Migraine:  Developing 
Drugs for Preventive 
Treatment 
Guidance for Industry  
 
 
 
 
 
 
DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 Dockets Management Staff (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 (CDER) Heather Fitter at 301-796-3984.  
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
June 2023 
Clinical/Medical 
35755476dft.docx 
05/30/23   
Migraine:  Developing 
Drugs for Preventive 
Treatment 
Guidance for Industry 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD  20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: 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) 
 
May 2023 
Clinical/Medical 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  DEVELOPMENT PROGRAM ....................................................................................... 2 
A.  Efficacy Considerations ................................................................................................................. 2 
1. Trial Design ..................................................................................................................................... 3 
2. Trial Population and Entry Criteria ................................................................................................ 3 
3. Dose Selection .................................................................................................................................. 4 
4. Concomitant Medications ................................................................................................................ 4 
5. Efficacy Endpoints ........................................................................................................................... 5 
6. Trial Procedures and Timing of Assessments .................................................................................. 5 
7. Patient-Reported Outcomes ............................................................................................................. 6 
8. Statistical Considerations ................................................................................................................ 6 
B.  Safety Considerations .................................................................................................................... 7 
C.  Other Considerations..................................................................................................................... 7 
1. Pediatric Studies .............................................................................................................................. 7 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Migraine:  Developing Drugs for Preventive Treatment  
2  Guidance for Industry1 
3   
4   
5   
6  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
7  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
8  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
9  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
10  for this guidance as listed on the title page. 
11   
12   
13   
14  I.  INTRODUCTION 
15   
16  The purpose of this guidance is to assist sponsors in the clinical development of drugs for the 
17  preventive treatment of migraine.2  Pharmacological approaches to the treatment of migraine 
18  include drugs to abort migraine attacks as they arise (acute treatment of migraine) and drugs to 
19  reduce the frequency of migraine attacks (preventive treatment).  Specifically, this guidance 
20  addresses the Food and Drug Administrations (FDAs) current thinking regarding the overall 
21  development program and clinical trial designs to support approval of drugs for the preventive 
22  treatment of migraine.3  This guidance does not address the development of drugs indicated for 
23  the acute treatment of migraine.  Such development has been addressed in the guidance for 
24  industry Migraine: Developing Drugs for Acute Treatment (February 2018).4 
25   
26  This guidance does not contain discussion of the general issues of statistical analysis or clinical 
27  trial design.  Refer to FDAs ICH guidances for industry E9 Statistical Principles for Clinical 
28  Trials (September 1998), E9(R1) Statistical Principles for Clinical Trials: Addendum: Estimands 
29  and Sensitivity Analysis in Clinical Trials (May 2021), and E10 Choice of Control Group and 
30  Related Issues in Clinical Trials (May 2001) for discussion of these topics. 
31   
 
1 This guidance has been prepared by the Division of Neurology II in the Center for Drug Evaluation and Research 
at the Food and Drug Administration.  
 
2 For the purposes of this guidance, all references to drugs include both drugs approved under section 505 of the 
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355) and biological products licensed under section 351 of the 
Public Health Service Act (42 U.S.C. 262), unless otherwise specified.  Also, see definitions of drug product and 
biological product in 21 CFR 314.3 and 600.3, respectively 
 
3 In addition to consulting guidances, sponsors are encouraged to contact the Division of Neurology II to discuss 
specific issues that arise during the development of drugs for the preventive treatment of migraine. 
 
4 We update guidances periodically.  For the most recent version of a guidance, check the FDA guidance web page 
at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
 
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
32  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
33  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
34  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
35  the word should in Agency guidances means that something is suggested or recommended, but 
36  not required.  
37   
38   
39  II.  BACKGROUND 
40   
41  Migraine is a chronic neurovascular disorder characterized by recurrent attacks of often severe 
42  headache, typically accompanied by nausea and sensitivity to light and/or sound.  In adults, 
43  migraine attacks usually last from 4 to 72 hours.  Migraine headache is typically throbbing, 
44  unilateral, and aggravated by physical activity.  Criteria proposed by the International Headache 
45  Society are called the International Classification for Headache Disorders (ICHD) and require a 
46  combination of some of these characteristics and associated symptoms in at least five attacks to 
47  establish a diagnosis of migraine.5 
48   
49  Patients may experience migraine with or without aura.  Migraine with aura is characterized by 
50  focal neurological symptoms (e.g., visual disturbances, abnormal sensations) that typically 
51  precede, or sometimes accompany, the headache.  These focal neurological symptoms are absent 
52  in migraine without aura.  Some patients may present with both types of migraine. 
53   
54   
55  III.  DEVELOPMENT PROGRAM 
56   
57  A.  Efficacy Considerations 
58   
59  Subjects enrolled in clinical trials for the preventive treatment of migraine should have a 
60  diagnosis of either chronic migraine or episodic migraine.  Chronic migraine is defined by the 
61  ICHD as headache occurring on 15 or more days per month for more than 3 months, which, on at 
62  least 8 days per month, has the features of migraine headache.  Patients with chronic migraine 
63  may overuse acute medication and may also fulfill the ICHD criteria for medication overuse 
64  headache.5  Randomization of subjects with chronic migraine into clinical trials should be 
65  stratified based on the presence or absence of a concomitant diagnosis of medication overuse 
66  headache.  Patients with episodic migraine have intermittent, recurrent attacks that meet ICHD 
67  criteria5 for migraine with or without aura, with headache occurring on 14 or fewer days per 
68  month.  Subjects eligible for enrollment in a chronic or episodic migraine clinical trial should 
69  have confirmation of the diagnosis based on their monthly frequency of migraine or headache 
70  during a baseline observation period.  
71   
72  Sponsors should consider chronic migraine and episodic migraine separately when developing 
73  drugs for the preventive treatment of migraine because the response to treatment may vary in 
74  these two patient populations.  In addition, episodic migraine patients may be more able to 
75  accurately define the beginning and end of a migraine attack, whereas chronic migraine patients 
 
5 International Classification of Headache Disorders is available at https://ichd-3.org/classification-outline/. 
 
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
76  may have difficulty distinguishing individual headache episodes when headache continues over 
77  several days.   
78   
79  To support an indication for the preventive treatment of migraine (i.e., an indication comprising 
80  both patients with chronic migraine and episodic migraine), efficacy should be demonstrated in a 
81  minimum of one adequate and well-controlled trial in each population.   
82   
83  If a drug is already approved for the acute treatment of migraine, a single additional adequate 
84  and well-controlled trial evaluating its efficacy for the preventive treatment of migraine could 
85  support a preventive treatment indication for the population studied in that trial (i.e., patients 
86  with either chronic or episodic migraine). 
87   
88  1.  Trial Design 
89   
90  In general, confirmatory trials should use a randomized, double-blind, placebo-controlled 
91  parallel group design.  There may be circumstances in which randomization to an active control 
92  may be appropriate.  It is usually preferable to study at least two dose levels in the confirmatory 
93  trial (see Section III. A. 3., Dose Selection).   
94   
95  2.  Trial Population and Entry Criteria 
96   
97  Subjects enrolled in clinical trials should have a diagnosis of either chronic migraine or episodic 
98  migraine, as stated previously.  Migraine subjects with and without aura may be enrolled in 
99  confirmatory trials.  The time since initial diagnosis of migraine should be at least 12 months 
100  before enrollment, with eligibility at enrollment based on a minimum 3-month history of 
101  migraine frequency, and with confirmation of migraine frequency observed during a minimum 1-
102  month prospective baseline period (although a longer baseline period can provide a more stable 
103  estimate of migraine frequency).  Although trials should attempt to enroll a broad age range of 
104  subjects, the age at the time of initial migraine diagnosis should generally be younger than 50 
105  years old to decrease the chance of enrolling subjects with headaches attributable to another 
106  underlying disorder that may mimic migraine (e.g., a brain neoplasm, stroke, temporal arteritis, 
107  etc.).  If subjects have more than one headache type, they should be able to distinguish their other 
108  headache types (e.g., tension-type headaches) from their migraines.   
109   
110  When developing clinical trial protocols, sponsors should ensure that trial sites and outreach 
111  efforts are broad enough to allow for a representative sample of the population for which the 
112  drug may be indicated.  Sponsors should try to include a diverse population, including a 
113  sufficient number of racial and ethnic minority subjects, male subjects, and a sufficient number 
114  of subjects over 65 years of age to conduct an adequate assessment of safety and efficacy in 
115  these subgroups.6  
116   
117   
118   
 
6 See the guidance for industry Enhancing the Diversity of Clinical Trial Populations  Eligibility Criteria, 
Enrollment Practices, and Trial Designs (November 2020). 
 
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
119  3.  Dose Selection 
120   
121  Early phase trials should explore a range of doses to assess dose-response relationships for safety 
122  and efficacy and to inform dose selection for the confirmatory trials.  Confirmatory trials should 
123  identify the lowest dose that provides a desirable treatment effect.  Sponsors should also conduct 
124  adequate evaluations of drug interaction potential with combined oral contraceptives.7 
125   
126  Sponsors should obtain plasma drug concentration data in subjects.  Establishing a plasma 
127  concentration (exposure)-response relationship can be useful to support optimal dose selection in 
128  the general population.  These data can be used to inform dosing recommendations based on 
129  specific intrinsic and extrinsic factors (e.g., body weight and hepatic and renal function).  
130   
131  In long-term safety studies, the majority of the safety experience should be in subjects who are 
132  on the highest dose planned for marketing. 
133   
134  4.  Concomitant Medications 
135   
136  During the conduct of early trials, and until the drug-drug interaction liability of the drug is 
137  adequately understood, concomitant medications should be avoided.  Assuming no important 
138  pharmacokinetic/pharmacodynamic drug-drug interactions are anticipated, sponsors can use 
139  concomitant preventive medications for migraine in later stage trials, but only if the dosage of 
140  those concomitant medications has been stable for an adequately justified period of time before 
141  inclusion into the trial.  Subjects should also remain on stable doses of the concomitant drug 
142  during the entire duration of the trial.  Sponsors should document prior and concomitant use of 
143  preventive treatments for migraine during the screening phase of the trials.  
144   
145  Drugs used for the preventive treatment of migraine are also often used for the treatment of 
146  nonmigraine indications and/or can be used to treat other comorbid disorders (e.g., epilepsy, 
147  depression, hypertension); therefore, sponsors should clearly document the diagnosis associated 
148  with each treatment.  Because the use of other preventive migraine treatments may influence the 
149  interpretation of both safety and efficacy, no more than 30 percent of the study population should 
150  be taking a concomitant medication for the preventive treatment of migraine during the trial, and 
151  randomization should be stratified by the use of such concomitant medications.  Subjects taking 
152  more than one such concomitant preventive medication should typically not be enrolled.  
153   
154  If subjects have recently discontinued a drug for the preventive treatment of migraine, 
155  withdrawal should be complete for at least 1 month or 5 half-lives, whichever is longer, before 
156  entry into the trial.  Generally, acute treatments for migraine (triptans, nonsteroidal anti-
157  inflammatories, etc.) should be allowed; however, sponsors should record the use of all such 
158  medications.  Changes in the frequency of use of medications for the acute treatment of migraine 
159  should be evaluated as a secondary efficacy endpoint (see Section III. A. 5). 
160   
 
7 See also the draft guidance for industry Clinical Drug Interaction Studies With Combined Oral Contraceptives 
(November 2020).  When final, this guidance will represent the FDAs current thinking on this topic.  For the most 
recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents. 
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
161  5.  Efficacy Endpoints 
162   
163  In episodic migraine trials, the primary efficacy endpoint should assess the change from baseline 
164  in the number of monthly migraine days (see the migraine day example below).  For chronic 
165  migraine trials, sponsors may use the change from baseline in the number of monthly migraine 
166  days or in the number of monthly headache days (of moderate/severe intensity and/or requiring 
167  use of an acute migraine medication) as the primary efficacy endpoint.  In the latter scenario, the 
168  change from baseline in monthly migraine days should be evaluated as a secondary efficacy 
169  endpoint instead.  
170   
171  Sponsors should assess the following secondary efficacy endpoints in a manner that controls for 
172  type I error: 
173    
174  a.  Change from baseline in the number of days per month subjects use an acute/rescue 
175  medication to treat an acute migraine 
176   
177  b.  Change from baseline in prospectively defined monthly headache days (if monthly 
178  migraine days is the primary endpoint) or in monthly migraine days (if monthly headache 
179  days is the primary endpoint) 
180   
181  Sponsors may consider evaluating secondary endpoints that assess responder rates for the 
182  primary efficacy endpoint (e.g., a reduction in the number of mean monthly migraine days from 
183  baseline by at least 50 percent).  Sponsors may also consider additional secondary endpoints (see 
184  Section III. A. 7., Patient-Reported Outcomes).  Ordering of secondary endpoints should be 
185  based on the trial objectives and intended claims in labeling.  Typically, secondary endpoints to 
186  be described in labeling should not be duplicative of the primary endpoint.   
187   
188  A migraine (and/or headache) day should be prospectively defined based on prespecified criteria.  
189  For example, a migraine day could be defined as any calendar day during which the subject 
190  experienced a qualified migraine headache lasting for at least 30 minutes and having at least two 
191  of the following features: unilateral location, throbbing, moderate to severe intensity, 
192  exacerbated by exercise/physical activity or at least one of the following symptoms: nausea 
193  and/or vomiting, photophobia, or phonophobia.  A migraine day should also include any day 
194  during which a subject takes acute migraine medications, regardless of the duration of pain.  
195   
196  A headache day could be defined as any calendar day during which the subject experienced a 
197  qualified migraine or nonmigraine headache that lasts continuously for greater than or equal to 4 
198  hours or a headache of any duration for which acute treatment is administered. 
199   
200  6.  Trial Procedures and Timing of Assessments 
201   
202  The double-blind treatment phase should be at least 3 months in duration.  A follow-up visit 
203  should occur at least 1 month or 5 half-lives after the last dose, whichever is longer, to 
204  adequately capture adverse events that may be related to the drug (including any increase in 
205  migraine frequency upon treatment discontinuation).    
206   
  5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
207  Data should be collected in a headache diary.  We recommend using electronic diaries so that 
208  data can be time stamped, tracked, and audited to monitor compliance, ensure data integrity, and 
209  reduce recall bias.  The headache diary should be shown to be well-defined and reliable for the 
210  target population based on the recommendations described in the draft guidance for industry 
211  Patient-Focused Drug Development: Selecting, Developing, or Modifying Fit-for-Purpose 
212  Clinical Outcome Assessments (June 2022).8  
213   
214  7.  Patient-Reported Outcomes 
215   
216  A patient-reported outcome (PRO) is any report of the status of a patients health condition that 
217  comes directly from a patient, without interpretation of the patients response by a clinician or 
218  other person.  In clinical studies for migraine, the primary endpoint is typically patient reported.  
219  Other PRO instruments can also be used as secondary endpoints to assess treatment benefit.  
220  Sponsors that intend to develop and/or include a PRO instrument in their programs should 
221  engage early with the review division.  In general, instruments should assess concepts or 
222  domains that are important to patients, are sensitive to clinically meaningful change, have 
223  scoring that can be easily interpreted, and have a recall period that is appropriate for the 
224  proposed study design and endpoints.  Further information on using a validated PRO may be 
225  found in the draft guidances for industry Patient-Focused Drug Development: Selecting, 
226  Developing, or Modifying Fit-for-Purpose Clinical Outcome Assessments and Patient-Focused 
227  Drug Development: Incorporating Clinical Outcome Assessments Into Endpoints For Regulatory 
228  Decision-Making (April 2023).9 
229   
230  8.  Statistical Considerations 
231   
232  The primary efficacy analysis should compare the reduction from baseline in monthly migraine 
233  days (or headache days) between treatment groups during a prospectively defined evaluation 
234  period.  The pharmacodynamic and/or pharmacokinetic (PK) characteristics of a drug may 
235  inform the appropriate duration of this period.  Sponsors may choose to define this evaluation 
236  period as the entire double-blind treatment period (i.e., a minimum of 3 months), or alternatively, 
237  over the last month of this period.  If the primary efficacy analysis only considers the final month 
238  of the double-blind treatment period, then a sensitivity analysis should assess the entire post-
239  randomization period.  
240   
241  To improve the precision of treatment effect estimation and inference, sponsors could consider 
242  adjusting for prespecified baseline factors (e.g., baseline use of concomitant medications for 
243  preventive treatment of migraine or baseline number of monthly headache/migraine days) that 
244  are anticipated to be prognostic of the outcome.  If randomization is stratified by baseline 
245  covariates, the analysis should account for the stratified randomization. 
246   
247  It is important to prospectively define the secondary endpoints and to include a statistical plan to 
248  control the type 1 error rate for multiple comparisons.  
249   
 
8 When final, this guidance will represent the FDAs current thinking on this topic. 
 
9 When final, these guidances will represent the FDAs current thinking on these topics. 
  6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
250  Study protocols should include provisions to limit missing data through design and monitoring.  
251  Sponsors should provide a prospective plan to handle missing diary data.  Sensitivity analyses 
252  should be conducted to evaluate the impact of missing data on efficacy results. 
253   
254  B.  Safety Considerations 
255   
256  Phase 1 trials, during which the investigational drug is administered under close medical 
257  supervision, provide the best opportunity to obtain safety data at time points close to 
258  administration of the investigational drug.  At a minimum, these early study safety assessments 
259  should include vital signs; laboratory evaluations including hematology, serum chemistry, and 
260  urinalysis; and a 12-lead electrocardiogram, at appropriate intervals pre- and post-dose.  Vital 
261  signs and electrocardiography should be assessed around the expected maximum concentration 
262  for the investigational drug and its major metabolites.  Sponsors should include risk assessments 
263  for QT prolongation.  Sponsors should obtain safety data during long-term phase 3 studies at 
264  baseline and at appropriate intervals post treatment.  The design of clinical studies should take 
265  into consideration the results of the nonclinical studies,10 prior human experience, and any other 
266  specific safety concerns with the investigational drug or with other drugs of the same class.    
267   
268  New molecular entities should follow the safety recommendations in the ICH guidance for 
269  industry E1A The Extent of Population Exposure to Assess Clinical Safety: For Drugs Intended 
270  for Long-Term Treatment of Non-Life-Threatening Conditions (March 1995).  The safety 
271  experience should be at relevant doses and frequency of administration, including substantial 
272  experience at the highest dose and highest frequency of administration proposed for marketing.  
273  The submission of additional product-specific safety data may also be necessary, including 
274  additional nonclinical studies and/or safety studies in populations at risk either before or post 
275  approval.  Consultation with FDA is advised early in the development program, especially if a 
276  safety signal has already been identified. 
277   
278  C.  Other Considerations 
279   
280  1.  Pediatric Studies 
281   
282  Sponsors are encouraged to begin discussions about their pediatric clinical development plan 
283  early in development because, for drug or biological product applications for a new active 
284  ingredient, new indication, new dosage form, new dosing regimen, or new route of 
285  administration,11 pediatric study plans are required to be submitted no later than 60 days (or such 
286  other time as agreed upon with FDA) after an end-of-phase 2 meeting.12  Migraine diagnosis for 
287  purposes of pediatric patient enrollment should be based on the most recent ICHD criteria.  
 
10 We support the principles of the 3Rs (reduce, refine, replace) for animal use in testing when feasible.  We 
encourage sponsors to consult with us if it they wish to use a nonanimal testing method they believe is suitable, 
adequate, validated, and feasible.  We will consider if such an alternative method could be assessed for equivalency 
to an animal test method.   
 
11 Section 505B(a)(1)(A) of the Federal Food, Drug, and Cosmetic Act (FD&C Act); 21 U.S.C. 355c(a)(1)(A). 
 
12 See section 505B(e)(2)(A) of the FD&C Act; 21 U.S.C. 355c(e)(2)(A). 
 
  7  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
288  Sponsors should refer to section 505B of the FD&C Act13 to review requirements for submission 
289  of an initial pediatric study plan, where appropriate.14   
290   
291  Migraine is a relatively common disorder in children.  The migraine phenotype is somewhat 
292  different between the adult and pediatric populations, and one cannot assume that a drug 
293  effective in adults will also be effective in children.  Therefore, studies in the pediatric 
294  population are needed to determine pediatric efficacy.  However, migraine, whether episodic or 
295  chronic, is less common in younger children and may be difficult to diagnose in children younger 
296  than 6 years old.  Of those children diagnosed before 6 years of age, even a smaller proportion of 
297  subjects are likely to require preventive therapy; therefore, studies of preventive treatment of 
298  either chronic or episodic migraine are considered highly impracticable.  For those applications 
299  that are subject to section 505B of the FD&C Act (i.e., applications for a new active ingredient, 
300  new indication, new dosage form, new dosing regimen, or new route of administration), and thus 
301  required to conduct pediatric studies, partial waivers of the pediatric study requirements are 
302  appropriate for studies of episodic migraine in subjects younger than 6 years of age.  Chronic 
303  migraine typically develops after the onset of episodic migraine and thus is rare in children 
304  younger than 12 years old.  Therefore, for those applications that are subject to section 505B of 
305  the FD&C Act, and thus required to conduct pediatric studies, partial waivers are appropriate for 
306  studies of chronic migraine in subjects younger than 12 years old.  Disease characteristics often 
307  change with puberty, and pediatric studies in episodic migraine should include adequate numbers 
308  of subjects to characterize safety and efficacy of the drug across the entire pediatric age range. 
309   
310  Sponsors should assess and compare the PK of the drug in the pediatric population with the PK 
311  of the drug in adults to permit proper dose selection for pediatric efficacy and safety studies.  PK 
312  data could be obtained either by a clinical PK evaluation or by modeling and simulations 
313  (currently accepted in adolescents if confirmed by sparse PK in the efficacy study).  The 
314  development of an age-appropriate formulation may be necessary.  Sponsors should consider 
315  adequate dose exploration in pediatric populations when feasible.  Sponsors may select the dose 
316  based on exposure matching to adults or conduct additional dose finding in pediatric 
317  populations.15 
318   
319  The pediatric studies required under section 505B of the FD&C Act will reflect the approved 
320  adult indication (i.e., preventive treatment of episodic migraine, preventive treatment of chronic 
321  migraine, or preventive treatment of migraine (which includes episodic and chronic migraine)).  
322  For drugs approved for the preventive treatment of migraine in adults (i.e., an indication 
323  comprising both episodic and chronic migraine), sponsors should conduct the following pediatric 
324  studies: 
 
13 Section 505B of the FD&C Act (21 U.S.C 355c) is often referred to as PREA, the acronym for the Pediatric 
Research Equity Act of 2003, which originally created it. 
 
14 See also the guidance for industry Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric 
Study Plans and Amended Initial Pediatric Study Plans (July 2020). 
 
15 See the draft guidance for industry General Clinical Pharmacology Considerations for Pediatric Studies for 
Drugs and Biological Products (December 2014).  When final, this guidance will represent the FDAs current 
thinking on this topic.  
 
  8  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
325   
326    Efficacy and safety study of episodic migraine in pediatric patients 6 to 17 years old 
327   
328  In a study of episodic migraine, a sufficient number of subjects in the 6- to 11-year-old and 
329  12- to 17-year-old subgroups should be included to be able to adequately characterize the 
330  efficacy and safety of the drug in each subgroup.  At least 25 percent of the subjects should 
331  be in the 6- to 11-year-old age group, and at least 25 percent of subjects should be male. 
332   
333    Efficacy and safety study of chronic migraine in pediatric patients 12 to 17 years old 
334   
335  In a study of chronic migraine, there should be a similar number of subjects in the 12- to 14-
336  year-old subgroup and in the 15- to 17-year-old subgroup.  At least 25 percent of subjects 
337  should be male. 
338   
339  The endpoints described above for adult studies should be evaluated in the pediatric safety and 
340  efficacy studies, with appropriate control of the type 1 error rate.  
341   
342  A 1-year long-term pediatric safety study should also be conducted.  Generally, if the drug is 
343  already approved in adults, the pediatric safety database should include data on at least 200 
344  subjects treated for 6 months and 75 subjects treated for 1 year.  The long-term safety study 
345  should include a sufficient representation of subjects across age subgroups, and at least 25 
346  percent of subjects should be male.  The study should evaluate the effects of the treatment on 
347  growth, cognition, and pubertal development.  
  9