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DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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  
2  Considerations for Inclusion in Clinical Trials 
3  Guidance for Industry1  
4   
5   
6   
7   
8  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
9  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
10  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
11  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
12  for this guidance as listed on the title page. 
13   
14   
15   
16   
17  I.  INTRODUCTION  
18   
19  This guidance provides recommendations about how and when to include pregnant women in 
20  drug development clinical trials for drugs and  biological products based on the Food and Drug 
21  Administrations (FDAs or Agencys) current thinking on this subject.2  Specifically, this 
22  guidance supports an informed and balanced approach to gathering data on the use of drugs and 
23  biological products during pregnancy through judicious inclusion of pregnant women in clinical 
24  trials and careful attention to potential fetal risk.  This draft guidance is intended to serve as a 
25  focus for continued discussions among various entities such as the Agency, pharmaceutical 
26  manufacturers, the academic community, institutional review boards (IRBs), and others who are 
27  involved with the conduct of clinical trials in pregnant women.3  
28   
29  This guidance discusses the scientific and ethical issues that should be addressed when 
30  considering the inclusion of pregnant women in drug development clinical trials.  From a 
31  scientific and ethical standpoint, the population of pregnant women is complex based on the 
32  interdependency of maternal and fetal well-being, and the need to take into consideration the 
33  risks and benefits of a drug to both woman and fetus (American College of Obstetricians and 
34  Gynecologists 2015).  The scientific and ethical issues discussed in this guidance apply both to 
35  clinical trials that enroll pregnant subjects and to clinical trials that allow enrolled subjects who 
36  become pregnant to remain in the trial.    
                                                 
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.  
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
37   
38  Some of the information provided in this guidance applies to drugs indicated to treat pregnancy-
39  specific conditions (e.g., preterm labor, pre-eclampsia), but the larger focus is on drugs indicated 
40  for conditions that occur commonly among females of reproductive potential.  Women in this 
41  group may require treatment for chronic disease or acute medical problems, and may become 
42  pregnant multiple times during the reproductive phase of their lives.   
43   
44  This guidance does not discuss general clinical trial design issues or statistical analysis.  Those 
45  topics are addressed in the ICH guidances for industry E9 Statistical Principles for Clinical 
46  Trials, E10 Choice of Control Group and Related Issues in Clinical Trials,4 and the draft ICH 
47  guidance for industry E9(R1) Statistical Principles for Clinical Trials:  Addendum:  Estimands 
48  and Sensitivity Analysis in Clinical Trials.5  The draft guidance for industry Pharmacokinetics in 
49  Pregnancy  Study Design, Data Analysis, and Impact on Dosing and Labeling6 and certain 
50  disease-specific and drug class-specific guidances may provide additional considerations for 
51  studying pregnant women during drug development. 
52   
53  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
54  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
55  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
56  the word should in Agency guidances means that something is suggested or recommended, but 
57  not required.  
58   
59   
60  II.  BACKGROUND 
61   
62  In the interests of promoting maternal/fetal health and informed prescribing decisions during 
63  pregnancy, this guidance addresses the challenges of including pregnant women in drug 
64  development research.  There are more than 60 million women in the United States between the 
65  ages of 15 and 44 years, and almost 4 million births per year (U.S. National Vital Statistics 
66  Reports).  Like women who are not pregnant, some pregnant women need to use drugs to 
67  manage chronic disease conditions or treat acute medical problems.  To the extent there is 
68  labeling information for pregnant women, it is usually based on nonclinical data with or without 
69  limited human safety data.  The frequent lack of information based on clinical data often leaves 
70  the health care provider (HCP) and the patient reluctant to treat the underlying condition, which 
71  in some cases may result in more harm to the woman and the fetus than if she had been treated.  
72  In addition, pregnant women often use medically necessary drugs without a clear scientific 
73  understanding of the risks and benefits to themselves or their developing fetuses (Lyerly et al. 
74  2008). 
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 FDAs current thinking on this topic. 
 
6 When final, this guidance will represent the FDAs current thinking on this topic. 
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
76   
77  Currently, information about drug use in pregnancy generally is collected in the postmarketing 
78  setting, using data from observational studies such as pregnancy exposure registries and other 
79  cohort studies, case control studies, and surveillance methods.  Historically, there have been 
80  barriers to obtaining data from pregnant women in clinical trials in an effort to protect them and 
81  their fetuses from research-related risks.  However, in certain situations, it may be helpful to 
82  collect data in pregnant women in the setting of a clinical trial (Goldkind et al. 2010).  For 
83  example, it may be useful to compare the safety and efficacy of a drug that has been considered 
84  the standard of care for pregnant women with a newer treatment (Jones et al. 2010).  In other 
85  situations, a womans health and the well-being of her fetus may benefit from clinical trial 
86  participation.  For example, a pregnant woman may need access to experimental therapies in a 
87  clinical trial setting because there are no approved treatment options available.  Sometimes a 
88  drug treatment offered only through a clinical trial will hold out the prospect of direct benefit to 
89  the pregnant woman and/or her fetus beyond otherwise available therapies.  For example, some 
90  clinical trials for drugs that treat human immunodeficiency virus (HIV), tuberculosis, and 
91  malaria enroll pregnant women (or provide that patients who become pregnant can continue 
92  enrollment) based on ethical principles and clinical need. 
93   
94  There are multiple reasons for considering the inclusion of pregnant women in clinical trials, 
95  including the following: 
96   
97    Women need safe and effective treatment during pregnancy    
98   
99    Failure to establish the dose/dosing regimen, safety, and efficacy of treatments during 
100  pregnancy may compromise the health of women and their fetuses  
101   
102    In some settings, enrollment of pregnant women in clinical trials may offer the possibility 
103  of direct benefit to the woman and/or fetus that is unavailable outside the research setting 
104   
105    Development of accessible treatment options for the pregnant population is a significant 
106  public health issue 
107   
108  Extensive physiological changes associated with pregnancy may alter drug pharmacokinetics and 
109  pharmacodynamics, which directly affects the safety and efficacy of a drug administered to a 
110  pregnant woman through alterations in drug absorption, distribution, metabolism, and excretion.7  
111  Pregnancy-related changes in various organ systems (e.g., gastrointestinal, cardiovascular, and 
112  renal) also may alter drug pharmacokinetics and pharmacodynamics.  For example, a 30 to 40 
113  percent increase in glomerular filtration rate results in much higher rates of clearance for some 
114  drugs during pregnancy (Mattison and Zajicek 2006); therefore, prescribing often occurs in the 
115  absence of knowledge regarding the dose required to achieve the desired therapeutic effect 
116  (Andrew et al. 2007).   
117   
                                                 
7 See the draft guidance for industry Pharmacokinetics in Pregnancy  Study Design, Data Analysis, and Impact on 
Dosing and Labeling.   
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
118  Filling the knowledge gaps regarding safe and effective use of drugs in pregnant women is a 
119  critical public health need, but one that raises complex issues.   
120   
121   
122  III.  ETHICAL CONSIDERATIONS 
123   
124  The inclusion of pregnant women in clinical trials is guided by human subject protection 
125  regulations and involves complex risk-benefit assessments that vary depending on the 
126  seriousness of the disease, the availability of other treatments, the trial design, and whether the 
127  proposed investigation will occur in the premarketing or postmarketing setting.  Because of the 
128  complex ethical issues involved in designing clinical trials that include pregnant women, 
129  sponsors should consider including an ethicist in planning their drug development programs.  
130  Moreover, sponsors should consider meeting with the appropriate FDA review division early in 
131  the development phase to discuss when and how to include pregnant women in the drug 
132  development plan.  These discussions should involve FDA experts in bioethics and maternal 
133  health. 
134   
135  A.  FDA Regulations That Govern Research in Pregnant Women 
136   
137  FDA-regulated clinical trials in pregnant women must conform to all applicable FDA 
138  regulations, including those related to human subject protections (21 CFR part 56, Institutional 
139  Review Boards, and 21 CFR part 50, subpart B, Informed Consent of Human Subjects).  In 
140  addition, if the trial is supported or conducted by the Department of Health and Human Services 
141  (HHS), then 45 CFR part 46 may also apply, which would include subpart B, Additional 
142  Protections for Pregnant Women, Human Fetuses and Neonates Involved in Research.8  The 
143  FDA regulations do not contain a section similar to 45 CFR part 46, subpart B; however, the 
144  FDA recommends that these requirements be satisfied for FDA-regulated clinical research.  
145  Subpart B requires that trials supported or conducted by HHS meet all of the following 10 
146  conditions:  
147   
148  1.  Where scientifically appropriate, nonclinical studies, including studies on pregnant 
149  animals, and clinical studies, including studies on nonpregnant women, have been 
150  conducted and provide data for assessing potential risks to pregnant women and fetuses; 
151   
152  2.  The risk to the fetus is caused solely by interventions or procedures that hold out the 
153  prospect of direct benefit for the woman or the fetus; or, if there is no such prospect of 
154  benefit, the risk to the fetus is not greater than minimal9 and the purpose of the research is 
155  the development of important biomedical knowledge which cannot be obtained by any 
156  other means; 
157   
158  3.  Any risk is the least possible for achieving the objectives of the research; 
159   
                                                 
8 See 45 CFR 46.204. 
 
9 See section III.B., Research-Related Risks, for discussion of minimal risk. 
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
160  4.  The pregnant womans consent is obtained in accord with the informed consent 
161  provisions of 45 CFR part 46, subpart A; 
162   
163  5.  If the research holds out the prospect of direct benefit solely to the fetus then the consent 
164  of the pregnant woman and the father is obtained in accord with the informed consent 
165  provisions of 45 CFR part 46, subpart A, except that the fathers consent need not be 
166  obtained if he is unable to consent because of unavailability, incompetence, or temporary 
167  incapacity or the pregnancy resulted from rape or incest; 
168   
169  6.  Each individual providing consent is fully informed regarding the reasonably foreseeable 
170  impact of the research on the fetus or neonate; 
171   
172  7.  For children as defined in  46.402(a) who are pregnant, assent and permission are 
173  obtained in accord with the provisions of 45 CFR part 46, subpart D; 
174   
175  8.  No inducements, monetary or otherwise, will be offered to terminate a pregnancy; 
176   
177  9.  Individuals engaged in the research will have no part in any decisions as to the timing, 
178  method, or procedures used to terminate a pregnancy; and 
179   
180  10. Individuals engaged in the research will have no part in determining the viability of a 
181  neonate. 
182   
183  IRBs are required to possess the professional competence necessary to review the specific 
184  research activities that they oversee (21 CFR 56.107(a)).  IRBs must include persons who are 
185  knowledgeable in areas about the acceptability of proposed research in terms of institutional 
186  commitments and regulations, applicable law, and standards of professional conduct and practice 
187  (21 CFR 56.107(a)).  Therefore, if an IRB regularly reviews research involving pregnant women, 
188  the IRB must consider including one or more individuals who are knowledgeable about and 
189  experienced in working with such subjects (21 CFR 56.107(a)).  When an IRB considers whether 
190  to approve a protocol involving pregnant women, it should consider only those risks and benefits 
191  (direct to the subjects, or generalizable knowledge) that may result from the research itself (as 
192  distinguished from risks and benefits of therapies that subjects would receive even if not 
193  participating in the research) (21 CFR 56.111(a)(2)).  Additionally, IRBs are required to 
194  determine that additional safeguards are included in the trial to protect the rights and welfare of 
195  subjects who are pregnant (21 CFR 56.111(b)).   
196   
197  Additional issues are raised by pregnant minors.  Depending on state law, a pregnant minor may 
198  be considered emancipated by virtue of her pregnancy, a mature minor, or still a child (see the 
199  definition of children under 21 CFR 50.3(o)).  IRBs should be familiar with applicable law of the 
200  jurisdiction in which a trial will be conducted.  In the event that a clinical trial regulated by the 
201  FDA allows the enrollment of pregnant minors, or a minor becomes pregnant while enrolled in a 
202  clinical trial, and the pregnant minor meets the definition of a child under applicable state law, 
203  the IRB would have to comply with the applicable requirements of 21 CFR part 50, subpart D, 
204  Additional Safeguards for Children in Clinical Investigations.  
205   
  5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
206  B.  Research-Related Risks 
207   
208  Research-related risks may meet the regulatory definition for minimal risk or may involve 
209  greater than minimal risk.  FDA regulations define minimal risk as follows (21 CFR 50.3(k)):  
210   
211  Minimal risk means that the probability and magnitude of harm or discomfort anticipated in 
212  the research are not greater in and of themselves than those ordinarily encountered in daily 
213  life or during the performance of routine physical or psychological examinations or tests.  
214   
215  Research-related risks are the risks specifically associated with the trial interventions or 
216  procedures.  If a woman is assigned to receive a drug while enrolled in a clinical trial (i.e., the 
217  assignment of the drug is determined by the protocol), then the risks associated with the drug 
218  would be considered research-related.  
219   
220  In contrast, risks are not research-related when they are independent of the study and not 
221  associated with a trial intervention or protocol requirements.  In other words, when a study 
222  collects data about drug treatment during pregnancy but the drug was prescribed before study 
223  enrollment by the patients HCP, then the risks associated with the drug use are not research-
224  related risks (Sheffield et al. 2014).  For example, in a study in which the investigator plans to 
225  assess the pharmacokinetics of a particular selective serotonin reuptake inhibitor (SSRI) during 
226  pregnancy, the investigator enrolls pregnant women with a history of major depression who are 
227  currently managed on this drug.  In this study the SSRI does not create research-related risk, 
228  because the patients are already using the SSRI (as previously prescribed by their HCPs) to 
229  manage their medical conditions.  The only risks of the study are those associated with study-
230  specific procedures (e.g., blood sample collection), and potential loss of confidentiality or 
231  privacy.  
232   
233  In this situation, the research-related risk to the fetus is minimal, and the purpose of the research 
234  is the development of important biomedical knowledge, which cannot be obtained by any other 
235  means.  Some dedicated pharmacokinetic (PK) studies conducted with pregnant women (such as 
236  the previous SSRI example) can offer direct benefit to subjects if the data are used during the 
237  trial to adjust the dosing for individual subjects when clinically appropriate.  The informed 
238  consent process should include discussion of expectations about whether trial data will be 
239  monitored and evaluated in a way that can potentially benefit the subject during the trial.   
240   
241  There may be circumstances in which a clinical trial can potentially expose a fetus to greater than 
242  minimal risk.  Pregnant women can be enrolled in clinical trials that involve greater than minimal 
243  risk to the fetuses if the trials offer the potential for direct clinical benefit to the enrolled pregnant 
244  women and/or their fetuses.  For example, this benefit may result from access to:  (1) a needed 
245  but otherwise unavailable therapy (e.g., a new antituberculosis drug for multidrug resistant 
246  disease); or (2) a drug or biologic that reduces the risk for acquiring a serious health condition 
247  (e.g., a vaginal microbicide that reduces transmission of HIV and herpes simplex virus).   
248   
249  C.  General Guidelines for Including Pregnant Women in Clinical Trials 
250   
  6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
251  This section provides general guidelines and considerations for including pregnant women in 
252  clinical trials.  However, every drug development situation is unique, and individualized 
253  approaches to clinical trial design may be required to facilitate inclusion of pregnant women in 
254  specific drug development plans.  
255   
256  The FDA considers it ethically justifiable to include pregnant women with a disease or medical 
257  condition requiring treatment in clinical trials under the following circumstances: 
258   
259  In the postmarketing setting (i.e., FDA-approved drugs) 
260   
261    Adequate nonclinical studies (including studies on pregnant animals) have been 
262  completed10 
263   
264  and 
265   
266    There is an established safety database in nonpregnant women from clinical trials or 
267  preliminary safety data from the medical literature and/or other sources regarding use in 
268  pregnant women   
269   
270  and one of the following: 
271   
272    Efficacy cannot be extrapolated 
273   
274  and/or 
275   
276    Safety cannot be assessed by other study methods 
277   
278  In the premarketing setting (i.e., investigational drugs) 
279   
280    Adequate nonclinical studies (including studies on pregnant animals) have been 
281  completed 
282   
283  and  
284   
285    The clinical trial holds out the prospect of direct benefit to the pregnant woman and/or 
286  fetus that is not otherwise available outside the research setting or cannot be obtained by 
287  any other means (e.g., the pregnant woman may not have responded to other approved 
288  treatments or there may not be any treatment options) 
289   
290  The above conditions would also apply to a drug that is being developed to treat a pregnancy-
291  specific condition. 
                                                 
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. 
  7  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
292   
293  Women who become pregnant while enrolled in a clinical trial  
294   
295  When a pregnancy has been identified during a clinical trial, unblinding should occur so that 
296  counseling may be offered based on whether the fetus has been exposed to the investigational 
297  drug, placebo, or control.  The risks and benefits of continuing versus stopping investigational 
298  treatment can be reviewed with the pregnant woman.  Pregnant women who choose to continue 
299  in the clinical trial should undergo a second informed consent process that reflects these 
300  additional risk-benefit considerations. 
301   
302  If fetal exposure has already occurred, a woman who becomes pregnant while enrolled in a 
303  clinical trial should be allowed to continue on the investigational drug if the potential benefits of 
304  continued treatment for the woman outweigh the risks of ongoing fetal exposure to the 
305  investigational drug, of discontinuing maternal therapy, and/or of exposing the fetus to additional 
306  drugs if placed on an alternative therapy.  Regardless of whether the woman continues in the 
307  trial, it is important to collect and report the pregnancy outcome. 
308   
309   
310  IV.  OTHER CONSIDERATIONS  
311   
312  Including pregnant women in a trial involves careful risk-benefit assessments.  All trials must be 
313  designed to minimize risk as much as possible while preserving the ability to achieve the 
314  objectives of the research (21 CFR 56.111).  Some general considerations for sponsors and 
315  investigators include:  
316   
317    Obtaining adequate reproductive and developmental toxicology data in relevant 
318  nonclinical models 
319   
320    Identifying the trial population that will derive the most benefit while trying to minimize 
321  risk 
322   
323    Considering the gestational timing of exposure to the investigational drug in relation to 
324  fetal development 
325   
326    Choosing appropriate control populations 
327   
328  Sponsors should also consider the issues discussed in the following sections when designing a 
329  clinical trial that will include pregnant women. 
330   
331  A.  Disease Type and Availability of Therapeutic Options in the Pregnant 
332  Population 
333   
334  Sponsors should take into account the incidence of the disease, the severity of the disease (e.g., 
335  whether or not it is life-threatening), and the availability of other therapeutic options and their 
336  risks.  Pregnant patients with no other viable therapeutic options (e.g., drug resistance, drug 
  8  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
337  intolerance, contraindication, drug allergy) to treat a serious or life-threatening disease or 
338  condition may be appropriate candidates to enroll in a clinical trial. 
339   
340  B.  Timing of Enrollment  
341   
342  The most appropriate time to include pregnant women in clinical trials during drug development 
343  may differ.  Nonclinical reproductive and developmental toxicology studies generally should be 
344  completed before enrolling pregnant women in clinical trials.11  In general, phase 1 and phase 2 
345  clinical trials in a nonpregnant population that include females of reproductive potential should 
346  be completed before sponsors enroll pregnant women in later phase clinical trials.  Sponsors 
347  should consider whether any of the following situations apply in determining when to enroll 
348  pregnant women in the drug development process. 
349   
350    If there are limited safety data or other approved (i.e., safe and effective) treatments are 
351  available:  In this situation, it may be more appropriate to complete phase 3 clinical trials 
352  in a nonpregnant population before enrolling pregnant women and exposing them to the 
353  investigational drug   
354   
355    If there are limited therapeutic options:  In these situations, the risk-benefit 
356  considerations may favor enrollment of pregnant women in earlier phase trials  
357   
358    If there are safety data for a drug that has been studied previously for other indications 
359  or populations:  In these situations, the risk-benefit considerations may favor enrollment 
360  of pregnant women in earlier phase trials   
361   
362  C.  Pharmacokinetic Data 
363   
364  Because of the extensive physiological changes associated with pregnancy, PK parameters may 
365  change, sometimes enough to justify changes in dose or dosing regimen.  For drug development 
366  programs where there are plans to enroll pregnant women in a phase 3 clinical trial, PK data in 
367  pregnant women should be collected during the phase 2 clinical trials to guide appropriate dosing 
368  in phase 3.  In situations where pregnant women are enrolled in phase 3 clinical trials for a 
369  marketed drug, PK data should be collected as part of the trial.  
370   
371  In appropriate situations, nonpregnant women who become pregnant while on the investigational 
372  drug and consent to remain on the drug can also consent to PK assessments at steady state to 
373  collect data on correct dosing during pregnancy.  Modeling and simulation have been 
374  increasingly used to support the design of clinical PK studies (Xia et al. 2013; Ke et al. 2013).  
375  For PK studies including pregnant patients, physiological changes during and after pregnancy 
376  that are critical for drug absorption and disposition may need to be considered in the model.  
377   
378  For additional information on PK modeling, study design considerations, and PK studies in 
379  pregnant women, refer to the draft guidance for industry Pharmacokinetics in Pregnancy  
380  Study Design, Data Analysis, and Impact on Dosing and Labeling.   
                                                 
11 See ICH M3(R2). 
  9  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
381   
382  D.  Safety Data Collection and Monitoring 
383   
384  When pregnant women are enrolled in a clinical trial, data collection elements should include, at 
385  a minimum:  gestational age at enrollment; gestational timing and duration of drug exposure; and 
386  pregnancy outcomes including adverse maternal, fetal, and neonatal events.  Enrolled pregnant 
387  patients should also receive obstetrical care that meets the recognized standards of care.  Infants 
388  born to mothers who were exposed to the investigational drug should have follow-up safety 
389  information collected.  Systemic drug exposure to the fetus/newborn can be evaluated by 
390  collecting cord blood or neonatal levels of drug and/or metabolites, depending on the timing of 
391  exposure to the drug and its half-life. 
392   
393  Clinical trials that enroll pregnant women should include investigators or consultants who have 
394  expertise in obstetrics and/or maternal/fetal medicine, depending on the underlying conditions 
395  treated by the investigational drug.   
396   
397  All clinical trials require monitoring (21 CFR 312.50 and 312.56), and no single approach to 
398  monitoring is appropriate or necessary for every clinical trial.12  Clinical trials that involve 
399  pregnant women should include a data monitoring plan that includes members with relevant 
400  specialty and perinatal expertise to permit ongoing recognition and evaluation of safety concerns 
401  that arise during the course of the trial.  This facilitates appropriate, expert assessment of adverse 
402  event reports.  
403   
404  E.  Stopping a Clinical Trial That Enrolls Pregnant Women 
405   
406  There may be situations where it would be appropriate to stop a randomized, controlled clinical 
407  trial that is enrolling pregnant women.  Examples include the following: 
408   
409    An appropriately planned interim analysis demonstrates superior efficacy of the control 
410  or active comparator arm. 
411   
412    There are documented serious maternal or fetal adverse events that can be reasonably 
413  attributed to drug exposure and are deemed to exceed the potential benefits of drug 
414  treatment.  This determination should include consideration of alternative effective 
415  treatments and the risks of the underlying condition.  
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. 
  10  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
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