Pregnant Women: Scientific and Ethical Considerations for Inclusion in Clinical Trials

Administrative draft guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Pregnant Women:
Scientific and Ethical
Considerations for
Inclusion in Clinical Trials
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DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft
guidance.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 the Division of Pediatric and Maternal
Health (CDER) at (301) 796-2200 or the Office of Communication, Outreach, and Development
(CBER) 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)
April 2018
Clinical/Medical
Revision 1

Pregnant Women:
Scientific and Ethical
Considerations for
Inclusion in Clinical Trials
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
10903 New Hampshire Ave., Bldg. 71, rm. 3128
Silver Spring, MD 20993-0002
Phone: 800-835-4709 or 240-402-8010; Email: ocod@fda.hhs.gov
http://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)
April 2018
Clinical/Medical
Revision 1

TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 2
III. 	ETHICAL CONSIDERATIONS ..................................................................................... 4
A. 	FDA Regulations That Govern Research in Pregnant Women ................................................. 4
B. 	Research-Related Risks ................................................................................................................. 6
C. 	General Guidelines for Including Pregnant Women in Clinical Trials .................................... 6
IV. 	OTHER CONSIDERATIONS......................................................................................... 8
A. 	Disease Type and Availability of Therapeutic Options in the Pregnant Population ............... 8
B. 	Timing of Enrollment .................................................................................................................... 9
C. 	Pharmacokinetic Data ................................................................................................................... 9
D. 	Safety Data Collection and Monitoring ..................................................................................... 10
E. 	Stopping a Clinical Trial That Enrolls Pregnant Women ........................................................ 10
REFERENCES............................................................................................................................ 11

Contains Nonbinding Recommendations
Draft — Not for Implementation
1
Pregnant Women: Scientific and Ethical	1
Considerations for Inclusion in Clinical Trials	2
Guidance for Industry1
3
4
5
6
7
This draft guidance, when finalized, will represent the current thinking of the Food and Drug	8
Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not	9
binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the	10
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible	11
for this guidance as listed on the title page.	12
13
14
15
16
I. 	INTRODUCTION	17
18
This guidance provides recommendations about how and when to include pregnant women in	19
drug development clinical trials for drugs and biological products based on the Food and Drug	20
Administration’s (FDA’s or Agency’s) current thinking on this subject.2 Specifically, this	21
guidance supports an informed and balanced approach to gathering data on the use of drugs and	22
biological products during pregnancy through judicious inclusion of pregnant women in clinical	23
trials and careful attention to potential fetal risk. This draft guidance is intended to serve as a	24
focus for continued discussions among various entities such as the Agency, pharmaceutical	25
manufacturers, the academic community, institutional review boards (IRBs), and others who are	26
involved with the conduct of clinical trials in pregnant women.3	
27
28
This guidance discusses the scientific and ethical issues that should be addressed when	29
considering the inclusion of pregnant women in drug development clinical trials. From a	30
scientific and ethical standpoint, the population of pregnant women is complex based on the	31
interdependency of maternal and fetal well-being, and the need to take into consideration the	32
risks and benefits of a drug to both woman and fetus (American College of Obstetricians and	33
Gynecologists 2015). The scientific and ethical issues discussed in this guidance apply both to	34
clinical trials that enroll pregnant subjects and to clinical trials that allow enrolled subjects who	35
become pregnant to remain in the trial.	36
1 This guidance has been prepared by the Division of Pediatric and Maternal Health in the Center for Drug
Evaluation and Research (CDER) in cooperation with the Center for Biologics Evaluation and Research and the
Office of Good Clinical Practice, Office of Special Medical Programs, in the Office of the Commissioner at the
Food and Drug Administration.
2 Throughout this guidance, the term drug means drug and biological products regulated by CDER or CBER.
3 In addition to consulting guidances, sponsors are encouraged to contact the appropriate review division to discuss
specific issues that arise during drug development.

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37
Some of the information provided in this guidance applies to drugs indicated to treat pregnancy-	38
specific conditions (e.g., preterm labor, pre-eclampsia), but the larger focus is on drugs indicated	39
for conditions that occur commonly among females of reproductive potential. Women in this	40
group may require treatment for chronic disease or acute medical problems, and may become	41
pregnant multiple times during the reproductive phase of their lives.	42
43
This guidance does not discuss general clinical trial design issues or statistical analysis. Those	44
topics are addressed in the ICH guidances for industry E9 Statistical Principles for Clinical	45
Trials, E10 Choice of Control Group and Related Issues in Clinical Trials,4 and the draft ICH	46
guidance for industry E9(R1) Statistical Principles for Clinical Trials: Addendum: Estimands	47
and Sensitivity Analysis in Clinical Trials.5 The draft guidance for industry Pharmacokinetics in	48
Pregnancy — Study Design, Data Analysis, and Impact on Dosing and Labeling6 and certain	49
disease-specific and drug class-specific guidances may provide additional considerations for	50
studying pregnant women during drug development.	51
52
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.	53
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only	54
as recommendations, unless specific regulatory or statutory requirements are cited. The use of	55
the word should in Agency guidances means that something is suggested or recommended, but	56
not required.	57
58
59
II. 	BACKGROUND	60
61
In the interests of promoting maternal/fetal health and informed prescribing decisions during	62
pregnancy, this guidance addresses the challenges of including pregnant women in drug	63
development research. There are more than 60 million women in the United States between the	64
ages of 15 and 44 years, and almost 4 million births per year (U.S. National Vital Statistics	65
Reports). Like women who are not pregnant, some pregnant women need to use drugs to	66
manage chronic disease conditions or treat acute medical problems. To the extent there is	67
labeling information for pregnant women, it is usually based on nonclinical data with or without	68
limited human safety data. The frequent lack of information based on clinical data often leaves	69
the health care provider (HCP) and the patient reluctant to treat the underlying condition, which	70
in some cases may result in more harm to the woman and the fetus than if she had been treated.	71
In addition, pregnant women often use medically necessary drugs without a clear scientific	72
understanding of the risks and benefits to themselves or their developing fetuses (Lyerly et al.	73
2008).	74
75
4 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA
Drugs or Biologics guidance web page at
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm or
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm.
5 When final, this guidance will represent the FDA’s current thinking on this topic.
6 When final, this guidance will represent the FDA’s current thinking on this topic.

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76
Currently, information about drug use in pregnancy generally is collected in the postmarketing	77
setting, using data from observational studies such as pregnancy exposure registries and other	78
cohort studies, case control studies, and surveillance methods. Historically, there have been	79
barriers to obtaining data from pregnant women in clinical trials in an effort to protect them and	80
their fetuses from research-related risks. However, in certain situations, it may be helpful to	81
collect data in pregnant women in the setting of a clinical trial (Goldkind et al. 2010). For	82
example, it may be useful to compare the safety and efficacy of a drug that has been considered	83
the standard of care for pregnant women with a newer treatment (Jones et al. 2010). In other	84
situations, a woman’s health and the well-being of her fetus may benefit from clinical trial	85
participation. For example, a pregnant woman may need access to experimental therapies in a	86
clinical trial setting because there are no approved treatment options available. Sometimes a	87
drug treatment offered only through a clinical trial will hold out the prospect of direct benefit to	88
the pregnant woman and/or her fetus beyond otherwise available therapies. For example, some	89
clinical trials for drugs that treat human immunodeficiency virus (HIV), tuberculosis, and	90
malaria enroll pregnant women (or provide that patients who become pregnant can continue	91
enrollment) based on ethical principles and clinical need.	92
93
There are multiple reasons for considering the inclusion of pregnant women in clinical trials,	94
including the following:	95
96
• 	Women need safe and effective treatment during pregnancy	97
98
• 	Failure to establish the dose/dosing regimen, safety, and efficacy of treatments during	99
pregnancy may compromise the health of women and their fetuses	100
101
• 	In some settings, enrollment of pregnant women in clinical trials may offer the possibility	102
of direct benefit to the woman and/or fetus that is unavailable outside the research setting	103
104
• 	Development of accessible treatment options for the pregnant population is a significant	105
public health issue	106
107
Extensive physiological changes associated with pregnancy may alter drug pharmacokinetics and	108
pharmacodynamics, which directly affects the safety and efficacy of a drug administered to a	109
pregnant woman through alterations in drug absorption, distribution, metabolism, and excretion.7	
110
Pregnancy-related changes in various organ systems (e.g., gastrointestinal, cardiovascular, and	111
renal) also may alter drug pharmacokinetics and pharmacodynamics. For example, a 30 to 40	112
percent increase in glomerular filtration rate results in much higher rates of clearance for some	113
drugs during pregnancy (Mattison and Zajicek 2006); therefore, prescribing often occurs in the	114
absence of knowledge regarding the dose required to achieve the desired therapeutic effect	115
(Andrew et al. 2007).	116
117
7 See the draft guidance for industry Pharmacokinetics in Pregnancy — Study Design, Data Analysis, and Impact on
Dosing and Labeling.

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Filling the knowledge gaps regarding safe and effective use of drugs in pregnant women is a	118
critical public health need, but one that raises complex issues.	119
120
121
III. 	ETHICAL CONSIDERATIONS	122
123
The inclusion of pregnant women in clinical trials is guided by human subject protection	124
regulations and involves complex risk-benefit assessments that vary depending on the	125
seriousness of the disease, the availability of other treatments, the trial design, and whether the	126
proposed investigation will occur in the premarketing or postmarketing setting. Because of the	127
complex ethical issues involved in designing clinical trials that include pregnant women,	128
sponsors should consider including an ethicist in planning their drug development programs.	129
Moreover, sponsors should consider meeting with the appropriate FDA review division early in	130
the development phase to discuss when and how to include pregnant women in the drug	131
development plan. These discussions should involve FDA experts in bioethics and maternal	132
health.	133
134
A. 	FDA Regulations That Govern Research in Pregnant Women	135
136
FDA-regulated clinical trials in pregnant women must conform to all applicable FDA	137
regulations, including those related to human subject protections (21 CFR part 56, Institutional	138
Review Boards, and 21 CFR part 50, subpart B, Informed Consent of Human Subjects). In	139
addition, if the trial is supported or conducted by the Department of Health and Human Services	140
(HHS), then 45 CFR part 46 may also apply, which would include subpart B, Additional	141
Protections for Pregnant Women, Human Fetuses and Neonates Involved in Research.8 The	142
FDA regulations do not contain a section similar to 45 CFR part 46, subpart B; however, the	143
FDA recommends that these requirements be satisfied for FDA-regulated clinical research.	144
Subpart B requires that trials supported or conducted by HHS meet all of the following 10	145
conditions:	146
147
1. 	Where scientifically appropriate, nonclinical studies, including studies on pregnant	148
animals, and clinical studies, including studies on nonpregnant women, have been	149
conducted and provide data for assessing potential risks to pregnant women and fetuses;	150
151
2. 	The risk to the fetus is caused solely by interventions or procedures that hold out the	152
prospect of direct benefit for the woman or the fetus; or, if there is no such prospect of	153
benefit, the risk to the fetus is not greater than minimal9 and the purpose of the research is	154
the development of important biomedical knowledge which cannot be obtained by any	155
other means;	156
157
3. 	Any risk is the least possible for achieving the objectives of the research;	158
159
8 See 45 CFR 46.204.
9 See section III.B., Research-Related Risks, for discussion of minimal risk.

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4. 	The pregnant woman’s consent is obtained in accord with the informed consent	160
provisions of 45 CFR part 46, subpart A;	161
162
5. 	If the research holds out the prospect of direct benefit solely to the fetus then the consent	163
of the pregnant woman and the father is obtained in accord with the informed consent	164
provisions of 45 CFR part 46, subpart A, except that the father’s consent need not be	165
obtained if he is unable to consent because of unavailability, incompetence, or temporary	166
incapacity or the pregnancy resulted from rape or incest;	167
168
6. 	Each individual providing consent is fully informed regarding the reasonably foreseeable	169
impact of the research on the fetus or neonate;	170
171
7. 	For children as defined in § 46.402(a) who are pregnant, assent and permission are	172
obtained in accord with the provisions of 45 CFR part 46, subpart D;	173
174
8. 	No inducements, monetary or otherwise, will be offered to terminate a pregnancy;	175
176
9. 	Individuals engaged in the research will have no part in any decisions as to the timing,	177
method, or procedures used to terminate a pregnancy; and	178
179
10. Individuals engaged in the research will have no part in determining the viability of a	180
neonate.	181
182
IRBs are required to possess the professional competence necessary to review the specific	183
research activities that they oversee (21 CFR 56.107(a)). IRBs must include persons who are	184
knowledgeable in areas about the acceptability of proposed research in terms of institutional	185
commitments and regulations, applicable law, and standards of professional conduct and practice	186
(21 CFR 56.107(a)). Therefore, if an IRB regularly reviews research involving pregnant women,	187
the IRB must consider including one or more individuals who are knowledgeable about and	188
experienced in working with such subjects (21 CFR 56.107(a)). When an IRB considers whether	189
to approve a protocol involving pregnant women, it should consider only those risks and benefits	190
(direct to the subjects, or generalizable knowledge) that may result from the research itself (as	191
distinguished from risks and benefits of therapies that subjects would receive even if not	192
participating in the research) (21 CFR 56.111(a)(2)). Additionally, IRBs are required to	193
determine that additional safeguards are included in the trial to protect the rights and welfare of	194
subjects who are pregnant (21 CFR 56.111(b)).	195
196
Additional issues are raised by pregnant minors. Depending on state law, a pregnant minor may	197
be considered emancipated by virtue of her pregnancy, a mature minor, or still a child (see the	198
definition of children under 21 CFR 50.3(o)). IRBs should be familiar with applicable law of the	199
jurisdiction in which a trial will be conducted. In the event that a clinical trial regulated by the	200
FDA allows the enrollment of pregnant minors, or a minor becomes pregnant while enrolled in a	201
clinical trial, and the pregnant minor meets the definition of a child under applicable state law,	202
the IRB would have to comply with the applicable requirements of 21 CFR part 50, subpart D,	203
Additional Safeguards for Children in Clinical Investigations.	204
205

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B. 	Research-Related Risks	206
207
Research-related risks may meet the regulatory definition for minimal risk or may involve	208
greater than minimal risk. FDA regulations define minimal risk as follows (21 CFR 50.3(k)):	209
210
“Minimal risk means that the probability and magnitude of harm or discomfort anticipated in	211
the research are not greater in and of themselves than those ordinarily encountered in daily	212
life or during the performance of routine physical or psychological examinations or tests.”	213
214
Research-related risks are the risks specifically associated with the trial interventions or	215
procedures. If a woman is assigned to receive a drug while enrolled in a clinical trial (i.e., the	216
assignment of the drug is determined by the protocol), then the risks associated with the drug	217
would be considered research-related.	218
219
In contrast, risks are not research-related when they are independent of the study and not	220
associated with a trial intervention or protocol requirements. In other words, when a study	221
collects data about drug treatment during pregnancy but the drug was prescribed before study	222
enrollment by the patient’s HCP, then the risks associated with the drug use are not research-	223
related risks (Sheffield et al. 2014). For example, in a study in which the investigator plans to	224
assess the pharmacokinetics of a particular selective serotonin reuptake inhibitor (SSRI) during	225
pregnancy, the investigator enrolls pregnant women with a history of major depression who are	226
currently managed on this drug. In this study the SSRI does not create research-related risk,	227
because the patients are already using the SSRI (as previously prescribed by their HCPs) to	228
manage their medical conditions. The only risks of the study are those associated with study-	229
specific procedures (e.g., blood sample collection), and potential loss of confidentiality or	230
privacy.	231
232
In this situation, the research-related risk to the fetus is minimal, and the purpose of the research	233
is the development of important biomedical knowledge, which cannot be obtained by any other	234
means. Some dedicated pharmacokinetic (PK) studies conducted with pregnant women (such as	235
the previous SSRI example) can offer direct benefit to subjects if the data are used during the	236
trial to adjust the dosing for individual subjects when clinically appropriate. The informed	237
consent process should include discussion of expectations about whether trial data will be	238
monitored and evaluated in a way that can potentially benefit the subject during the trial.	239
240
There may be circumstances in which a clinical trial can potentially expose a fetus to greater than	241
minimal risk. Pregnant women can be enrolled in clinical trials that involve greater than minimal	242
risk to the fetuses if the trials offer the potential for direct clinical benefit to the enrolled pregnant	243
women and/or their fetuses. For example, this benefit may result from access to: (1) a needed	244
but otherwise unavailable therapy (e.g., a new antituberculosis drug for multidrug resistant	245
disease); or (2) a drug or biologic that reduces the risk for acquiring a serious health condition	246
(e.g., a vaginal microbicide that reduces transmission of HIV and herpes simplex virus).	247
248
C. 	General Guidelines for Including Pregnant Women in Clinical Trials	249
250

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This section provides general guidelines and considerations for including pregnant women in	251
clinical trials. However, every drug development situation is unique, and individualized	252
approaches to clinical trial design may be required to facilitate inclusion of pregnant women in	253
specific drug development plans.	254
255
The FDA considers it ethically justifiable to include pregnant women with a disease or medical	256
condition requiring treatment in clinical trials under the following circumstances:	257
258
In the postmarketing setting (i.e., FDA-approved drugs)	259
260
• 	Adequate nonclinical studies (including studies on pregnant animals) have been	261
completed10	
262
263
and	264
265
• 	There is an established safety database in nonpregnant women from clinical trials or	266
preliminary safety data from the medical literature and/or other sources regarding use in	267
pregnant women	268
269
and one of the following:	270
271
• 	Efficacy cannot be extrapolated	272
273
and/or	274
275
• 	Safety cannot be assessed by other study methods	276
277
In the premarketing setting (i.e., investigational drugs)	278
279
• 	Adequate nonclinical studies (including studies on pregnant animals) have been	280
completed	281
282
and	283
284
• 	The clinical trial holds out the prospect of direct benefit to the pregnant woman and/or	285
fetus that is not otherwise available outside the research setting or cannot be obtained by	286
any other means (e.g., the pregnant woman may not have responded to other approved	287
treatments or there may not be any treatment options)	288
289
The above conditions would also apply to a drug that is being developed to treat a pregnancy-	290
specific condition.	291
10 The phrase adequate nonclinical studies refers to recommendations for the design and conduct of reproductive
toxicology and other nonclinical studies described in the ICH guidances for industry M3(R2) Nonclinical Safety
Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals and S5(R2)
Detection of Toxicity to Reproduction for Medicinal Products: Addendum on Toxicity to Male Fertility.

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292
Women who become pregnant while enrolled in a clinical trial	293
294
When a pregnancy has been identified during a clinical trial, unblinding should occur so that	295
counseling may be offered based on whether the fetus has been exposed to the investigational	296
drug, placebo, or control. The risks and benefits of continuing versus stopping investigational	297
treatment can be reviewed with the pregnant woman. Pregnant women who choose to continue	298
in the clinical trial should undergo a second informed consent process that reflects these	299
additional risk-benefit considerations.	300
301
If fetal exposure has already occurred, a woman who becomes pregnant while enrolled in a	302
clinical trial should be allowed to continue on the investigational drug if the potential benefits of	303
continued treatment for the woman outweigh the risks of ongoing fetal exposure to the	304
investigational drug, of discontinuing maternal therapy, and/or of exposing the fetus to additional	305
drugs if placed on an alternative therapy. Regardless of whether the woman continues in the	306
trial, it is important to collect and report the pregnancy outcome.	307
308
309
IV. 	OTHER CONSIDERATIONS	310
311
Including pregnant women in a trial involves careful risk-benefit assessments. All trials must be	312
designed to minimize risk as much as possible while preserving the ability to achieve the	313
objectives of the research (21 CFR 56.111). Some general considerations for sponsors and	314
investigators include:	315
316
• 	Obtaining adequate reproductive and developmental toxicology data in relevant	317
nonclinical models	318
319
• 	Identifying the trial population that will derive the most benefit while trying to minimize	320
risk	321
322
• 	Considering the gestational timing of exposure to the investigational drug in relation to	323
fetal development	324
325
• 	Choosing appropriate control populations	326
327
Sponsors should also consider the issues discussed in the following sections when designing a	328
clinical trial that will include pregnant women.	329
330
A. 	Disease Type and Availability of Therapeutic Options in the Pregnant	331
Population	332
333
Sponsors should take into account the incidence of the disease, the severity of the disease (e.g.,	334
whether or not it is life-threatening), and the availability of other therapeutic options and their	335
risks. Pregnant patients with no other viable therapeutic options (e.g., drug resistance, drug	336

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intolerance, contraindication, drug allergy) to treat a serious or life-threatening disease or	337
condition may be appropriate candidates to enroll in a clinical trial.	338
339
B. 	Timing of Enrollment	340
341
The most appropriate time to include pregnant women in clinical trials during drug development	342
may differ. Nonclinical reproductive and developmental toxicology studies generally should be	343
completed before enrolling pregnant women in clinical trials.11 In general, phase 1 and phase 2	344
clinical trials in a nonpregnant population that include females of reproductive potential should	345
be completed before sponsors enroll pregnant women in later phase clinical trials. Sponsors	346
should consider whether any of the following situations apply in determining when to enroll	347
pregnant women in the drug development process.	348
349
• 	If there are limited safety data or other approved (i.e., safe and effective) treatments are	350
available: In this situation, it may be more appropriate to complete phase 3 clinical trials	351
in a nonpregnant population before enrolling pregnant women and exposing them to the	352
investigational drug	353
354
• 	If there are limited therapeutic options: In these situations, the risk-benefit	355
considerations may favor enrollment of pregnant women in earlier phase trials	356
357
• 	If there are safety data for a drug that has been studied previously for other indications	358
or populations: In these situations, the risk-benefit considerations may favor enrollment	359
of pregnant women in earlier phase trials	360
361
C. 	Pharmacokinetic Data	362
363
Because of the extensive physiological changes associated with pregnancy, PK parameters may	364
change, sometimes enough to justify changes in dose or dosing regimen. For drug development	365
programs where there are plans to enroll pregnant women in a phase 3 clinical trial, PK data in	366
pregnant women should be collected during the phase 2 clinical trials to guide appropriate dosing	367
in phase 3. In situations where pregnant women are enrolled in phase 3 clinical trials for a	368
marketed drug, PK data should be collected as part of the trial.	369
370
In appropriate situations, nonpregnant women who become pregnant while on the investigational	371
drug and consent to remain on the drug can also consent to PK assessments at steady state to	372
collect data on correct dosing during pregnancy. Modeling and simulation have been	373
increasingly used to support the design of clinical PK studies (Xia et al. 2013; Ke et al. 2013).	374
For PK studies including pregnant patients, physiological changes during and after pregnancy	375
that are critical for drug absorption and disposition may need to be considered in the model.	376
377
For additional information on PK modeling, study design considerations, and PK studies in	378
pregnant women, refer to the draft guidance for industry Pharmacokinetics in Pregnancy —	379
Study Design, Data Analysis, and Impact on Dosing and Labeling.	380
11 See ICH M3(R2).

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381
D. 	Safety Data Collection and Monitoring	382
383
When pregnant women are enrolled in a clinical trial, data collection elements should include, at	384
a minimum: gestational age at enrollment; gestational timing and duration of drug exposure; and	385
pregnancy outcomes including adverse maternal, fetal, and neonatal events. Enrolled pregnant	386
patients should also receive obstetrical care that meets the recognized standards of care. Infants	387
born to mothers who were exposed to the investigational drug should have follow-up safety	388
information collected. Systemic drug exposure to the fetus/newborn can be evaluated by	389
collecting cord blood or neonatal levels of drug and/or metabolites, depending on the timing of	390
exposure to the drug and its half-life.	391
392
Clinical trials that enroll pregnant women should include investigators or consultants who have	393
expertise in obstetrics and/or maternal/fetal medicine, depending on the underlying conditions	394
treated by the investigational drug.	395
396
All clinical trials require monitoring (21 CFR 312.50 and 312.56), and no single approach to	397
monitoring is appropriate or necessary for every clinical trial.12 Clinical trials that involve	398
pregnant women should include a data monitoring plan that includes members with relevant	399
specialty and perinatal expertise to permit ongoing recognition and evaluation of safety concerns	400
that arise during the course of the trial. This facilitates appropriate, expert assessment of adverse	401
event reports.	402
403
E. 	Stopping a Clinical Trial That Enrolls Pregnant Women	404
405
There may be situations where it would be appropriate to stop a randomized, controlled clinical	406
trial that is enrolling pregnant women. Examples include the following:	407
408
• 	An appropriately planned interim analysis demonstrates superior efficacy of the control	409
or active comparator arm.	410
411
• 	There are documented serious maternal or fetal adverse events that can be reasonably	412
attributed to drug exposure and are deemed to exceed the potential benefits of drug	413
treatment. This determination should include consideration of alternative effective	414
treatments and the risks of the underlying condition.	415
416
12 See the guidance for clinical trial sponsors Establishment and Operation of Clinical Trial Data Monitoring
Committees and the guidance for industry Oversight of Clinical Investigations — A Risk-Based Approach to
Monitoring.

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REFERENCES	417
418
American College of Obstetricians and Gynecologists, 2015, Ethical Considerations for	419
Including Women as Research Participants, Committee Opinion No. 646, November.	420
421
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