Clinical Lactation Studies: Considerations for Study Design

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24840658dft.docx
05/01/19
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DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft
guidance.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

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
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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
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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	1
Guidance for Industry1
2
3
4
5
This draft guidance, when finalized, will represent the current thinking of the Food and Drug	6
Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not	7
binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the	8
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible	9
for this guidance as listed on the title page.	10
11
12
13
I. 	INTRODUCTION	14
15
This guidance provides recommendations for sponsors conducting clinical lactation studies. The	16
Food and Drug Administration (FDA or Agency) has required lactation studies under section	17
505(o)(3) of the Food, Drug, and Cosmetic Act (FD&C Act) under some circumstances and is	18
considering additional circumstances in which lactation studies may be required. In addition,	19
sponsors in some circumstances may elect to conduct lactation studies absent a requirement or	20
request from the Agency.	21
22
This guidance reflects FDA’s current recommendations regarding pre- or post-marketing	23
lactation studies by drug sponsors.2 This guidance provides information to facilitate the conduct	24
of lactation studies. Such studies can inform breastfeeding with drug use recommendations	25
included in the Lactation subsection of labeling.	26
27
The recommendations in this guidance reflect discussions from the 2007 Pediatric Advisory	28
Committee meeting3 and the 2016 Lactation Workshop,4 which considered how data from	29
clinical lactation studies can inform the safety of a drug when used during lactation.5 This draft	30
guidance replaces the draft guidance for industry Clinical Lactation Studies — Study Design,	31
Data Analysis, and Recommendations for Labeling, which published in February 2005.	32
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):736–744.

Contains Nonbinding Recommendations
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This guidance does not address specific lactation labeling recommendations. These topics are	34
addressed in 21 CFR 201.57(c)(9)(ii) and the draft guidance for industry Pregnancy, Lactation,	35
and Reproductive Potential: Labeling for Human Prescription Drug and Biological Products —	36
Content and Format (December 2014).6	
37
38
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.	39
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only	40
as recommendations, unless specific regulatory or statutory requirements are cited. The use of	41
the word should in Agency guidances means that something is suggested or recommended, but	42
not required.	43
44
45
II. 	BACKGROUND	46
47
Despite significant efforts to improve the quantity and quality of information in labeling for drug	48
use during lactation, there remains a paucity of human data. Therefore, lactating women and	49
their health care providers often must make decisions about drug treatment and continuation of	50
breastfeeding during therapy without quality human data in labeling. For that decision to be	51
evidence based, lactating women and health care providers would need information including, at	52
a minimum, the amount of drug in human milk, the effect of the drug on milk production, and an	53
understanding of the risks posed by the drug on the breastfed infant based on expected levels of	54
exposure and adverse drug event data.	55
56
Data from clinical lactation studies, along with other relevant data (e.g., drug physicochemical	57
characteristics, mechanism of drug entry into breast milk, data from nonclinical studies,	58
important infant factors) can be analyzed to evaluate the safety of a drug when used during	59
lactation. The data can also be used to develop recommendations to minimize infant exposure,	60
when appropriate.	61
62
63
III. 	CONSIDERATIONS FOR CLINICAL LACTATION STUDIES	64
65
A. 	Considerations for Conduct of a Clinical Lactation Study	66
67
FDA has required lactation studies under section 505(o)(3) of FD&C Act under some	68
circumstances and is considering additional circumstances in which lactation studies may be	69
required. In addition, sponsors in some circumstances may elect to conduct lactation studies	70
absent a requirement or request from the Agency.	71
72
FDA encourages sponsors to consider conducting a clinical lactation study whenever such study	73
would be appropriate, even if the study is not being required by the Agency. The following are	74
situations when a sponsor may wish to consider whether conducting a clinical lactation study	75
would be appropriate:	76
77
6 When final, this guidance will represent the FDA’s 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.

Contains Nonbinding Recommendations
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• 	A drug under review for approval is expected to be used by women of reproductive age	78
79
• 	After approval, use of a drug in lactating women becomes evident (e.g., via reports in the	80
medical literature or lay press)	81
82
• 	A new indication is being sought for an approved drug and there is evidence of use or	83
anticipated use of the drug by lactating women	84
85
• 	Marketed medications that are commonly used by women of reproductive age (e.g.,	86
antidepressants, antihypertensives, anti-infectives, diabetic and pain medications)	87
88
These and other factors should be considered on a case-by-case basis.	89
90
B. 	Ethical Considerations	91
92
FDA-regulated clinical trials, including lactation studies, must conform to all applicable FDA	93
regulations, including those related to human subject protections (21 CFR part 56, Institutional	94
Review Boards, and 21 CFR part 50, Protection of Human Subjects (including subpart D,	95
Additional Safeguards for Children in Clinical Investigations)). Sponsors should consider the	96
following ethical considerations with respect to three populations of lactating women who may	97
potentially participate in clinical lactation studies:7	
98
99
1. 	Lactating women who are prescribed the drug, which is the subject of the lactation study,	100
as part of standard clinical care	101
102
• 	If a lactating woman was prescribed and is continuing to take a medically necessary	103
drug, it is not necessary to stop the drug for the purposes of enrollment in a research	104
setting. It would be ethically acceptable to enroll women who have already made a	105
decision to take a medically necessary drug while breastfeeding and allow them to	106
continue breastfeeding while taking the drug. The drug exposure, specifically, to the	107
infant would be considered a clinical risk. Any risks associated with the research	108
would still need to be described.	109
110
2. 	Women in a research setting who are administered an investigational drug	111
112
• 	In a research setting, where a woman who is currently breastfeeding starts an	113
investigational drug for a disorder or condition, breastfeeding must be discontinued	114
for the duration of the study because the risks of the exposure to the drug in the	115
breastfeeding infant may outweigh the benefits. The potential drug exposure of a	116
breastfeeding infant must be considered a research risk (and offers no clinical benefit	117
to the infant).	118
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):736–744.

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• 	It is acceptable to enroll breastfeeding women who are participating in a clinical trial	120
of an investigational drug in clinical lactation studies if the breastfeeding woman	121
agrees to temporarily pump and discard milk to avoid exposing an infant to the	122
investigational drug. The length of time that the milk will need to be discarded	123
should be specified in the protocol and will vary depending on factors such as the	124
half-life of the drug.	125
126
3. 	Women who are healthy volunteers and are administered the investigational drug for the	127
purpose of clinical research	128
129
• 	In a research setting where a healthy woman who is currently breastfeeding	130
volunteers for a clinical lactation study, breastfeeding must be discontinued for the	131
duration of the study so that an infant is not exposed to the investigational drug.	132
133
C. 	Study Design Considerations	134
135
In considering the appropriate type of clinical lactation study to conduct, the sponsor should	136
consider strategies that minimize the burden of data collection on the mother while obtaining	137
adequate data. The study should avoid disruption of the breastfeeding routine and support return	138
to breastfeeding if breastfeeding must be temporarily discontinued. Additionally, use of remote	139
clinical study sites may provide access to a patient population that may not otherwise be willing	140
or able to participate. Home health care nursing visits can be particularly important to successful	141
recruitment and conduct of lactation studies of drugs with longer half-lives, when many visits	142
occur over a period of several weeks.	143
144
1. 	General Study Designs	145
146
Sponsors should consider the following types of study designs for clinical lactation studies:	147
148
• 	Lactating woman (milk-only) study	149
150
— 	A milk-only study can be used to detect the presence of a drug in breast milk,	151
quantify or estimate the total amount of a drug transferred into breast milk (when	152
plasma concentrations are known), and evaluate the effects of a drug on milk	153
production (when milk production in lactating women not taking the drug is known).	154
If the concentration of a drug in breast milk is found to be clinically relevant, this	155
finding could lead to further studies.	156
157
— 	In general, FDA recommends milk-only studies unless there is a reason to conduct	158
another type of clinical lactation study.	159
160
• 	Lactating woman (milk and plasma) study	161
162
— 	Milk and plasma collection in lactating women can provide pharmacokinetic (PK)	163
data on a drug in a lactating woman, the amount of drug transferred into breast milk,	164
and the effects of a drug on milk production. In certain situations, the PK data of the	165

Contains Nonbinding Recommendations
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drug may be unknown in lactating women such that obtaining such data would	166
provide additional information in the amount of drug transferred into breast milk	167
(e.g., when there is a concern for accumulation of a drug in breast milk).	168
169
• 	Mother-infant pair study	170
171
— 	Mother-infant pair studies that include assessment of drug concentrations in infants	172
can provide information on absorption of drugs in infants through breast milk and	173
safety assessments in infants enrolled in these studies. A sponsor should consider this	174
design if information is already available about the extent of drug transfer into breast	175
milk including evidence that the drug accumulates in breast milk and if the drug is	176
likely to be absorbed by the breastfed infant.	177
178
2. 	Other Study Design Considerations	179
180
In addition to the type of study design, sponsors should also consider the following study design	181
issues:	182
183
• 	Single-dose design	184
185
— 	For drugs that are given acutely (e.g., single-dose drug, drugs that do not accumulate	186
with chronic dosing), a single-dose study may be sufficient.	187
188
• 	Longitudinal design	189
190
— 	For drugs that are administered chronically or given for several treatment cycles, a	191
sponsor may consider a longitudinal study design. Under such a design, samples are	192
obtained from each lactating woman at different time points (e.g., at 2–3 months and	193
then again at 5–6 months).	194
195
• 	Multiple-arm design	196
197
— 	For drugs that are given acutely (e.g., single dose or short course of therapy), a	198
multiple-arm study can be used to compare different lactating patients at different	199
postpartum times. Under such a study, samples are obtained from different lactating	200
women at different time points (e.g., at 2–3 months, 5–6 months).	201
202
3. 	Study Subject Considerations	203
204
The following maternal and infant factors can affect the results of a clinical lactation study.	205
These factors should be collected in all lactation studies.	206
207
• 	Maternal factors	208
209

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— 	Maternal weight, age, gestational age at delivery, stage of lactation, length of time	210
postpartum, smoking, alcohol intake, concomitant drugs, ethnicity, race, and existing	211
medical conditions should be collected and reported for each study subject.	212
213
— 	The study should specify subjects who exclusively breastfeed versus those who	214
supplement with infant formula. Although FDA recommends that studies include	215
only women who exclusively breastfeed, including women who are supplementing	216
with infant formula provides real life data and may allow for easy collection of	217
pumped milk that would otherwise be discarded. However, studies should report the	218
extent of use of infant formula.	219
220
• 	Infant factors (for infants enrolled in mother-infant pair studies)	221
222
— 	Age, weight, history of prematurity, drugs, existing medical conditions, ethnicity, and	223
race should be collected and reported for each infant enrolled in a mother-infant pair	224
study.	225
226
4. 	Sample Size Considerations	227
228
Sponsors should consider the following for sample sizes in clinical lactation studies:	229
230
• 	Sample size considerations include PK variability for the drug being studied, the study	231
design (i.e., single dose versus multiple dose), and the variability in lactation physiology.	232
233
• 	A sponsor should consider the inter- and intra-subject variability for both mother and	234
breastfed infant, depending on the design and primary objective of the study. For	235
example, an increase to the sample size may be warranted if there is evidence of high	236
inter- or intra-subject variability.	237
238
D. 	Milk Sampling Methods	239
240
For milk sampling during clinical lactation studies, sponsors should consider the following:	241
242
• 	Type of milk collected	243
244
— 	The study design should specify the type of milk to be collected. For example,	245
differences in composition of foremilk versus hindmilk should be accounted for with	246
some drugs because transfer of drugs may be affected by the composition of the milk	247
(e.g., foremilk contains more water and less fat which may affect the transfer of	248
lipophilic drugs).	249
250
— 	Sampling should ideally take place after the development of mature milk (after	251
approximately 10 days postpartum). Colostrum or transitional milk collection may	252
not reflect drug transfer in mature milk because drug transfer may be transiently	253
increased because of a more porous mammary epithelium. However, sampling of	254
colostrum or transitional milk may be important under certain circumstances. For	255

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example, if concern exists about exposure of the drug in the immediate neonatal	256
period, colostrum samples may be needed.	257
258
— 	The specific timing of the milk sample relative to both the dose and days postpartum	259
should routinely be collected.	260
261
• 	Milk sampling method	262
263
— 	In general, FDA recommends the collection of the entire milk volume from both	264
breasts over 24 hours. Sampling should occur when drug exposure is at steady state	265
during chronic maternal dosing. For drugs with dosing intervals of more than 24	266
hours, consideration should be made to collect milk over the entire dosing interval or	267
to collect 24-hour samples during the expected time to peak plasma concentration.	268
The sampling schedule should take into consideration a drug’s known PK parameters	269
and be adjusted for drugs with longer dosing intervals, balancing the need for	270
adequate data collection with feasibility.	271
272
— 	After the milk is collected, the necessary aliquots for assay should be saved using	273
proper storage methods. The remainder of the milk collected can be refed to the	274
infant under certain circumstances (see section III. B., Ethical Considerations). If the	275
milk is allowed to be refed to the infant, the amount taken for assay should not	276
deprive the infant of his or her nutritionally required volume.	277
278
— 	FDA recommends the use of an electric pump rather than hand expression because	279
electric pumps are more efficient in milk extraction. However, hospital grade pumps	280
are not necessary; modern personal electric pumps utilize the same technology and	281
are less costly.	282
283
E. 	Measurement of Infant Milk Intake	284
285
Sponsors should consider the following for measuring infant milk intake during clinical lactation	286
studies:	287
288
• 	While a 150 mL/kg/day estimated milk intake is a reasonable assumption to estimate	289
daily infant dosage, greater volumes do occur in early infancy and often correlate to the	290
time of most reported infant adverse drug events. Additional consideration should be	291
given to estimates of infant risk based on a 200 mL/kg/day milk intake in early infancy.	292
293
• 	Measurement of milk volume and weighing infants before and after feeding are methods	294
that provide milk volume data for use in calculating infant exposure.	295
296

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F. 	Pharmacokinetic Analysis	297
298
Analytical methods should be adequately validated, including both blood and breast milk, to	299
address the accuracy, precision, selectivity, sensitivity, reproducibility, and stability of the parent	300
drug and active metabolites of pharmacological importance.8	
301
302
• 	Milk pharmacokinetics	303
304
— 	The area under the milk concentration-time curve (AUC) should be calculated.	305
306
— 	Average concentration should be based on AUC derived from collections at multiple	307
time points, not just concentrations obtained at one sampling time.	308
309
— 	Total milk concentration data should be used to estimate PK parameters of the parent	310
drug and metabolites.	311
312
— 	Peak and trough milk concentrations, as well as time to reach peak milk	313
concentration, should be reported.	314
315
• 	Plasma pharmacokinetics (for milk and plasma study)	316
317
— 	In general, plasma PK parameter estimates can include the following:	318
319
 	Area under the plasma concentration curve	320
 	Peak plasma concentration	321
 	Time to peak plasma concentration	322
 	Plasma clearance or apparent oral clearance	323
 	Apparent volume of distribution	324
 	Terminal half-life	325
326
— 	PK parameters should be expressed in terms of total and unbound concentrations. For	327
drugs and metabolites with a relatively low extent of plasma protein binding, FDA	328
recommends that sponsors describe and analyze the pharmacokinetics in terms of	329
total concentrations.	330
331
— 	FDA also recommends noncompartmental and/or compartmental modeling	332
approaches to parameter estimation.	333
334
G. 	Estimation of Infant Dosage	335
336
Sponsors should consider the following for calculating or estimating infant dosage:	337
338
8 See the guidance for industry Bioanalytical Method Validation (May 2018).

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• 	The daily infant dosage (total drug present in milk and consumed by the infant per day)	339
should be calculated or estimated. Sponsors should consider the following to calculate	340
daily infant dosage:	341
342
Daily Infant Dosage (mg/day) = Σ (total drug concentration in each milk collection	343
multiplied by the expressed milk volume in each milk collection)	344
345
or	346
347
Estimated Daily Infant Dosage (mg/kg/day) = M/P multiplied by the average	348
maternal plasma concentration multiplied by 150 mL/kg/day	349
350
M/P is the milk-plasma ratio. The calculation of M/P should be based on AUC and on	351
multiple time points over 24 hours and not just a single point in time. Sponsors should	352
consider an estimate of infant risk based on a 200 mL/kg/day infant milk intake in early	353
infancy.	354
355
• 	The relative infant dose (the percent of the weight-adjusted maternal dosage consumed in	356
breast milk over 24 hours) should be calculated. Sponsors should consider the following	357
for relative infant dose:	358
359
Relative Infant Dose = Infant Dosage (mg/kg/day)/Maternal Dosage (mg/kg/day)	360
multiplied by 100	361
362
• 	If the drug has an approved indication for use in pediatric patients younger than 1 year of	363
age, the estimated daily infant dosage should be compared to the approved dose.	364
Calculation of the percentage of estimated daily infant dosage to the approved dose can	365
provide an estimate of the risk to the infant.	366
367
• 	Infant pharmacokinetics (for a mother-infant pair study) should be considered. If infant	368
drug concentration data are not collected, the average infant drug concentration (C ss,ave)	369
can be estimated by using the following formula:	370
371
C ss,ave = F multiplied by infant dosage/CL	372
373
F is the bioavailability, and CL is the drug clearance in the infant, if these data are known	374
for the pediatric population.	375
376
H. 	Infant Safety Data Collection	377
378
An important component of clinical lactation studies is the collection of safety information in the	379
breastfed infant. Follow-up examination or testing of the infant to evaluate for adverse drug	380
events may be considered depending on the specific risk profile of the drug. Adverse drug event	381
data can also be collected about the infant from mothers through surveys conducted	382
electronically, by phone, or through maternal diaries.	383
384

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I. 	Data on Effect of Drug on Milk Production	385
386
The clinical lactation studies described in this guidance are not formally designed to assess the	387
effect of a drug on milk production. However, a sponsor should consider assessments about the	388
effect of the drug on milk production in clinical lactation studies. For example, clinical lactation	389
studies may include reports from enrolled women of any effects on milk production and, when	390
feasible, a comparison of milk production before (or after discontinuation of) treatment to milk	391
production during treatment.	392