential for 
135  local and distant spread of toxin effect.  Therefore, safety data related to this specific potential 
136  effect should be obtained through directed query and physical examination to evaluate for signs 
137  and symptoms of local and distant spread of toxin effect (see Appendix A).  Assessment for 
138  effects on the neuromusculature should be performed for a sufficient duration post-treatment to 
139  capture late-onset events. 
140   
141  Sponsors should conduct repeat-dose trials to evaluate efficacy and safety after repeated 
142  administration of the investigational drug product for the improvement of upper facial lines.  For 
143  drug products that seek an indication for upper facial lines in more than one anatomic area, drug 
144  product safety information would be needed for each area independently as well as for 
145  concomitant administration to more than one anatomic area, because adverse reactions related to 
146  local spread of toxin effect often will be specific to the anatomic area. 
147   
148  Drug products for the temporary improvement of upper facial lines have the potential for chronic 
149  intermittent use; therefore, sponsors should establish the long-term safety of the drug product in 
150  the proposed population at the proposed dose. Long-term controlled trial data are preferred over 
151  open-label extension safety data because of the difficulty in interpreting adverse events data in 
152  the absence of a concurrent control.  The ICH guidance for industry E1A The Extent of 
153  Population Exposure to Assess Clinical Safety:  For Drugs Intended for Long-Term Treatment of 
154  Non-Life-Threatening Conditions provides advice regarding the number of subjects exposed and 
155  duration of treatment needed to inform the safety database.  However, because upper facial lines 
156  are aesthetic indications and the risk-benefit assessment for this indication differs from that for 
157  indications such as blepharospasm, cervical dystonia, migraine, or spasticity, the minimum 
158  number of subjects described in ICH E1A may not be sufficient to allow assessment of the risk 
159  versus the benefit for the indications of upper facial lines, conditions with minimal morbidity.  
160  The size of the safety database may vary depending on the formulation and anatomic location to 
161  be treated. We recommend consulting the review division regarding this issue.  
162   
163  Sponsors should address the potential for immunogenicity of botulinum toxin, especially for a 
164  long-term treatment paradigm, and evaluate the effect of immunogenicity on the efficacy and 
165  safety. 
166   
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167  B.  Phase 3 Efficacy Trial Considerations 
168   
169  The protocol should describe the trial objectives, the target population, investigational drug 
170  product dosage and duration of treatment, the primary endpoints, and key planned statistical 
171  analyses. In addition, the trial design should support the proposed claims by taking into 
172  consideration the following factors. 
173   
174  1.  Trial Design 
175   
176  In general, sponsors should conduct two randomized, double-blind, controlled trials to establish 
177  efficacy and safety. The preferred design should include a comparison to placebo or vehicle.  In 
178  a placebo-controlled design, potential influences on the course of the condition other than those 
179  arising from the pharmacologic action of the investigational drug product can be controlled via 
180  randomization and blinding.  The sponsor is referred to the guidance for industry Providing 
181  Clinical Evidence of Effectiveness for Human Drug and Biological Products.  
182   
183  2.  Trial Population 
184   
185  The trial population should reflect the patient population that would be reasonably considered for 
186  treatment with the drug product, should the drug product be shown to be effective.  It is 
187  important that the trial population not be made artificially narrow.  
188   
189  The past use of botulinum toxin drug products may affect the outcome with regard to both safety 
190  and efficacy and should be addressed in protocols for the temporary treatment of upper facial 
191  lines. In addition, the likelihood of unintentional unblinding could increase because individuals 
192  previously treated with botulinum toxin for upper facial lines may be more likely to determine 
193  whether they received the investigational drug product or placebo.  If subjects are enrolled who 
194  have had previous treatment with botulinum toxin, sponsors should record this status at baseline 
195  to allow for a subgroup analysis to explore how previous exposure affects safety and efficacy.  
196   
197  To adequately represent the population of future use, the pivotal trials should enroll subjects with 
198  all levels of severity of facial lines who meet the inclusion criteria, including subjects at the 
199  upper end of severity. 
200   
201  We encourage enrollment of subjects with a diversity of Fitzpatrick skin types.   
202   
203  A sufficient number of subjects 65 years of age and older should be evaluated at the level of 
204  exposure (dose and duration) proposed for use to support conclusions regarding drug safety and 
205  efficacy in this population. Refer to the ICH guidance for industry E7 Studies in Support of 
206  Special Populations: Geriatrics. 
207   
208  3.  Inclusion and Exclusion Criteria 
209   
210  Inclusion criteria should specify a minimum baseline level of condition severity.   
211   
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212  Subjects with the following characteristics should be excluded from trials for the temporary 
213  improvement of upper facial lines: 
214   
215     Concurrent or recent (e.g., within the last 6 months) use of any other botulinum toxin 
216  drug product 
217   
218     Known immunization or hypersensitivity to any botulinum toxin serotype 
219   
220     Anticipated need for treatment with botulinum toxin of any serotype for any reason 
221  during the trial (other than the investigational treatment) 
222   
223     Any medical condition that may put the subject at increased risk with exposure to 
224  botulinum toxin including diagnosed myasthenia gravis, Eaton-Lambert syndrome, 
225  amyotrophic lateral sclerosis, or any other condition that might interfere with 
226  neuromuscular function 
227   
228     Pregnancy or lactation 
229   
230  4.  Concomitant Treatments 
231   
232  Sponsors should address in the protocol the use of other drug products that are intended for the 
233  treatment of wrinkles or facial lines, such as retinoids and fillers, for the temporary improvement 
234  of upper facial lines because concomitant use of these drug products may affect the outcomes.  
235  The protocol should define the concomitant therapy that is acceptable, and sponsors should 
236  record information on use of concomitant medications for a prespecified period before and 
237  during the trial. One option would be to exclude use of such drug products (such as retinoids and 
238  fillers) for an appropriate interval before trial initiation and for the duration of the trial (or at least 
239  up to the primary assessment time point).   
240   
241  5.  Randomization, Stratification, and Blinding 
242   
243  Subjects should be randomized for receipt of the investigational drug product at enrollment.  All 
244  trials should be multicenter, well-controlled, and double-blind.  Randomization and blinding are 
245  important to minimize biases. 
246   
247  Efficacy assessments in the evaluation of drug products for the temporary treatment of upper 
248  facial lines have a certain level of subjectivity.  In addition, the mechanism of action of 
249  botulinum toxin (paralysis or diminution of facial muscular activity) may lead to unblinding even 
250  in subjects who do not meet objective criteria to be considered responders.  Therefore, it is 
251  important that the protocol documents steps to maintain double-blinding (subject and assessor) to 
252  the extent possible. (See section III.B.11., Endpoint Adjudication.)  
253   
254  If the effects of treatment are expected to differ substantially among different groups of subjects 
255  (e.g., baseline condition severity, prior botulinum toxin use), it may be desirable to stratify at 
256  randomization on that factor. 
257   
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258  6.  Specific Populations 
259   
260  The currently approved botulinum toxin drug products labeling indicates that there are no 
261  adequate and well-controlled trials in pregnant women.  
262   
263  As noted in section III.B.3., Inclusion and Exclusion Criteria, pregnant subjects and nursing 
264  mothers should be excluded from trials of botulinum drug products for the temporary treatment 
265  of upper facial lines. 
266   
267  With regard to pediatric subjects, as noted in section III.A.2., Drug Development Population, 
268  upper facial lines are uncommon in the pediatric population; the sponsor may request a waiver 
269  for the requirement to submit a pediatric assessment.  
270   
271  With regard to geriatric subjects, as noted in section III.A.2., Drug Development Population, a 
272  sufficient number of subjects 65 years of age and older should be evaluated at the level of 
273  exposure (dose and duration) proposed for use to support conclusions regarding drug safety and 
274  efficacy in this population. 
275   
276  7.  Dose Selection 
277   
278  Clinical trials to identify an appropriate (safe and effective) dose are an important component of 
279  phase 2 development for a botulinum toxin drug product.  (See section III.A.1., Early Phase 
280  Clinical Development Considerations, for a more detailed discussion of dose-ranging.)  
281  Assessment of the safety and efficacy of repeat treatment should be included in the development 
282  program.  
283   
284  8.  Choice of Comparators 
285   
286  See section III.B.1., Trial Design, for a discussion of comparators.   
287   
288  9.  Efficacy Endpoints  
289   
290  a.  Assessment measures 
291   
292  Measurements at maximum contraction should be used to assess the efficacy of botulinum toxin 
293  drug products to demonstrate the paralytic effect of the botulinum toxin.  This is needed to 
294  justify the use of botulinum toxin in a drug product intended for aesthetic use (i.e., to show that 
295  the toxin has a paralytic effect on muscle and therefore is necessary for drug product 
296  effectiveness).  
297   
298  The recommended co-primary efficacy endpoints should be based on well-defined and reliable6  
299  clinician-reported and patient-reported assessments that are developed to measure the critical 
300  outcomes that contribute to a conclusion of overall success or failure.   
301   
                                                 
6 See 21 CFR 314.126. 
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302  Instrument development for the subject assessment of line severity in the targeted area should be 
303  based upon qualitative research conducted in the target patient population to ensure the 
304  instrument content is appropriate for the targeted patient population to be studied in clinical 
305  trials.7  Similarly, clinician input is valuable in the development of well-defined and reliable 
306  clinician-reported outcome measures.  Upper facial lines are aesthetic conditions; therefore, the 
307  endpoints should include an assessment of the effect of the drug product on outcomes that are 
308  important to the targeted patient population.  If an adequate patient-reported or clinician-reported 
309  instrument is not available for assessment of upper facial lines, the new instrument development 
310  process should begin well in advance of phase 3 clinical trials so that the instrument can be ready 
311  for incorporation into the phase 3 protocol.  
312   
313  For both investigator- and subject-assessment instruments, the scales should be ordinal, static 
314  (meaning the evaluation is of the current severity rather than a change in severity relative to a 
315  previous time point), and comprised of a limited number of categories or grades.  Each category 
316  should represent a distinct and clinically meaningful gradation of the condition, and should be 
317  defined by a noncomparative, nonoverlapping, clinically relevant morphologic description to 
318  minimize interobserver variability.  The category of none or zero should represent true absence 
319  of the condition. A photonumeric guide with examples of each grade can be provided to 
320  investigators and subjects as an assessment aid to facilitate optimal inter- and intrarater  
321  reliability. The same scale should be used throughout the trial, including at enrollment, at the 
322  primary efficacy time point, and at time of assessment for loss of effect.  To provide internal 
323  correlation, the subjects self-assessment (SSA) and the investigators assessment (IA) scales 
324  should contain the same number of categories.   
325   
326  The degree of improvement determined to be clinically meaningful (and therefore appropriate for 
327  regulatory decisions) should be determined during instrument development and should be 
328  discussed with the FDA before trial initiation.  Statistically significant differences between 
329  comparator regimens may not be sufficient for demonstrating benefit if response to treatment has 
330  not been shown to be clinically meaningful. 
331   
332  For LCLs, efficacy should be based on bilateral results (both sides of the face) rather than results 
333  from each side of the face counted separately.  Success should be determined at the subject level 
334  such that a subject would be considered a success only if both left and right side assessments 
335  meet the success criteria.   
336   
337  We also encourage sponsors to discuss endpoint measures with the FDA in the early planning 
338  phases of clinical development.  For novel outcome measures, we recommend that the sponsor 
339  submit a draft instrument (complete instrument and description of plans for the development and 
340  testing of the instrument) to the investigational new drug application for FDA review as early as 
341  possible in the development program.  
342   
                                                 
7 For recommendations on how to  determine whether a clinical outcome assessment is well-defined  and  reliable, 
refer to the guidance for industry Patient-Reported Outcome Measures:   Use in Medical  Product Development to 
Support Labeling Claims.  
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343  b.  Endpoints 
344   
345  For each anatomic region, the primary efficacy endpoint should be based on responder rates 
346  defined by an IA scale at maximum contraction and an SSA scale at maximum contraction.  
347  Maximum contraction should be defined based on the targeted area (e.g., maximum frown for 
348  glabellar lines, maximum smile for LCLs).   
349   
350  As discussed in section III.B.9.a., Assessment measures, assessment at maximum contraction is 
351  needed to show that the toxin has a paralytic effect on muscle and therefore is necessary for the 
352  drug products efficacy. A drug product containing botulinum toxin that fails to demonstrate an 
353  effect at maximum contraction might have difficulty showing a favorable risk-benefit profile that 
354  is at the heart of regulatory decision making.  In addition, demonstration of efficacy at both 
355  extremes (maximum contraction (which represents the worst appearance of upper facial lines 
356  with maximum load on the muscle) and at rest (which represents the best appearance of upper 
357  facial lines with the least load on the muscle)) allows one to impute benefit when the face is in 
358  dynamic motion (variable load on the muscle).  
359   
360  The clinicians and subjects assessments of line severity at maximum contraction should be 
361  used at baseline to establish enrollment eligibility.  There should be a sufficient score at 
362  enrollment on each instrument such that a clinically meaningful response can be observed.   
363   
364  Success should be defined as achievement of a score of 0 or 1 and a two-grade improvement 
365  from the baseline, on both the IA and the SSA scales concurrently, to ensure clinical 
366  significance.  Because it may be possible to move to an adjacent category on the assessment 
367  scale with only a small level of improvement, a one-grade change may not represent a clinically 
368  meaningful intrasubject change.   
369   
370  Secondary endpoints should be clinically relevant, limited in number, and adjusted for 
371  multiplicity to control the type I error rate.  Assessments at rest (as opposed to at-maximum 
372  contraction) provide supportive evidence of efficacy and may be useful as secondary endpoints.  
373   
374  10.  Trial Procedures and Timing of Assessments 
375   
376  Clinical trial duration should be based on the onset of action of the drug product and should be of 
377  sufficient length to assess the durability of therapy benefits.  The clinical development program  
378  should include a trial that incorporates repeated doses for at least 1 year to assess for the safety of 
379  repeat doses. 
380   
381  Sponsors should also provide adequate evidence to support the selection of the time point(s) for 
382  assessment of the primary efficacy outcome.  The time point for assessment of the primary 
383  outcome should be at or after the onset of the full effect of the botulinum toxin drug product. 
384   
385  Sponsors should evaluate duration of effect with a clinically and statistically meaningful 
386  approach. Assessment measures for duration of effect should be the same as for the primary 
387  efficacy endpoint. Assessment of the duration of effect should reflect the time period for which 
388  a clinically meaningful proportion of subjects maintain response.  
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389   
390  11.  Endpoint Adjudication 
391   
392  Unblinding is a significant concern in trials for botulinum toxin drug products for the 
393  improvement in the appearance of facial lines.  Therefore, results of review of photographs at 
394  maximum contraction by a masked, independent committee of experts using the investigators 
395  static scale should be provided as a secondary endpoint.   
396   
397  12.  Statistical Considerations 
398   
399  Sponsors should address general statistical principles (e.g., randomization, blinding, 
400  prespecification, multiplicity control of type I error) in trials for botulinum toxin drug products 
401  for the improvement of upper facial lines in the same way as in trials for other medical drug 
402  products. However, some statistical issues may need special consideration in clinical trials for 
403  upper facial lines. 
404   
405  Sponsors should describe the randomization scheme, including the randomization ratio, and any 
406  stratification factors or block size, along with adequate details  about how subject assignment will 
407  be carried out.  Double-blind trials should be conducted whenever possible because of the 
408  subjective nature of the efficacy assessments. 
409   
410  Clinical trials should be adequately powered for the primary efficacy endpoints.  Sample size 
411  calculations are typically based on type I error, power, and expected outcomes.  In some cases, 
412  there may be a need to power the trial for safety as well, so that important adverse reactions can 
413  be adequately characterized, because there may be a low tolerance for serious or bothersome 
414  adverse reactions associated with aesthetic use drug products.   
415   
416  If the trial is designed with more than one primary endpoint, the protocol should specify the 
417  methodology that will be used to control the overall type I error rate.  The protocol should 
418  include a plan for adjusting for multiplicity in cases with more than one primary or secondary 
419  endpoint. If the primary efficacy endpoint is a success rate based on meeting multiple criteria for 
420  achieving response, then the criteria for achieving success should be defined (e.g., achieving a 
421  score of 0 or 1 and at least two grades reduction on both the IA and SSA scales).  
422   
423  Sponsors should specify the statistical methods to be used for the analysis of all endpoints.  They 
424  should be appropriate for the type of data collected.  The statistical methods should be specified 
425  with sufficient details, including any model terms, covariates, or stratification factors.  If there 
426  are particular subgroups of interest, subgroup analyses should be planned in the protocol.  The 
427  subgroup analyses should be designed so as to maintain control of the type I error rate. 
428   
429  The primary analysis population should be the intent-to-treat population defined as all subjects 
430  randomized and dispensed the investigational drug product.  The protocol should prespecify a 
431  plan for handling missing data, along with the justification for any assumptions needed for the 
432  imputation method.  The protocol should also prespecify a plan for sensitivity analyses regarding 
433  the handling of missing data.   
434   
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435  Sponsors should describe the follow-up visit schedule.  Long-term follow-up may be needed to 
436  assess duration of effect. Protocols should include plans to minimize loss to follow-up, because 
437  subjects may not be motivated to return for follow-up after receiving treatment or may comply 
438  with only some of the post-treatment visits. 
439   
440  Because botulinum toxin drug products generally are administered by the investigator, 
441  investigator technique or skill may affect the results.  Trials should be designed to enroll a 
442  sufficient number of subjects per center so that investigator-to-investigator variability and 
443  treatment-by-center interactions can be adequately assessed.   
444   
445  13.  Accelerated Approval (Subpart H) Considerations  
446   
447  Upper facial lines are not a serious or life-threatening condition; therefore, accelerated 
448  approval is not appropriate. 
449   
450  14.  Risk-Benefit Considerations 
451   
452  Assessment of risks and benefits involves an assessment of the effect of the botulinum toxin drug 
453  product on the condition of upper facial lines.  The primary efficacy analysis should demonstrate 
454  a statistically significant result and the measured clinical effect of the botulinum toxin drug 
455  product should be clinically meaningful.  Toxicities related to the pharmacologic effects of the 
456  botulinum toxin drug product (e.g., potential for distant spread of toxin effect) also should be 
457  considered as part of this overall risk-benefit assessment. 
458   
459  C.  Other Considerations 
460   
461  1.  Risk Management Considerations 
462   
463  Botulinum toxin drug products for the treatment of upper facial lines are prescriber-administered.  
464  Patients need to be aware of the potential safety issues that have arisen with the use of these drug 
465  products to make an informed decision as to whether they wish to receive this therapy.  For this 
466  reason, a Medication Guide should be provided to each patient before treatment after approval.   
467   
468  2.  Pharmacokinetic/Pharmacodynamic Considerations 
469   
470  Currently, it is not possible to detect botulinum toxin in the peripheral blood following 
471  intramuscular injection at doses recommended for use for approved drug products for upper 
472  facial lines because of the limits of available analytical technology.  The need for 
473  pharmacokinetic assessment may be reevaluated as new technologies become available. 
474   
475  3.  Special Investigation Considerations 
476   
477  For topical products, dermal safety studies with the final to-be-marketed drug product should 
478  provide information regarding cumulative irritancy, contact sensitization, phototoxicity, and 
479  photo-contact allergic potential. 
480   
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481  4.  Labeling Considerations 
482   
483  The labeling for botulinum toxin drug products should include a boxed warning that describes 
484  the risk of distant spread of toxin effect as well as a Medication Guide to help patients better 
485  understand the potential risks associated with these drug products. 
486   
487  The labeling also should include a subsection in the WARNINGS AND PRECAUTIONS section 
488  that warns that the potency units of one botulinum toxin drug product are not interchangeable 
489  with other preparations of botulinum toxin drug products.  Recommended frequencies for 
490  retreatment should be included in the DOSAGE AND ADMINISTRATION section. 
491   
492  The INDICATIONS AND USAGE section of labeling for botulinum toxin drug products 
493  intended to improve upper facial lines should identify the anatomic location of the lines and the 
494  underlying musculature involved in their development.  The nonpermanent nature of the 
495  treatment should be conveyed.   
496   
497  Representative examples of indication statements for a botulinum toxin drug product intended to 
498  improve upper facial lines can include: 
499   
500     The temporary improvement in the appearance of moderate to severe glabellar lines 
501  associated with corrugator and procerus muscle activity in adults  
502   
503     The temporary improvement in the appearance of mild to moderate LCLs associated with 
504  orbicularis oculi activity in adults  
505   
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506  APPENDIX A 
507   
508  The following adverse events potentially suggestive of distant spread of toxin, and therefore of 
509  special interest, include:  
510   
accommodation disorder  extraocular muscle paresis   paresis cranial nerve 
areflexia  eyelid function disorder   peripheral nerve palsy  
aspiration  eyelid ptosis  peripheral paralysis  
blurred vision  facial palsy  pelvic floor muscle weakness 
botulism    facial paresis  pneumonia aspiration 
Bradycardia  fourth cranial nerve paresis  pupillary reflex impaired 
bulbar palsy  hemiparesis  quadriparesis 
constipation  hypoglossal nerve paresis  respiratory arrest 
cranial nerve palsies  hyporeflexia  respiratory depression 
cranial nerve paralysis  hypotonia  respiratory failure 
diaphragmatic paralysis  monoparesis  speech disorder 
diplopia  muscular weakness  third cranial nerve paresis 
dry mouth  paralysis  trigeminal nerve paresis 
dysarthria  paralysis flaccid   urinary retention  
dysphagia  paralytic ileus  vocal cord paralysis  
dysphonia  paraparesis  vocal cord paresis 
dyspnea  paresis   
511   
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