"Women of childbearing age must have a negative pregnancy test and must useadequate contraception during the treatment phase of the study and for 9months afterwards. Women who wish to breast feed are not eligible for thestudy"
"Females must be of non-childbearing potential. Women of non-childbearing potential are defined as those who have no uterus, ligation of the fallopian tubes, or permanent cessation of ovarian function due to ovarian failure or surgical removal of the ovaries. Documentation of surgical procedure or physical examination is required for subjects who have had a hysterectomy or tubal ligation. In the absence of such documentation, a urine pregnancy test is required for inclusion into the study. A woman is also presumed to be infertile due to natural causes if she has been amenorrheic for greater than 12 months and has an FSH greater than 40 IU/L"
"Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (>= 5 mIU/mL) "
"Pregnant or breast-feeding patients. Women of childbearing potential must have
a negative pregnancy test performed within seven days prior to the start of study
drug. Both men and women enrolled in this trial must use adequate birth control"
The females that are childbearing potential are typically allowed to be enrolled in the clinical trials as long as they are willing to practice a highly effective method of contraception (oral, injectable or implanted hormonal methods of contraception, placement of an intrauterine device [IUD] or intrauterine system [IUS] condom or occlusive cap with spermicidal foam/gel/film/cream/suppository, male sterilization, or true abstinence) throughout the study.
However, it is not uncommon to have female subjects who become pregnant during a clinical investigation. In such instances, should the pregnancy be reported as AE or SAE?
The answer depends on the outcome of the pregnancy (either on mother side or on fetus side).
Pregnancy occurring during a patient’s participation in a clinical trial, although not
typically considered an SAE, must be notified to the sponsor within the same timelines as an
SAE (within one working day) on a Pregnancy Monitoring Form. The
outcome of a pregnancy should be followed up carefully and any abnormal outcome
of the mother or the child should be reported. This also applies to pregnancies
following the administration of the investigational product to the father prior to
Based on the outcome and the timing of the delivery, the pregnancies during the clinical trial can be categoried into the followings:
Female is study participant and becomes pregnant during study participation:
- Normal outcome before end of study
- Abnormal outcome before end of study
- Normal outcome after end of study
- Abnormal outcome after end of study
Female is partner of study participation and becomes pregnant during study:
5. Normal outcome before or after end of study
6. Abnormal outcome before or after end of study
In all of these situations, the Pregnancy Monitoring Form should always be filled out. However, only for situation #2, a SAE needs to be reported.
Since the typical clinical trials do not include the pregnancy women, the potential impact of the drug on pregnancy women is not obtained during the pre-market studies. A lot of drug labels contain a statement in the contradiction section about the pregancy women. Drug exposure could also have impact on fetus - a term called 'Teratogenicity'. Teratogenicity refers to the capability of a drug to cause fetal abnormalities when administered to the pregnant mother. One of the best-known examples of such a drug- induced birth defect is the Thalidomide disaster. The drug was prescribed on a wide scale to pregnant mothers to ease the anxiety associated with it. The large-scale consumption of the drug resulted in children born with seal like limbs, often referred to as phocomelia. The drug was banned for prescription in 1961.
The potential impact of the drug on pregnancy could be obtained from observational studies - pregnancy registries. Refer to FDA's website about "General Information about Pregnancy Exposure Registries".
In ICH E2D "Post-Approval Safety Data Management: Definitions and Standards for Expedited Reporting", the following paragraph is stated:
"5.4.1 Pregnancy Exposure
MAHs (market authorization holders) are expected to follow up all pregnancy reports from healthcare professionals or consumers where the embryo/foetus could have been exposed to one of its medicinal products. When an active substance, or one of its metabolites, has a long half-life, this should be taken into account when considering whether a foetus could have been exposed (e.g., if medicinal products taken before the gestational period should be considered). "
A sample pregnancy registry form can be found from GSK website.