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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DRAFT GUIDANCE This guidance document is being distributed for comment purposes only.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be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance.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:

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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: [email protected] https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

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Office of Communication, Outreach, and Development

Center for Biologics Evaluation and Research Food and Drug Administration

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Phone: 800-835-4709 or 240-402-8010; Email: [email protected] 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

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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.

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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.

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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

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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 (Css,ave) 369 can be estimated by using the following formula: 370

371 Css,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