Considerations for 
Long-Term Clinical 
Neurodevelopmental 
Safety Studies in 
Neonatal Product 
Development 
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DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 (OC) Office of Clinical Policy and 
Programs, Office of Pediatric Therapeutics, Email: OPT@fda.hhs.gov, (CDER) Office of 
Communications, Division of Drug Information 301-301-796-3400, or (CBER) Office of 
Communication, Outreach and Development, 800-835-4709 or 240-402-8010 or (CDRH) Office 
of Policy Email: CDRH-Guidance@fda.hhs.gov 
 
 
   
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Office of Pediatric Therapeutics (OPT) 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
Center for Devices and Radiological Health (CDRH) 
 
 
[February 2023] 
[Clinical/Medical] 
 
   
Considerations for 
Long-Term Clinical 
Neurodevelopmental 
Safety Studies in 
Neonatal Product 
Development 
Guidance for Industry 
 
Additional copies are available from: 
Office of Pediatric Therapeutics 
Office of Clinical Policy and Programs, Office of the Commissioner 
Food and Drug Administration 
10903 New Hampshire Avenue 
Silver Spring, MD 20993 
(Tel) (240) 402-2865 
and/or 
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/guidance-compliance-regulatory-information/guidances-drugs  
and/or 
Office of Communication, Outreach and Development  
Center for Biologics Evaluation and Research 
 Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 71, Room 3128 
Silver Spring, MD 20993-0002 
Phone: 800-835-4709 or 240-402-8010 
   
Email: ocod@fda.hhs.gov 
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances     
and/or 
Office of Policy 
Center for Devices and Radiological Health 
Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 66, Room 5431 
Silver Spring, MD 20993-0002 
Email: CDRH-Guidance@fda.hhs.gov 
https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-assistance/guidance-documents-medical-devices-
and-radiation-emitting-products  
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Office of Pediatric Therapeutics (OPT) 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
Center for Devices and Radiological Health (CDRH) 
 [February 2023] 
[Clinical/Medical] 
 
  Contains Nonbinding Recommendations 
1  TABLE OF CONTENTS 
2 
3  I.  INTRODUCTION............................................................................................................. 2 
 
4  II.  BACKGROUND ............................................................................................................... 3 
5  III.  NEURODEVELOPMENTAL FOLLOW-UP FOR NEONATAL PRODUCT 
6  DEVELOPMENT PROGRAMS ................................................................................................. 4 
7  A.  Determining the Need for Neurodevelopmental Follow-up Evaluation .................................... 4 
8  1. General Considerations ................................................................................................................... 4 
9  2. Patient/Population-specific Considerations .................................................................................... 4 
10  3. Product-specific Considerations ...................................................................................................... 5 
11  B.    Factors to Consider When Developing a Long-term Safety Study Plan ................................... 5 
12  1. General Considerations ................................................................................................................... 6 
13  2. Patient and Population-specific Considerations ............................................................................. 6 
14  3. Product-specific Considerations ...................................................................................................... 7 
15  C.  What to Measure, When, and For How Long? ........................................................................... 7 
16  1. Timing of Assessment ....................................................................................................................... 8 
17  2. Key Characteristics of Measurement Tools ..................................................................................... 8 
18  2. Domains of Assessment .................................................................................................................... 9 
19  3. Relevant Covariates (see Section III.B.2.b.) .................................................................................. 10 
20  4. Adjunctive Assessments (i.e. Biomarkers of Neurodevelopmental Outcome) ................................ 11 
21   
22   
23   
24   
25   
26   
27   
28   
29   
30   
31   
32   
33   
34   
35   
36   
37   
38   
39   
40   
41   
42   
43   
  1  Contains Nonbinding Recommendations 
44  Considerations for Long-Term Clinical Neurodevelopmental Safety 
45  Studies in Neonatal Product Development: Guidance for Industry1 
46   
47   
48  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
49  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
50  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
51  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
52  for this guidance as listed on the title page.   
53   
54   
55   
56   
57  I.  INTRODUCTION  
58   
59  The purpose of this guidance is to provide a framework for considering whether and what type of 
60  long-term neurologic, sensory and developmental evaluations could be useful to support a 
61  determination of safety of a drug, biological product, or device (referred to as medical product 
62  in this guidance) for use in neonates2, and if so, which domains of neurodevelopment may be 
63  most applicable.  
64   
65  This guidance will not specifically address efficacy or effectiveness assessments for products 
66  primarily intended to improve neurologic outcomes, e.g., neuroprotective agents. This guidance 
67  is focused on long-term evaluations of neurodevelopmental safety. Although assessments of 
68  nephrotoxicity, pulmonary toxicity, and toxicity to other tissues and organs may also be 
69  warranted in neonatal medical product development, the approach to those assessments is outside 
70  the scope of this guidance. 
71   
72  Pertinent information on planning clinical pharmacology studies in neonates3 and pediatric 
73  patients4 can be found in existing guidance documents.5 This guidance does not focus on 
74  nonclinical safety studies to support clinical studies in neonates, nor does it address clinical study 
 
1 This guidance has been prepared by the Food and Drug Administration: Office of Pediatric Therapeutics in the 
Office of the Commissioner; the Division of Pediatric and Maternal Health, the Division of Antivirals, the Office of 
Surveillance and Epidemiology, and the Office of Neuroscience in the Center for Drug Evaluation and Research;, 
the Center for Biologics Evaluation and Review; and the Center for Devices and Radiological Health.  
2 The neonatal period is defined in the Addendum to ICH E11: Clinical Investigation of Medicinal Products in the 
Pediatric Population E11 (R1) (2017) as including term, post-term, and preterm newborn infants. The neonatal 
period for term and post-term infants is the day of birth plus 27 days. For preterm infants, the neonatal period is 
defined as the day of birth through the expected age of delivery plus 27 days. These same definitions will apply for 
purposes of this guidance. 
3 See the FDA Guidance for Industry, General Clinical Pharmacology Considerations for Neonatal Studies for 
Drugs and Biological Products; July 2022. 
4 See the FDA Draft Guidance for Industry, General Clinical Pharmacology Considerations for Pediatric Studies of 
Drugs, Including Biological Products; September 2022.  When finalized, this guidance will represent the Agencys 
current thinking. 
5 FDA updates guidances periodically.  For the most recent version of a guidance, check the FDA guidance web 
page at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm. 
  2  Contains Nonbinding Recommendations 
75  design in neonatology. This guidance also does not address neonatal or pediatric safety 
76  assessments following studies conducted during pregnancy.6 
77   
78  In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
79  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
80  as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
81  the word should in Agency guidances means that something is suggested or recommended, 
82  but not required. 
83   
84  II.  BACKGROUND 
85   
86  In 2012, the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity 
87  Act (PREA) were made permanent under Title V of the Food and Drug Administration Safety 
88  and Innovation Act (FDASIA). FDASIA contained several provisions to encourage medical 
89  product development in neonates.7 
90   
91  Treatment with medical products during the neonatal period coincides with a time of critical 
92  growth and physiologic development. Short-term safety evaluations typical for adults or other 
93  populations may fail to identify important adverse effects in the neonatal population, as latent 
94  effects may follow early-life exposures. Historically, most medical products used to treat 
95  neonates and young infants were not approved for use in this population for the relevant 
96  indications, and thus, long-term effects were rarely systematically evaluated.  
97   
98  Clinical investigators and sponsors8 of neonatal studies should consider and assess potential 
99  short-term and long-term effects of an investigational therapy, whether the therapy is novel or 
100  previously developed for a different indication or population. Short-term clinical improvement, 
101  such as that observed after high-dose corticosteroids for infants with bronchopulmonary 
102  dysplasia, may be followed by unexpected long-term harm.9 While adjunctive neurological 
103  assessments (e.g., neuroimaging, electroencephalography) may provide information on early 
104  safety concerns, they cannot replace clinical assessments of long-term functional outcomes. 
105  Although there is no universal definition of long-term, for the purpose of this guidance, the 
106  time frame can be generally thought of as at least 2 years of age or at such time when relevant 
107  clinical neurodevelopmental parameters can be reasonably assessed (refer to sections IIIB2a and 
108  IIIC1). Prospectively designed long-term follow-up is often important to understand medical 
109  product safety in neonates.  
110   
111  Neonates should have access to medical products adequately evaluated for dosing, efficacy or 
112  effectiveness, and/or safety for that population. There are conditions unique to term or preterm 
 
6 For additional information, see the FDA Draft Guidance for Industry, Pregnant Women: Scientific and Ethical 
Considerations for Inclusion in Clinical Studies; April 2018.  When finalized, this guidance will represent the 
Agencys current thinking. 
7 8 Title V Sec 501(a) of FDASIA can be found at 
https://www.congress.gov/112/plaws/publ144/PLAW112publ144.pdf. 
8 For the purposes of this guidance, sponsor refers to commercial sponsors and academic investigators who may 
plan and carry out neonatal clinical studies. 
9 Committee on Fetus and Newborn. Postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia. 
Pediatrics. 2010;126:800-808. 
  3  Contains Nonbinding Recommendations 
113  neonates, such as necrotizing enterocolitis and retinopathy of prematurity, that will not have 
114  analogous development programs in older populations. As new medical products are developed 
115  for these and other unique neonatal conditions, novel development programs and first-in-human 
116  studies may be initiated in neonates, and these development programs should also demonstrate 
117  long-term neurologic, sensory, and developmental safety. Neonates should also be enrolled in 
118  clinical studies for medical products and diagnostic tools initially developed for indications in 
119  other populations that will be used for neonates. Inclusion of neonates in such studies may be 
120  useful to establish dosing, safety, and efficacy or effectiveness, and these studies may also 
121  warrant long-term safety evaluations. 
122   
123  III.  NEURODEVELOPMENTAL FOLLOW-UP FOR PRODUCT DEVELOPMENT 
124  PROGRAMS THAT INCLUDE NEONATES 
125   
126  Long-term neurodevelopmental safety should be considered as part of neonatal product 
127  development plans. Sponsors should communicate as early as possible with the relevant FDA 
128  review division to reach alignment on the appropriate approach for long-term safety evaluations.  
129   
130  A.  Determining the Need for Long-term Neurodevelopmental Safety 
131  Evaluations 
132   
133  Sponsors should assess whether a long-term neurodevelopmental safety evaluation for 
134  neonates enrolled in clinical studies should be conducted. This assessment should be 
135  initiated early in product development and should be reevaluated as new information 
136  becomes available.  
137   
138  1.  General Considerations   
139  a.  Systemic Exposure: Any route of administration may result in a systemic 
140  exposure. The degree of systemic exposure, which should be quantified in 
141  early pharmacokinetic or animal studies if possible, may inform the need for 
142  long-term safety assessment. In general, higher levels of systemic exposure 
143  may be associated with higher central nervous system (CNS) exposure and 
144  potential risk for long-term sequelae. 
145  b.  Timing of Exposure: The timing of exposure to a drug, biological product, or 
146  device relative to a particularly vulnerable stage of organ and tissue 
147  development may inform the need for and the type of long-term safety 
148  assessment.  
149  c.  Duration of Exposure: Repeated dosing, repeated treatment, prolonged 
150  exposure and medical products with persistent effects may be associated with 
151  higher risk for long-term sequelae; however, long-term safety assessments 
152  may also be required after single doses or treatment, short durations of 
153  investigational therapies, based on the other considerations described in this 
154  guidance.  
155   
156  2.  Patient and Population-specific Considerations 
157  a.  Neurodevelopmental vulnerability: The anticipated rates of developmental, 
158  behavioral, and sensory impairments are inversely related to gestational age 
  4  Contains Nonbinding Recommendations 
159  and birth weight and differ significantly across various congenital or acquired 
160  conditions. Sponsors should seek the most current data to understand 
161  background rates of specific long-term neurodevelopmental outcomes in the 
162  population of interest.  
163  b.  Disease state characteristics: The disease or pathophysiology of the condition 
164  under study (e.g., metabolic processes or conditions associated with 
165  compromised blood-brain barrier integrity or altered cerebral blood flow such 
166  as meningitis, hypoxic-ischemic encephalopathy or perinatal arterial ischemic 
167  stroke) may increase the risk for adverse neurodevelopmental outcomes. 
168  Sponsors should address disease-specific vulnerabilities in the proposed 
169  evaluation of neurodevelopmental safety.  
170   
171  3.  Product-specific Considerations 
172  a.  Nonclinical toxicity: Nonclinical studies conducted to specifically evaluate the 
173  potential adverse effects of an investigational medical product on the 
174  developing CNS of neonates and young infants should include pre- and 
175  postnatal development studies, and, if warranted, embryo-fetal development 
176  and/or dedicated juvenile animal studies testing the investigational medical 
177  product in very young animals at critical and comparable stages of brain 
178  development.10  These studies can test both the intended effects of an 
179  investigational product and also can identify unintended or off-target effects.  
180  These data can and should be used to inform risk assessments for neonates 
181  and young infants and can also inform the design of clinical studies (e.g., 
182  inclusion of specific endpoints, identification of potential windows of 
183  developmental vulnerability). However, because CNS development and 
184  maturation are extremely complex, extrapolation across species development 
185  is challenging. Nonclinical studies cannot test all potential neurological effects 
186  of a medical product, and the lack of adverse effects in nonclinical studies 
187  alone does not necessarily exclude the possibility of adverse effects in 
188  neonates. 
189  b.  Clinical pharmacology: The mechanism of action, target organ or tissue, 
190  disposition and tissue distribution of the product, and/or accumulation of 
191  metabolites (and ontogeny of these factors) may evoke concerns about long-
192  term neurodevelopmental safety.  For example, drugs and biological products 
193  thought to penetrate the CNS are likely to warrant long-term safety 
194  assessment in neonates. Exposures may also be affected by developmental 
195  changes in the activity of drug metabolizing enzymes and the ontogeny of 
196  renal function in the neonatal period.11 
197  c.  Clinical experience: Data from use of a drug or device in other populations 
198  may be incorporated into the discussion about potential toxicities and need for 
199  follow-up after neonatal studies. Neurologic safety signals identified in older 
200  pediatric and adult patients should be carefully evaluated in neonates.  It is 
 
10 See the ICH Guidance for Industry, S11 Nonclinical Safety Testing in Support of Development of Pediatric 
Pharmaceuticals; May 2021. 
11 See the FDA Guidance for Industry, General Clinical Pharmacology Considerations for Neonatal Studies for 
Drugs and Biological Products; July 2022. 
  5  Contains Nonbinding Recommendations 
201  important to note that the absence of a safety signal in older populations may 
202  not preclude adverse effects in neonates. Novel medical products developed 
203  for conditions that occur only in neonates may not have available safety data 
204  from other populations and a comprehensive neurodevelopmental safety 
205  evaluation may be useful in these situations (see section III.C.3). 
206  d.  Product components: Both the active pharmaceutical ingredient and all 
207  excipients (e.g., ethyl alcohol and benzyl alcohol) and impurities (e.g., heavy 
208  metals and trace elements) should be considered when assessing the potential 
209  of a drug to cause neurodevelopmental toxicity. For devices that directly or 
210  indirectly contact human tissues, a biocompatibility evaluation should be 
211  conducted to assess for the potential for adverse responses resulting from 
212  contact of the component materials with the body.12 
213   
214  B.    Factors to Consider When Developing a Plan to Evaluate Long-term 
215  Neurodevelopmental Safety  
216   
217  If after conducting the assessment described in section IIIA, a sponsor determines that a 
218  long-term neurodevelopmental safety evaluation should be conducted, the sponsor should 
219  justify and design such an evaluation based on sound scientific rationale. A controlled 
220  study design is recommended, whenever feasible. Although a single-arm study may be 
221  useful for collecting some types of safety information, the absence of a concurrent control 
222  arm (placebo or active comparator) will generally make clear interpretation of the results 
223  difficult, if not impossible. A control group allows for easier discrimination of drug or 
224  device-related patient outcomes from outcomes caused by other factors, including 
225  underlying disease and developmental progression, especially if the natural history of the 
226  condition in the patient population is not well-established.   
227   
228  1.  General Considerations  
229  a.  Standardization: Sponsors should ensure reliability of administration and 
230  scoring of evaluations across sites and examiners, including consistency in 
231  the study instruments used and the age at follow-up.   
232  b.  Community acceptance and inclusivity: Development of a long-term safety 
233  study plan should include an assessment of family perceptions and early 
234  identification of barriers to study participation, including potential mistrust. 
235  Engagement of patient families and community leaders early in 
236  development and at the protocol development stage may help promote 
237  participation of historically underrepresented communities and improve 
238  overall study recruitment and retention.  
239  c.  Multidisciplinary input: Sponsors may identify and address challenges and 
240  opportunities in study development through engagement of key 
241  stakeholders.  Stakeholders may include, but are not limited to, patients, 
242  parents, caregivers, health care providers, educators, and developmental 
243  specialists. These stakeholders are instrumental in identifying clinically 
 
12 See the FDA Guidance for Industry and Food and Drug Administration Staff, Use of International Standard ISO 
10993-1, Biological evaluation of medical devices  Part 1: Evaluation and testing within a risk management 
process; Sept. 2020. 
  6  Contains Nonbinding Recommendations 
244  meaningful outcomes and assessing the acceptability and feasibility of the 
245  study design.   
246  d.  Patient recruitment and retention: Ideally, sponsors should include the 
247  long-term follow-up evaluation as a component of the initial study 
248  enrollment. Although this will not eliminate missing data, early recruitment 
249  will reinforce the importance of the long-term safety evaluation. Loss of 
250  patients over time threatens the integrity of long-term neurodevelopmental 
251  safety studies. There should be appropriate plans in place to keep families 
252  engaged and to collect relevant contact information (e.g., home and mobile 
253  phone numbers, email addresses, other messaging modalities) as needed to 
254  encourage retention of study participants and important data. Study 
255  participants may relocate during the follow-up period and maintaining 
256  contact is an important means to reduce the risk of missing patient 
257  information.  
258  e.  Patient burden: Sponsors developing long-term safety evaluations should 
259  consider and mitigate barriers to follow-up study enrollment as well as 
260  minimize the short-term and long-term burdens of study participation to the 
261  subjects and their family. Sponsors may consider and propose a strategy for 
262  integrating data from community-level services and providers involved in 
263  routine? neurodevelopmental evaluations and tracking (e.g., early 
264  intervention and Child Find programs) and pediatric evaluations during 
265  usual care (see maintaining data quality considerations below, Section 
266  B.1.c). Additional strategies may include use of mobile technology for 
267  information collection and transfer.   
268  f.  Data quality: While some information can be reasonably gathered through 
269  evaluations in usual clinical practice, general developmental screening 
270  performed during routine care is rarely a reliable substitute for a formal 
271  diagnostic neurodevelopmental evaluation. In addition, some 
272  neurodevelopmental evaluations require specialist evaluation. A sponsor 
273  may be able to rely on certain objective developmental measures with 
274  established reference standards (e.g., growth, vision, and hearing screening) 
275  captured during routine care where the sponsor can ensure they are 
276  collected reliably.  
277   
278  2.  Patient/Population-specific Considerations  
279  a.  Timing and duration: For the evaluation of neurodevelopmental safety, 
280  outcomes should be evaluated up to at least 2 years of age, adjusted for 
281  prematurity,13 if appropriate. The duration and frequency of follow-up 
282  assessments should be supported by scientific data and sound rationale. 
283  Considerations may include the static or dynamic nature of the 
284  neurodevelopmental outcome(s) being evaluated. The follow-up plan also 
285  should consider the ages at which the outcomes of interest can be 
 
13 Adjusted age, (also called corrected age or post-menstrual age) is defined as the chronological age reduced by 
the number of weeks born before 40 weeks of gestation. Refs: AAP Committee on Fetus and Newborn. Age 
terminology during the perinatal period; Pediatrics 2004;114(5):1362-4 and E11: Clinical Investigation of 
Medicinal Products in the Pediatric Population; International Council for Harmonization, 2000. 
  7  Contains Nonbinding Recommendations 
286  reasonably measured. For example, some learning difficulties or neurologic 
287  disorders may not present or be reasonably discernable with available 
288  assessment tools until after 2 years adjusted age.  
289  b.  Related factors: Sponsors should consider how other factors that relate to 
290  and affect neurodevelopmental outcomes may influence the interpretability 
291  of study results and should collect relevant covariate data accordingly. 
292  i.  Comorbidities (e.g., prematurity, congenital heart disease) 
293  ii.  Socioeconomic factors (e.g., food insecurity, social stressors, parental 
294  education level) 
295  iii.  Perinatal factors (e.g., substance use during pregnancy, depression) 
296  iv.  Regional differences in health care systems and accepted standards of 
297  medical practice 
298  v.  Environmental factors (e.g., lead or chemical exposure)  
299  vi.  Intercurrent events (e.g., illness, injury, therapies [such as early 
300  intervention], and other medications) 
301  c.  Developmental domains: In most cases, a general assessment of all the key 
302  neurodevelopmental domains is recommended. (See Section C.3, below). If 
303  specific domains of vulnerability are known or suspected in the study 
304  population based on product characteristics, then sponsors should identify 
305  the existing validated, age-appropriate tools to carefully measure relevant 
306  outcomes within those domains.  
307  d.  Feasibility: There may be population or study-specific issues that affect the 
308  feasibility of planned long-term follow-up studies. Sponsors should assess 
309  feasibility early in drug or device development and provide study plans for 
310  Agency review. This may include alternate strategies (e.g., patient 
311  registries, observational studies) if needed.  
312   
313  3.  Product-specific Considerations  
314  a.  Tissue specificity: Sponsors should determine whether the product has 
315  effects on organ systems that may impact neurodevelopment. Medical 
316  products may have direct and/or indirect effects on the developing CNS. 
317  Understanding these effects can help determine not only the extent of long-
318  term follow-up but also the type of assessment needed.  
319  b.  Ontogeny of therapeutic target: Sponsors should determine whether a 
320  medical products target changes in distribution or function throughout 
321  maturation. The extent of medical product exposure in relation to known 
322  target tissue developmental changes should be considered when designing 
323  the plan for neurodevelopmental safety evaluation. 
324   
325  C.  What to Measure, When and For How Long?  
326   
327  The most useful type of neurodevelopmental safety evaluation will depend upon whether 
328  it is determined (based on considerations discussed in sections IIIA. and IIIB. above) that 
329  a comprehensive neurodevelopmental evaluation is appropriate and/or whether there are 
330  specific developmental domains of concern that warrant targeted evaluations (see section 
331  III.C.3).  As sponsors are planning long-term neurodevelopmental evaluations, they 
  8  Contains Nonbinding Recommendations 
332  should consider what assessment tools to use, at what time point(s), and for how long. 
333  Neurodevelopmental safety evaluations should include validated tools, when available, to 
334  ensure rigor and should provide broad-ranging assessments of neurologic function, 
335  including relevant clinical outcome assessment (COA) tools. Note that general 
336  developmental screening and formalized assessments of neurodevelopment are not 
337  interchangeable. 
338   
339  1.  Timing of Safety Evaluations 
340   
341  In general, outcomes should be evaluated at a minimum of 2 years adjusted age. Earlier 
342  and/or later evaluations also may be warranted. 
343  a.  Evaluations that can be reliably performed during the first 2 years (adjusted age) 
344  of life and require longitudinal monitoring, including head growth, hearing and 
345  vision testing, neurologic exam, and developmental milestones, provide important 
346  information and may be appropriate.  
347  b.  Comprehensive neurodevelopmental outcomes should be evaluated at a minimum 
348  at 2 years adjusted age.   
349  c.  Assessment of more subtle, but important cognitive, language, behavioral, and 
350  other outcomes may require children to be followed until later in childhood. 
351  Problems in these areas may not be clearly discernable or adequately assessed in 
352  the first 46 years of life. Depending on the specific domains of concern, longer 
353  follow-up may be useful even if there are no neurodevelopmental concerns 
354  observed at the initial 2-year assessment.  
355   
356  2.  Key Characteristics of Measurement Tools  
357    
358  Long-term safety evaluations should be based on well-defined and reliable COAs. 
359  Specifically, COAs should assess clearly defined concepts of interest with appropriate 
360  justification to support their use in neonatal long-term safety evaluations.14  Assessments 
361  should include those that measure how a subject is functioning in daily life.  Key 
362  considerations relevant to long-term safety assessment after neonatal studies include:  
363  a.  Minimizing participant burden and avoiding duplication can increase pediatric 
364  patient testing compliance and reduce behavioral interference (e.g., refusal to 
365  participate in testing), which can confound or invalidate test scores. It can also 
366  reduce missing data and increase the feasibility for administration across large 
367  cohort studies. 
368  b.  Identifying and accounting for potential confounding factors that may 
369  compromise the validity of an assessment and score interpretability is 
370  important when devising a plan for analyzing test scores. For example, a 
371  cognitive assessment that depends on patients having typical fine motor 
 
14 See the Draft Guidance for Industry, Food and Drug Administration Staff and Other Stakeholders, Patient-focused 
Drug Development: Selecting, Developing or Modifying Fit-for-Purpose Clinical Outcome Assessments; June 2022, 
for further discussion of these characteristics.  When finalized, this guidance will represent the Agencys current 
thinking. 
  9  Contains Nonbinding Recommendations 
372  functioning (e.g., a time-limited block design task) may yield unreliable 
373  scores for children with fine motor impairments.  
374  c.  Carefully considering score selection within neurodevelopmental assessments, 
375  especially for patient populations that may be at the greatest risk of 
376  impairment, can help contextualize results if the selected COA has known 
377  limitations. Some scores (e.g., standardized scores) may demonstrate floor 
378  effects in severely impaired children and ceiling effects in children with 
379  developmentally advanced skills. 
380  d.  Selecting COAs that are methodologically sound with well-established 
381  psychometric properties is important, particularly to ensure validity across 
382  multicenter studies.  
383  e.  Ensuring that selected COAs have demonstrated reliability across the 
384  demographic groups included in the study, including availability in languages 
385  appropriate for global sites to support generalizability of study results. 
386  Consider, for example, that a language assessment developed for U.S. English 
387  speakers may yield unreliable, uninterpretable scores when used with patients 
388  at non-U.S. English speaking sites. Selected COAs should include robust 
389  norms for term and preterm infants. 
390   
391  3.  Domains of Assessment 
392   
393  When a comprehensive neurodevelopmental evaluation is needed, it should also include 
394  evaluation of physical, mental, and social health. The assessment may include the 
395  following domains: 
396   
397  a.  General  
398  i.  Physical Healthincluding ongoing health conditions (e.g., seizure 
399  disorder, pulmonary conditions, renal impairment), feeding problems, 
400  somatic growth (height, weight, and head circumference)15, sleep 
401  ii.  Quality of life and global function in daily life 
402  iii.  Receipt of developmental interventions and educational services 
403  b.  Neurodevelopment 
404  i.  Sensory  
405  ii.  Motor  
406  iii.  Cognition16  
407  iv.  Emotional and Behavioral Health 
408  v.  Communication  
409  vi.  Social Functioning  
410  vii.  Adaptive Functioning 
411   
412  4.  Relevant Covariates  
413   
 
15 See the Draft Guidance, Measuring Growth and Evaluating Pubertal Development in Pediatric Clinical Trials: 
Guidance for Industry for information on measuring growth parameters.  When finalized, this guidance will 
represent the Agencys current thinking. 
16 Cognition also includes executive function, attention, working memory, and processing speed. 
  10  Contains Nonbinding Recommendations 
414  Relevant covariates such as demographic variables and other factors that may change 
415  over time should be assessed longitudinally and systematic data collection of these 
416  factors should be incorporated into the proposed follow-up plan. (See Section IIIB2b.) 
417   
418  5.  Adjunctive Assessments (i.e., Biomarkers of Neurodevelopmental Outcome) 
419   
420  In general, adjunctive assessments and biomarker measures may not provide as 
421  meaningful information as long-term functional outcomes assessments and may not 
422  substitute for the above evaluations. However, adjunctive assessments may be useful to 
423  support the evaluation of neurodevelopmental safety, especially when following a known 
424  signal of concern from nonclinical studies, studies in a different population, or known 
425  effects of medical products from a similar pharmacological or therapeutic class. Thus, 
426  how useful an adjunctive assessment could be is typically product-specific and should be 
427  discussed with the appropriate review division at the time of protocol development.   
428   
429  a.  Neuroimaging studies may be used to assess anatomical evidence of toxicity (e.g., 
430  brain MRI to assess disruptions in myelination) but should typically have clinical 
431  correlation. 
432  b.   Neurophysiologic testing may also be used to evaluate a specific safety signal and   
433  may include (not a comprehensive list): 
434  i.  Visual-evoked-response 
435  ii.  Somatosensory evoked potentials to facilitate differentiation between 
436  peripheral and central nervous system insults 
437  iii.  Auditory-evoked response 
438  iv.  Electromyography with or without nerve-conduction studies 
439  v.  Electroencephalography 
440   
441   
442   
  11