Attention Deficit 
Hyperactivity Disorder: 
Developing Stimulant 
Drugs for 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DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 https://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 Tiffany Farchione or Juliette Toure 301-
796-2260.  
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
May 2019 
Clinical/Medical
26479406dft.docx 
04/30/19   
Attention Deficit 
Hyperactivity Disorder:  
Developing Stimulant 
Drugs for 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 
https://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 2019 
Clinical/Medical 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION AND BACKGROUND ..................................................................... 1 
II.  GENERAL CONSIDERATIONS ................................................................................... 1 
A.  Clinical Pharmacology................................................................................................................... 2 
B.  Trial Design .................................................................................................................................... 2 
C.  Pregnancy ....................................................................................................................................... 4 
III.  METHYLPHENIDATE AND AMPHETAMINE 505(b)(2) DEVELOPMENT 
PROGRAMS ..................................................................................................................... 4 
IV.  NEW MOLECULAR ENTITY ....................................................................................... 6 
REFERENCES .............................................................................................................................. 7 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Attention Deficit Hyperactivity Disorder:  
2  Developing Stimulant Drugs for Treatment 
3  Guidance for Industry1 
4   
5   
6   
7  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
8  Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not 
9  binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the 
10  applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible 
11  for this guidance as listed on the title page. 
12   
13   
14   
15  I.  INTRODUCTION AND BACKGROUND 
16   
17  This guidance is intended to provide general framework recommendations to sponsors 
18  developing stimulant drugs for treatment of attention deficit hyperactivity disorder (ADHD) in 
19  pediatric and adult patients. This guidance does not address development programs for 
20  nonstimulant drugs. 
21   
22  ADHD is a common neurobehavioral disorder with onset in childhood. It is characterized by a 
23  pattern of developmentally inappropriate and maladaptive inattentiveness, impulsivity, and 
24  hyperactivity, resulting in impairment in family, social, academic, and occupational functioning. 
25  Stimulant drugs (e.g., methylphenidate, amphetamine) are the most commonly prescribed 
26  medications for treatment of ADHD.  
27   
28  In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
29  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
30  as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
31  the word should in Agency guidances means that something is suggested or recommended, but 
32  not required. 
33   
34  II.  GENERAL CONSIDERATIONS 
35   
36  The principles outlined below apply to drug development programs for methylphenidate and 
37  amphetamine products developed and submitted under the 505(b)(2) application pathway 
38  (hereafter referred to as 505(b)(2) products) (section 505(b)(2) of the Federal Food, Drug, and 
39  Cosmetic Act (FD&C Act)) as well as for novel (i.e., new molecular entity (NME)) stimulant 
40  drugs. 
41   
                                                 
1 This guidance has been prepared by the Division of Psychiatry Products in the Center for Drug Evaluation and 
Research at the Food and Drug Administration. 
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
42  A.  Clinical Pharmacology 
43   
44  In general, central nervous system stimulant drugs demonstrate a strong concentration-response 
45  relationship for efficacy and safety (Kimko et al. 2012; Li et al. 2017). Therefore, sponsors can 
46  develop formulations using the same active moiety with the objective of creating drug product-
47  specific release features intended to affect the shape of the pharmacokinetic (PK) profile and the 
48  onset or duration of effect. Various clinical and clinical pharmacology trials may be of value in 
49  the clinical development program based on the characteristics of the active moiety, formulation 
50  features, and clinical experience.  
51   
52  The PK and pharmacodynamic (PD) features of a drug product, including the following, should 
53  be characterized in early-phase development in the target pediatric and adult patient populations:  
54   
55    The sponsor should characterize the relationship between blood concentrations of the 
56  drug product and cardiac parameters (e.g., heart rate, blood pressure) over time. 
57   
58    The sponsor should use dose-response or exposure-response modeling and simulation to 
59  inform the dose regimen selection for the adequate and well-controlled trials intended to 
60  support a marketing indication.  
61   
62  B.  Trial Design 
63   
64  Sponsors developing stimulant drug products for treatment of ADHD should consider the 
65  following for trial design: 
66   
67    Because ADHD is a disorder that begins in childhood, a new drug application (NDA) for 
68  any drug intended to treat ADHD should include data from adequate and well-controlled 
69  studies in pediatric patients (see sections III., Methylphenidate and Amphetamine 
70  505(b)(2) Development Programs, and IV., New Molecular Entity).  
71   
72    In general, the pathophysiology, disease characteristics, and treatment outcomes in 
73  ADHD are sufficiently similar between pediatric and adult patients such that, with two 
74  positive pediatric studies, an adult indication can be supported by a single trial in adult 
75  patients.  
76   
77    An NDA for a stimulant drug product should include data that are adequate to assess the 
78  safety and effectiveness of the drug for pediatric patients 4 years of age and older. The 
79  relevant pediatric age groups are 4 to 5 years of age, 6 to 12 years of age, and 13 to 17 
80  years of age. FDA recommends one study in adolescent patients (13 to 17 years of age) 
81  and one study in younger pediatric patients (4 to 12 years of age) to provide substantial 
82  evidence of effectiveness, as long as the following apply: 
83   
84    The duration of drug product effect is less than 12 hours 
85   
86    The shape of the PK profile is similar across age groups 
87   
2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
88    No safety concerns exist that preclude studying specific pediatric age groups (see 
89  sections III., Methylphenidate and Amphetamine 505(b)(2) Development Programs, 
90  and IV., New Molecular Entity) 
91   
92    For drug products with a long duration of effect (i.e., greater than 12 hours) and thus a 
93  greater potential to lead to important adverse events (e.g., significant effect on growth), 
94  or for new molecular entities about which little is known, safety data from pediatric 
95  patients 6 years of age and older may be necessary before the sponsor initiates studies in 
96  pediatric patients 4 to 5 years of age. FDA encourages sponsors to discuss the details and 
97  timing of their development programs with the Agency early, particularly for the studies 
98  in pediatric patients 4 to 5 years of age and, preferably, before initiating studies in 
99  pediatric patients 6 to 12 years of age. 
100   
101    For drug products with a long duration of effect or with PK profiles that are not similar in 
102  different age groups, FDA encourages sponsors to discuss their development strategies 
103  with the Agency. 
104   
105    The investigator should confirm the diagnosis of ADHD using a structured or semi-
106  structured clinical interview (e.g., Kiddie Schedule for Affective Disorders and 
107  Schizophrenia, Diagnostic Interview Schedule for Children).  
108   
109    The sponsor should evaluate safety and effectiveness in randomized, double-blind, 
110  placebo-controlled, parallel-group design trials. At least one randomized, fixed-dose trial 
111  examining more than one dose should be conducted. Patients should be randomized to 
112  drug or placebo, without open-label titration or dose-optimization before randomization 
113  that may obscure important safety findings. 
114   
115    Potentially acceptable primary efficacy measures include the ADHD Rating Scale; the 
116  Conners Comprehensive Behavior Rating Scales; Permanent Product Measure of 
117  Performance; and the Swanson, Kotkin, Agler, M-Flynn, and Pelham Scale. Sponsors 
118  should use a scale or version of a scale that has been appropriately validated for the age 
119  range of the patients in a given clinical trial. FDA may consider other endpoints 
120  acceptable following review by the Division of Psychiatry Products and the Clinical 
121  Outcome Assessments staff. For clinical studies with pediatric patients, the primary 
122  endpoint should be assessed in a laboratory classroom setting by a trained clinician rater. 
123  For clinical trials with adult patients, sponsors can consider using a simulated workplace 
124  environment in lieu of a laboratory classroom. 
125   
126    Adverse events of special interest in stimulant drug trials include changes in vital signs, 
127  insomnia, decreased appetite, weight loss, irritability or mood changes, and psychosis. 
128  Pulse, blood pressure, and weight should be evaluated at every clinic visit. Sleep, 
129  appetite, mood, and psychotic symptoms should be assessed using specific questioning 
130  rather than relying on patients to volunteer symptoms and problems spontaneously. 
131   
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
132  C.  Pregnancy 
133   
134  Women of reproductive potential are sometimes prescribed treatment for ADHD. Therefore, 
135  sponsors should consider inclusion of pregnant women in clinical trials when scientifically and 
136  ethically justified. If a sponsor excludes pregnant women from trial enrollment, the sponsor 
137  should provide a scientific justification.2 In addition, FDA may also require postmarketing safety 
138  data collection pursuant to section 505(o)(3) of the FD&C Act. Sponsors should use existing 
139  stimulant drug pregnancy registries (e.g., National Pregnancy Registry for Psychiatric 
140  Medications) or establish their own registries. 
141   
142   
143  III.  METHYLPHENIDATE AND AMPHETAMINE 505(b)(2) DEVELOPMENT 
144  PROGRAMS 
145   
146  Methylphenidate and amphetamine drug products are available in multiple formulations with a 
147  variety of dosage forms and durations of effect. The safety profiles of these products are well 
148  characterized and their PD effects are tightly linked to their PK profiles. Thus, FDA believes it is 
149  reasonable to rely on safety information from a listed drug to develop new methylphenidate or 
150  amphetamine product via the 505(b)(2) application pathway and, in certain cases, it may be 
151  reasonable to rely on the efficacy information. For instance, if a 505(b)(2) applicant can establish 
152  a bridge to the relied-upon listed drug by demonstrating either bioequivalence or comparative 
153  bioavailability of the proposed drug product with the listed drug, additional clinical trials may 
154  not be necessary to support approval of the 505(b)(2) application. The sponsor should consult the 
155  FDAs drug product-specific guidances regarding trial design and data analysis for 
156  bioequivalence evaluations.3 
157   
158  Sponsors should consider the following when developing methylphenidate and amphetamine 
159  products via the 505(b)(2) application pathway: 
160   
161    The listed drug(s) should be selected to reflect the active moiety or moieties of the new 
162  505(b)(2) product. A relative bioavailability study should be conducted in adult patients 
163  to bridge the new product to each selected listed drug. In general, cross-trial bridging is 
164  not recommended.  
165   
166    For drug products that are not bioequivalent to a listed drug, the sponsor should explore 
167  the following PK and PD characteristics of the drug product in the clinical development 
168  program:  
169   
                                                 
2 See the draft guidance for industry Pregnant Women: Scientific and Ethical Considerations for Inclusion in 
Clinical Trials (April 2018). 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/RegulatoryInformation/Guidances/default.htm.  
 
3 We note that product-specific guidances are typically used in the context of generic drug development, but the 
bioequivalence principles discussed in those guidances are equally applicable to sponsors of 505(b)(2) products 
seeking to establish bioequivalence. For the most recent version of a product-specific guidance, check the web page 
at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm075207.htm.  
4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
170    The shape of PK profiles for drug products with complicated release features (e.g., a 
171  combination of immediate-release and extended-release components in the 
172  formulation) should be characterized in the relevant pediatric age groups and in adults 
173  to ensure consistent drug release and performance in patients of different ages.  
174   
175    For pediatric patients, the sponsor should evaluate the onset and duration of the 
176  clinical effect in an adequate and well-controlled trial conducted in a laboratory 
177  classroom setting. For adult patients, the sponsor can use a simulated workplace 
178  setting. 
179   
180    A standalone PK study in each relevant pediatric age group may not be needed if a 
181  population PK model based on data available in adults can be used to simulate anticipated 
182  PK profiles in pediatric patients. The sponsor should discuss the modeling strategy with 
183  the Agency. The sponsor should use results of simulations to guide dose selection in 
184  clinical trials and inform the timing of assessments of adverse events. Confirmatory 
185  sparse PK data can be collected at designated time windows in efficacy and safety 
186  studies.  
187   
188    For some clinical development programs of a methylphenidate or amphetamine 505(b)(2) 
189  product, the findings of safety and effectiveness in younger pediatric patients (4 to 12 
190  years of age) can be extrapolated to support the use of the drug product in adolescent and 
191  adult patients. FDA strongly encourages the sponsor to discuss the development strategy 
192  with the Agency during the pre-investigational new drug application stage. Some of the 
193  factors that should be considered to allow the extrapolation include the following:  
194   
195    The 505(b)(2) product is given in the morning and has a duration of effect of 12 hours 
196  or less. 
197   
198    The shape of the PK profile of the active moiety or moieties of the 505(b)(2) product 
199  is similar in younger pediatric, adolescent, and adult patients.  
200   
201    The approved patient population of the listed drug includes younger pediatric, 
202  adolescent, and adult patients. The dose for each patient population is clearly defined.  
203   
204    Adequate bridging through a relative bioavailability study should be established 
205  between the 505(b)(2) product and the listed drug, such that the dose of the 505(b)(2) 
206  product in each patient population can be reliably derived.  
207   
208    Sponsors should include pediatric patients 4 and 5 years of age in clinical studies. 
209  Although it is reasonable to extrapolate effectiveness from older pediatric patients to 
210  pediatric patients 4 to 5 years of age, clinical study data are necessary to compare the 
211  safety profile in this population to what is known about the listed drug. 
212   
213    For a 505(b)(2) product (e.g., a methylphenidate product, amphetamine product) that 
214  targets a treatment duration greater than 12 hours or is not intended to be given in the 
215  morning, a study focused on safety, tolerability, and pharmacokinetics in the target 
5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
216  patient populations may be necessary before an evaluation of safety and effectiveness can 
217  proceed. FDA recommends specific assessments for concentrations around dinner time 
218  and sleep time in the target populations. In the relevant pediatric and adult clinical 
219  studies, assessment of both frequency and severity of insomnia, loss of appetite, body 
220  weight, and neurological/psychiatric adverse events is critical. Sponsors should perform 
221  evaluations of long-term (e.g., 12 months) growth change in pediatric patients 4 years of 
222  age and older.  
223   
224   
225  IV.  NEW MOLECULAR ENTITY 
226   
227  Unlike 505(b)(2) products, the safety, effectiveness, and PK-PD relationship for NMEs are 
228  unknown and must be evaluated in the development program (i.e., the pharmacologic properties 
229  alone are not sufficient evidence of effectiveness and safety). Although a sponsor cannot rely on 
230  information from other stimulant drug products for the evidence of effectiveness and safety, 
231  knowledge of the class and the indication can help to inform the drug development program.   
232   
233    A demonstration of safety and effectiveness of stimulant drugs for the treatment of 
234  ADHD in 4- to 5-year-old pediatric patients would require at least one adequate and well-
235  controlled clinical study in this population (21 CFR 314.126); this study should be a 
236  randomized, double-blind, placebo-controlled, parallel group study. A placebo control is 
237  necessary to provide interpretable results. The timing of such a study would depend 
238  largely on what is known about the safety of the particular investigational drug. FDA 
239  encourages sponsors to discuss the details and timing of the 4- to 5-year-old pediatric 
240  patient portion of the drug development programs early, preferably before initiating 
241  studies in 6- to 12-year-old pediatric patients. 
242   
243    A sponsor should include the following safety assessments (in addition to those listed in 
244  section II., General Considerations) in the drug development program: 
245   
246    Thorough QT study or alternative agreed upon by the QT Interdisciplinary Review 
247  Team 
248   
249    Human abuse potential study 
250   
251    Long-term safety, including assessment of growth using replicated and standardized 
252  measurements of weight (using a calibrated scale) and height (using a stadiometer), 
253  for at least 1 year in prepubertal patients 
254   
6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
255  REFERENCES 
256   
257  Kimko H, Gibiansky E, Gibiansky L, Starr HL, Berwaerts J, Massarella J, and Wiegand F, 2012, 
258  Population Pharmacodynamic Modeling of Various Extended-Release Formulations of 
259  Methylphenidate in Children with Attention Deficit Hyperactivity Disorder Via Meta-Analysis, J 
260  Pharmacokinet Pharmacodyn, 39(2):161176.  
261   
262  Li L, Wang Y, Uppoor RS, Mehta MU, Farchione T, Mathis MV, and Zhu H, 2017, Exposure-
263  Response Analyses of Blood Pressure and Heart Rate Changes for Methylphenidate in Healthy 
264  Adults, J Pharmacokinet Pharmacodyn, 44(3):245262. 
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