Clinical Lactation 
Studies: Considerations 
for Study Design 
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DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 (CDER) Jian Wang at 301-796-3846 or 
(CBER) the Office of Communication, Outreach, and Development at 800-835-4709 or 240-402-
8010.  
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
May 2019 
Clinical/Medical 
24840658dft.docx 
05/01/19   
Clinical Lactation 
Studies: Considerations 
for Study Design  
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 
 
and/or 
 
Office of Communication, Outreach, and Development  
Center for Biologics Evaluation and Research 
Food and Drug Administration 
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Silver Spring, MD  20993-0002 
Phone: 800-835-4709 or 240-402-8010; Email: ocod@fda.hhs.gov 
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
May 2019 
Clinical/Medical 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION..................................................................................................1 
II.  BACKGROUND ....................................................................................................2 
III.  CONSIDERATIONS FOR CLINICAL LACTATION STUDIES ...................2 
A.  Considerations for Conduct of a Clinical Lactation Study ............................................ 2 
B.  Ethical Considerations ...................................................................................................... 3 
C.  Study Design Considerations ............................................................................................ 4 
1. General Study Designs ........................................................................................................ 4 
2. Other Study Design Considerations .................................................................................... 5 
3. Study Subject Considerations .............................................................................................. 5 
4. Sample Size Considerations ................................................................................................ 6 
D.  Milk Sampling Methods .................................................................................................... 6 
E.  Measurement of Infant Milk Intake ................................................................................ 7 
F.  Pharmacokinetic Analysis ................................................................................................ 8 
G.  Estimation of Infant Dosage ............................................................................................. 8 
H.  Infant Safety Data Collection ........................................................................................... 9 
I.  Data on Effect of Drug on Milk Production .................................................................. 10 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Clinical Lactation Studies: Considerations for Study Design 
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  This guidance provides recommendations for sponsors conducting clinical lactation studies.  The 
17  Food and Drug Administration (FDA or Agency) has required lactation studies under section 
18  505(o)(3) of the Food, Drug, and Cosmetic Act (FD&C Act) under some circumstances and is 
19  considering additional circumstances in which lactation studies may be required.  In addition, 
20  sponsors in some circumstances may elect to conduct lactation studies absent a requirement or 
21  request from the Agency. 
22   
23  This guidance reflects FDAs current recommendations regarding pre- or post-marketing 
24  lactation studies by drug sponsors.2  This guidance provides information to facilitate the conduct 
25  of lactation studies.  Such studies can inform breastfeeding with drug use recommendations 
26  included in the Lactation subsection of labeling.   
27   
28  The recommendations in this guidance reflect discussions from the 2007 Pediatric Advisory 
29  Committee meeting3 and the 2016 Lactation Workshop,4 which considered how data from 
30  clinical lactation studies can inform the safety of a drug when used during lactation.5  This draft 
31  guidance replaces the draft guidance for industry Clinical Lactation Studies  Study Design, 
32  Data Analysis, and Recommendations for Labeling, which published in February 2005.   
33   
                                                 
1 This guidance has been prepared by the Division of Pediatrics and Maternal Health in the Center for Drug 
Evaluation and Research in cooperation with the Center for Biologics Evaluation and Research at the Food and Drug 
Administration. 
 
2 For the purposes of this guidance, all references to drugs include both human drugs and therapeutic biological 
products unless otherwise specified. 
 
3 See https://wayback.archive-it.org/7993/20170403222238/https://www.fda.gov/ohrms/dockets/ac/oc07.htm#pac. 
 
4 See https://www.fda.gov/Drugs/NewsEvents/ucm486761.htm. 
 
5 Wang J, Johnson T, Sahin L, et al., 2017, Evaluation of the Safety of Drugs and Biological Products Used During 
Lactation: Workshop Summary, Clinical Pharmacol Ther, 101(6):736744. 
 
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
34  This guidance does not address specific lactation labeling recommendations.  These topics are 
35  addressed in 21 CFR 201.57(c)(9)(ii) and the draft guidance for industry Pregnancy, Lactation, 
36  and Reproductive Potential:  Labeling for Human Prescription Drug and Biological Products  
37  Content and Format (December 2014).6 
38   
39  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
40  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
41  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
42  the word should in Agency guidances means that something is suggested or recommended, but 
43  not required. 
44   
45   
46  II.  BACKGROUND 
47   
48  Despite significant efforts to improve the quantity and quality of information in labeling for drug 
49  use during lactation, there remains a paucity of human data.  Therefore, lactating women and 
50  their health care providers often must make decisions about drug treatment and continuation of 
51  breastfeeding during therapy without quality human data in labeling.  For that decision to be 
52  evidence based, lactating women and health care providers would need information including, at 
53  a minimum, the amount of drug in human milk, the effect of the drug on milk production, and an 
54  understanding of the risks posed by the drug on the breastfed infant based on expected levels of 
55  exposure and adverse drug event data.  
56   
57  Data from clinical lactation studies, along with other relevant data (e.g., drug physicochemical 
58  characteristics, mechanism of drug entry into breast milk, data from nonclinical studies, 
59  important infant factors) can be analyzed to evaluate the safety of a drug when used during 
60  lactation.  The data can also be used to develop recommendations to minimize infant exposure, 
61  when appropriate.   
62   
63   
64  III.  CONSIDERATIONS FOR CLINICAL LACTATION STUDIES 
65   
66  A.  Considerations for Conduct of a Clinical Lactation Study 
67   
68  FDA has required lactation studies under section 505(o)(3) of FD&C Act under some 
69  circumstances and is considering additional circumstances in which lactation studies may be 
70  required.  In addition, sponsors in some circumstances may elect to conduct lactation studies 
71  absent a requirement or request from the Agency. 
72   
73  FDA encourages sponsors to consider conducting a clinical lactation study whenever such study 
74  would be appropriate, even if the study is not being required by the Agency.  The following are 
75  situations when a sponsor may wish to consider whether conducting a clinical lactation study 
76  would be appropriate:  
77   
                                                 
6 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.  
2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
78    A drug under review for approval is expected to be used by women of reproductive age 
79   
80    After approval, use of a drug in lactating women becomes evident (e.g., via reports in the 
81  medical literature or lay press) 
82   
83    A new indication is being sought for an approved drug and there is evidence of use or 
84  anticipated use of the drug by lactating women 
85   
86    Marketed medications that are commonly used by women of reproductive age (e.g., 
87  antidepressants, antihypertensives, anti-infectives, diabetic and pain medications) 
88   
89  These and other factors should be considered on a case-by-case basis. 
90   
91  B.  Ethical Considerations 
92   
93  FDA-regulated clinical trials, including lactation studies, must conform to all applicable FDA 
94  regulations, including those related to human subject protections (21 CFR part 56, Institutional 
95  Review Boards, and 21 CFR part 50, Protection of Human Subjects (including subpart D, 
96  Additional Safeguards for Children in Clinical Investigations)).  Sponsors should consider the 
97  following ethical considerations with respect to three populations of lactating women who may 
98  potentially participate in clinical lactation studies:7 
99   
100  1.  Lactating women who are prescribed the drug, which is the subject of the lactation study, 
101  as part of standard clinical care 
102   
103    If a lactating woman was prescribed and is continuing to take a medically necessary 
104  drug, it is not necessary to stop the drug for the purposes of enrollment in a research 
105  setting.  It would be ethically acceptable to enroll women who have already made a 
106  decision to take a medically necessary drug while breastfeeding and allow them to 
107  continue breastfeeding while taking the drug.  The drug exposure, specifically, to the 
108  infant would be considered a clinical risk.  Any risks associated with the research 
109  would still need to be described.   
110   
111  2.  Women in a research setting who are administered an investigational drug 
112   
113    In a research setting, where a woman who is currently breastfeeding starts an 
114  investigational drug for a disorder or condition, breastfeeding must be discontinued 
115  for the duration of the study because the risks of the exposure to the drug in the 
116  breastfeeding infant may outweigh the benefits.  The potential drug exposure of a 
117  breastfeeding infant must be considered a research risk (and offers no clinical benefit 
118  to the infant). 
119   
                                                 
7 Wang J, Johnson T, Sahin L, et al., 2017, Evaluation of the Safety of Drugs and Biological Products Used During 
Lactation: Workshop Summary, Clin Pharmacol Ther, 101(6):736744. 
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
120    It is acceptable to enroll breastfeeding women who are participating in a clinical trial 
121  of an investigational drug in clinical lactation studies if the breastfeeding woman 
122  agrees to temporarily pump and discard milk to avoid exposing an infant to the 
123  investigational drug.  The length of time that the milk will need to be discarded 
124  should be specified in the protocol and will vary depending on factors such as the 
125  half-life of the drug. 
126   
127  3.  Women who are healthy volunteers and are administered the investigational drug for the 
128  purpose of clinical research 
129   
130    In a research setting where a healthy woman who is currently breastfeeding 
131  volunteers for a clinical lactation study, breastfeeding must be discontinued for the 
132  duration of the study so that an infant is not exposed to the investigational drug.   
133   
134  C.  Study Design Considerations 
135   
136  In considering the appropriate type of clinical lactation study to conduct, the sponsor should 
137  consider strategies that minimize the burden of data collection on the mother while obtaining 
138  adequate data.  The study should avoid disruption of the breastfeeding routine and support return 
139  to breastfeeding if breastfeeding must be temporarily discontinued.  Additionally, use of remote 
140  clinical study sites may provide access to a patient population that may not otherwise be willing 
141  or able to participate.  Home health care nursing visits can be particularly important to successful 
142  recruitment and conduct of lactation studies of drugs with longer half-lives, when many visits 
143  occur over a period of several weeks. 
144   
145  1.  General Study Designs  
146   
147  Sponsors should consider the following types of study designs for clinical lactation studies: 
148   
149    Lactating woman (milk-only) study 
150   
151    A milk-only study can be used to detect the presence of a drug in breast milk, 

152  quantify or estimate the total amount of a drug transferred into breast milk (when 
153  plasma concentrations are known), and evaluate the effects of a drug on milk 
154  production (when milk production in lactating women not taking the drug is known).  
155  If the concentration of a drug in breast milk is found to be clinically relevant, this 
156  finding could lead to further studies. 
157   
158    In general, FDA recommends milk-only studies unless there is a reason to conduct 

159  another type of clinical lactation study. 
160   
161    Lactating woman (milk and plasma) study 
162   
163    Milk and plasma collection in lactating women can provide pharmacokinetic (PK) 

164  data on a drug in a lactating woman, the amount of drug transferred into breast milk, 
165  and the effects of a drug on milk production.  In certain situations, the PK data of the 
4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
166  drug may be unknown in lactating women such that obtaining such data would 
167  provide additional information in the amount of drug transferred into breast milk 
168  (e.g., when there is a concern for accumulation of a drug in breast milk).     
169   
170    Mother-infant pair study 
171   
172    Mother-infant pair studies that include assessment of drug concentrations in infants 

173  can provide information on absorption of drugs in infants through breast milk and 
174  safety assessments in infants enrolled in these studies.  A sponsor should consider this 
175  design if information is already available about the extent of drug transfer into breast 
176  milk including evidence that the drug accumulates in breast milk and if the drug is 
177  likely to be absorbed by the breastfed infant.  
178   
179  2.  Other Study Design Considerations 
180   
181  In addition to the type of study design, sponsors should also consider the following study design 
182  issues: 
183   
184    Single-dose design 
185   
186    For drugs that are given acutely (e.g., single-dose drug, drugs that do not accumulate 

187  with chronic dosing), a single-dose study may be sufficient. 
188   
189    Longitudinal design 
190   
191    For drugs that are administered chronically or given for several treatment cycles, a 

192  sponsor may consider a longitudinal study design.  Under such a design, samples are 
193  obtained from each lactating woman at different time points (e.g., at 23 months and 
194  then again at 56 months).    
195   
196    Multiple-arm design 
197   
198    For drugs that are given acutely (e.g., single dose or short course of therapy), a 

199  multiple-arm study can be used to compare different lactating patients at different 
200  postpartum times.  Under such a study, samples are obtained from different lactating 
201  women at different time points (e.g., at 23 months, 56 months). 
202   
203  3.  Study Subject Considerations 
204   
205  The following maternal and infant factors can affect the results of a clinical lactation study.  
206  These factors should be collected in all lactation studies. 
207   
208    Maternal factors 
209   
5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
210    Maternal weight, age, gestational age at delivery, stage of lactation, length of time 

211  postpartum, smoking, alcohol intake, concomitant drugs, ethnicity, race, and existing 
212  medical conditions should be collected and reported for each study subject.   
213   
214    The study should specify subjects who exclusively breastfeed versus those who 

215  supplement with infant formula.  Although FDA recommends that studies include 
216  only women who exclusively breastfeed, including women who are supplementing 
217  with infant formula provides real life data and may allow for easy collection of 
218  pumped milk that would otherwise be discarded.  However, studies should report the 
219  extent of use of infant formula. 
220   
221    Infant factors (for infants enrolled in mother-infant pair studies) 
222   
223    Age, weight, history of prematurity, drugs, existing medical conditions, ethnicity, and 

224  race should be collected and reported for each infant enrolled in a mother-infant pair 
225  study.   
226   
227  4.  Sample Size Considerations 
228   
229  Sponsors should consider the following for sample sizes in clinical lactation studies: 
230   
231    Sample size considerations include PK variability for the drug being studied, the study 
232  design (i.e., single dose versus multiple dose), and the variability in lactation physiology.   
233   
234    A sponsor should consider the inter- and intra-subject variability for both mother and 
235  breastfed infant, depending on the design and primary objective of the study.  For 
236  example, an increase to the sample size may be warranted if there is evidence of high 
237  inter- or intra-subject variability.    
238   
239  D.  Milk Sampling Methods 
240   
241  For milk sampling during clinical lactation studies, sponsors should consider the following:  
242   
243    Type of milk collected 
244   
245    The study design should specify the type of milk to be collected.  For example, 

246  differences in composition of foremilk versus hindmilk should be accounted for with 
247  some drugs because transfer of drugs may be affected by the composition of the milk 
248  (e.g., foremilk contains more water and less fat which may affect the transfer of 
249  lipophilic drugs). 
250   
251    Sampling should ideally take place after the development of mature milk (after 

252  approximately 10 days postpartum).  Colostrum or transitional milk collection may 
253  not reflect drug transfer in mature milk because drug transfer may be transiently 
254  increased because of a more porous mammary epithelium.  However, sampling of 
255  colostrum or transitional milk may be important under certain circumstances.  For 
6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
256  example, if concern exists about exposure of the drug in the immediate neonatal 
257  period, colostrum samples may be needed.   
258   
259    The specific timing of the milk sample relative to both the dose and days postpartum 

260  should routinely be collected. 
261   
262    Milk sampling method 
263   
264    In general, FDA recommends the collection of the entire milk volume from both 

265  breasts over 24 hours.  Sampling should occur when drug exposure is at steady state 
266  during chronic maternal dosing.  For drugs with dosing intervals of more than 24 
267  hours, consideration should be made to collect milk over the entire dosing interval or 
268  to collect 24-hour samples during the expected time to peak plasma concentration.  
269  The sampling schedule should take into consideration a drugs known PK parameters 
270  and be adjusted for drugs with longer dosing intervals, balancing the need for 
271  adequate data collection with feasibility. 
272   
273    After the milk is collected, the necessary aliquots for assay should be saved using 

274  proper storage methods.  The remainder of the milk collected can be refed to the 
275  infant under certain circumstances (see section III. B., Ethical Considerations).  If the 
276  milk is allowed to be refed to the infant, the amount taken for assay should not 
277  deprive the infant of his or her nutritionally required volume. 
278   
279    FDA recommends the use of an electric pump rather than hand expression because 

280  electric pumps are more efficient in milk extraction.  However, hospital grade pumps 
281  are not necessary; modern personal electric pumps utilize the same technology and 
282  are less costly. 
283   
284  E.  Measurement of Infant Milk Intake 
285   
286  Sponsors should consider the following for measuring infant milk intake during clinical lactation 
287  studies:  
288   
289    While a 150 mL/kg/day estimated milk intake is a reasonable assumption to estimate 
290  daily infant dosage, greater volumes do occur in early infancy and often correlate to the 
291  time of most reported infant adverse drug events.  Additional consideration should be 
292  given to estimates of infant risk based on a 200 mL/kg/day milk intake in early infancy. 
293   
294    Measurement of milk volume and weighing infants before and after feeding are methods 
295  that provide milk volume data for use in calculating infant exposure. 
296   
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Draft  Not for Implementation 
297  F.  Pharmacokinetic Analysis 
298   
299  Analytical methods should be adequately validated, including both blood and breast milk, to 
300  address the accuracy, precision, selectivity, sensitivity, reproducibility, and stability of the parent 
301  drug and active metabolites of pharmacological importance.8 
302   
303    Milk pharmacokinetics 
304   
305    The area under the milk concentration-time curve (AUC) should be calculated. 

306   
307    Average concentration should be based on AUC derived from collections at multiple 

308  time points, not just concentrations obtained at one sampling time. 
309   
310    Total milk concentration data should be used to estimate PK parameters of the parent 

311  drug and metabolites.   
312   
313    Peak and trough milk concentrations, as well as time to reach peak milk 

314  concentration, should be reported. 
315   
316    Plasma pharmacokinetics (for milk and plasma study) 
317   
318    In general, plasma PK parameter estimates can include the following: 

319   
320    Area under the plasma concentration curve 
321    Peak plasma concentration 
322    Time to peak plasma concentration 
323    Plasma clearance or apparent oral clearance 
324    Apparent volume of distribution 
325    Terminal half-life 
326   
327    PK parameters should be expressed in terms of total and unbound concentrations.  For 

328  drugs and metabolites with a relatively low extent of plasma protein binding, FDA 
329  recommends that sponsors describe and analyze the pharmacokinetics in terms of 
330  total concentrations. 
331   
332    FDA also recommends noncompartmental and/or compartmental modeling 

333  approaches to parameter estimation. 
334   
335  G.  Estimation of Infant Dosage 
336   
337  Sponsors should consider the following for calculating or estimating infant dosage: 
338   
                                                 
8 See the guidance for industry Bioanalytical Method Validation (May 2018). 
8  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
339    The daily infant dosage (total drug present in milk and consumed by the infant per day) 
340  should be calculated or estimated.  Sponsors should consider the following to calculate 
341  daily infant dosage: 
342   
343  Daily Infant Dosage (mg/day) =  (total drug concentration in each milk collection 
344  multiplied by the expressed milk volume in each milk collection) 
345   
346  or 
347   
348  Estimated Daily Infant Dosage (mg/kg/day) = M/P multiplied by the average 
349  maternal plasma concentration multiplied by 150 mL/kg/day 
350   
351  M/P is the milk-plasma ratio.  The calculation of M/P should be based on AUC and on 
352  multiple time points over 24 hours and not just a single point in time.  Sponsors should 
353  consider an estimate of infant risk based on a 200 mL/kg/day infant milk intake in early 
354  infancy. 
355   
356    The relative infant dose (the percent of the weight-adjusted maternal dosage consumed in 
357  breast milk over 24 hours) should be calculated.  Sponsors should consider the following 
358  for relative infant dose: 
359   
360  Relative Infant Dose = Infant Dosage (mg/kg/day)/Maternal Dosage (mg/kg/day) 
361  multiplied by 100 
362   
363    If the drug has an approved indication for use in pediatric patients younger than 1 year of 
364  age, the estimated daily infant dosage should be compared to the approved dose.  
365  Calculation of the percentage of estimated daily infant dosage to the approved dose can 
366  provide an estimate of the risk to the infant.   
367   
368    Infant pharmacokinetics (for a mother-infant pair study) should be considered.  If infant 
369  drug concentration data are not collected, the average infant drug concentration (C ) 
ss,ave
370  can be estimated by using the following formula:  
371   
372  C = F multiplied by infant dosage/CL 
ss,ave 
373   
374  F is the bioavailability, and CL is the drug clearance in the infant, if these data are known 
375  for the pediatric population. 
376   
377  H.  Infant Safety Data Collection 
378   
379  An important component of clinical lactation studies is the collection of safety information in the 
380  breastfed infant.  Follow-up examination or testing of the infant to evaluate for adverse drug 
381  events may be considered depending on the specific risk profile of the drug.  Adverse drug event 
382  data can also be collected about the infant from mothers through surveys conducted 
383  electronically, by phone, or through maternal diaries. 
384   
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385  I.  Data on Effect of Drug on Milk Production 
386   
387  The clinical lactation studies described in this guidance are not formally designed to assess the 
388  effect of a drug on milk production.  However, a sponsor should consider assessments about the 
389  effect of the drug on milk production in clinical lactation studies.  For example, clinical lactation 
390  studies may include reports from enrolled women of any effects on milk production and, when 
391  feasible, a comparison of milk production before (or after discontinuation of) treatment to milk 
392  production during treatment.    
10