TRP Protocol Eligibility Criteria Templates for Pregnancy Prevention
Guidance for Selecting and Modifying the Appropriate Protocol Eligibility Criteria
Template for Pregnancy Prevention
These eligibility criteria templates have been developed based on the FDA Use-In-Pregnancy Drug Categories [21CFR §
201.57 (f)(6)(i)(a)-(e)] (http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=201.57). These
Categories are:
 Category A: Controlled studies show no risk. Adequate, well-controlled studies in pregnant women have failed to
demonstrate a risk to the fetus in any trimester of pregnancy. The possibility of fetal harm appears remote.

Category B: No evidence of risk in humans. Animal reproduction studies have failed to demonstrate a risk to the
fetus, and there are no adequate and well-controlled studies in pregnant women, OR animal reproduction studies, have
shown an adverse effect; however, adequate and well-controlled studies in pregnant women have failed to demonstrate
a risk to the fetus during the first trimester of pregnancy (and there is no evidence of a risk in later trimesters). The
possibility of fetal harm is remote but cannot be ruled out. The drug should be used during pregnancy only if clearly
needed.

Category C: Risk cannot be ruled out. Adequate, well-controlled human studies are lacking, and animal studies
have shown a risk to the fetus or studies in women and animals are not available. There is a chance of fetal harm if the
drug is administered during pregnancy; but the benefits from the use of the drug in pregnant women may be acceptable
despite its potential risks.

Category D: Positive evidence of risk. There is positive evidence of human fetal risk based on adverse reaction data
from investigational or marketing experience or studies in humans, but the potential benefits from the use of the drug in
pregnant women may be acceptable despite its potential risks. For example, the drug may be acceptable if needed in a
life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective.

Category X: Contraindicated in pregnancy. Studies in animals or humans, or investigational or post-marketing
reports, have demonstrated positive evidence of fetal abnormalities and the risk of the use of the drug in a pregnant
woman clearly outweighs any possible benefit.
Instructions:
1.
The protocol eligibility template should be selected and modified by the protocol team based on the medication
with the highest risk for teratogenicity that is included in the protocol-specified regimen. For investigational agents, the
reproductive toxicity data currently available should be used to guide selection of the most appropriate template. The type
of study should be also considered in selecting the eligibility criteria template, i.e. pregnancy studies, perinatal transmission
studies, etc.
2.
For FDA Use in Pregnancy Category A and B study agents used for FDA-approved indications, at approved doses
in approved populations, protocol-mandated contraception is not required. The language outlined below is not required to
be in the protocol document.
3.
The selected protocol eligibility criteria template must be appropriately modified to include additional information
or more specific requirements related to the prevention of pregnancy that are cited in the latest product labeling or
investigator’s brochure.
4.
The protocol team must also specify the length of time that contraception should be started before the protocolspecified medications is started, if applicable, and continued after these medications have been stopped. This decision
should be based on product labeling and/or the pharmacokinetic half-lives of the relevant therapies under study. For
example, the EFV package insert recommends continuing adequate contraception for 12 weeks after discontinuation of the
drug.
5.
The acceptable time period between obtaining a negative pregnancy test and initiation of protocol-specified
medications should be based on product labeling. If the information is not available, the protocol team should decide what
is clinically appropriate. For protocol regimens that specify combination therapy, the timeframe between negative
pregnancy test and initiation of therapy should be based on the medication with the highest risk.
6.
A template appendix provides lists of acceptable contraception methods sorted by Use-In-Pregnancy Categories.
Please also refer to the FDA Birth Control Guide found at
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TRP Protocol Eligibility Criteria Templates for Pregnancy Prevention
http://www.fda.gov/ForConsumers/ByAudience/ForWomen/ucm118465.htm for updates on acceptable contraception
methods. The most appropriate of these lists should be chosen for use in the protocol and modified as needed. This
appendix also specifies acceptable documentation for sterilization, menopause, and a child’s or adolescent’s reproductive
potential.
Protocol Eligibility Criteria Templates for Pregnancy Prevention
The following templates are proposed language for use in writing the protocol eligibility criteria. For protocols using
Investigational agents, the reproductive toxicity data should guide the selection of the most appropriate template.
Any additional requirements related to prevention of pregnancy specified in the latest package insert, medical alert, or
investigator’s brochure for a protocol-specified drug, e.g. specifying two contraceptive methods or the types of methods
that should be used, must be included in the protocol eligibility criteria. The suggested eligibility criteria in the template
below are minimal requirements and should be used only when specific information for a protocol-specified medication is
not available.
1.
2.
FOR MEDICATIONS WITH LITTLE EVIDENCE OF RISK IN HUMANS: including those designated as
FDA Use-In-Pregnancy Category C:

Female study volunteers of reproductive potential (defined as girls who have reached menarche and women who
have not been post-menopausal for at least 24 consecutive months, i.e. who have had menses within the preceding
24 months, and have not undergone surgical sterilization (e.g. hysterectomy, bilateral oophorectomy, tubal ligation
or salpingectomy) must have a negative serum or urine pregnancy test performed within (specify) days before
initiating study-specified medication(s).

If participating in sexual activity that could lead to pregnancy, the female study volunteer must use a form of
contraception as listed in the Appendix while receiving protocol-specified medication(s) and for (specify) number
of months after stopping the medication(s).

If the female volunteer is not of reproductive potential (girls who have not reached menarche, or women who have
been post-menopausal for at least 24 consecutive months, or women who have undergone surgical sterilization,
(e.g. hysterectomy, bilateral oophorectomy, tubal ligation or salpingectomy) she is eligible without requiring the
use of a contraceptive method. Acceptable documentation of sterilization, other contraceptive methods,
menopause, and a child’s reproductive potential are specified in the Appendix.
FOR MEDICATIONS WITH EVIDENCE SUGGESTING SIGNIFICANT RISK, including those designated as
FDA Use-In-Pregnancy Category D:
Note: Two methods of contraception must be used by all study volunteers receiving protocol-specified Category D
medications unless otherwise specified in the package insert or investigator’s brochure. Any additional
requirements related to prevention of pregnancy specified in the latest package insert, medical alert, or
investigator’s brochure for that drug (e.g., the type of contraceptive methods that should be used) must be
included in the protocol eligibility criteria.
NOTE: EFV is a special Category D agent: two methods of contraception are required, including a
barrier method, but only for female volunteers.

Female study volunteers of reproductive potential (defined as girls who have reached menarche and women who
have not been post-menopausal for at least 24 consecutive months, i.e. who have had menses within the preceding
24 months, and have not undergone a sterilization procedure (e.g. hysterectomy, bilateral oophorectomy, or
salpingectomy) must have a negative serum or urine pregnancy test performed within 48 hours before initiating the
protocol-specified medication(s) unless otherwise specified by product labeling.

All study volunteers must agree not to participate in a conception process (e.g. active attempt to become pregnant
or to impregnate, sperm donation, in vitro fertilization).
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TRP Protocol Eligibility Criteria Templates for Pregnancy Prevention
3.

If participating in sexual activity that could lead to pregnancy, all study volunteers must agree to use two reliable
methods of contraception simultaneously while receiving protocol-specified medication(s) and for (specify)
number of months after stopping the medication(s).
Note: See the latest package insert for the length of time needed after stopping medication.

Study volunteers who are not of reproductive potential (girls who have not reached menarche, or women who have
been post-menopausal for at least 24 consecutive months, or women who have undergone hysterectomy, bilateral
oophorectomy or salpingectomy, or prepubescent boys or men who have documented azoospermia) are eligible
without requiring the use of a contraceptive method. Acceptable documentation of sterilization, other
contraceptive methods, menopause and a child’s reproductive potential are specified in the Appendix.
FOR KNOWN TERATOGENS OR MEDICATIONS WITH DEFINITIVE EVIDENCE OF FETAL RISK,
including those designated as FDA Use-In-Pregnancy Category X:
Note:
Specifications and requirements vary among Category X medications. For any protocol-specified Category X
medication, the specific requirements related to prevention of pregnancy in the latest package insert, medical
alert, or investigator’s brochure (e.g., type and timing of initiation of contraceptive methods) must be included
in the protocol eligibility criteria. The suggested eligibility criteria below are minimal requirements and
should be used only when specific information is not available in the package insert, medical alert or
investigator’s brochure. For example, teams involved in pediatric studies or using study drugs felt to be very
high risk for fetal effects, may wish to consider the onset of puberty to be Tanner stage greater than 1 for both
boys and girls to minimize the risk of fetal exposure. Teams should also consider using two forms of effective
contraception in women of reproductive potential for at least one month before starting any category X
product.

Female study volunteers of reproductive potential (defined as girls who have reached menarche, and women who
have not been post-menopausal for at least 24 consecutive months, i.e. who have had menses within the preceding
24 months, and women who have not undergone surgical sterilization, specifically hysterectomy and/or bilateral
oophorectomy) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/ml
performed within 24 hours before initiating the protocol-specified medication(s).

All study volunteers must agree not to participate in a conception process (e.g. active attempt to become pregnant
or to impregnate, sperm donation, in vitro fertilization).

If participating in sexual activity that could lead to pregnancy, all study volunteers must agree to use two reliable
methods of contraception simultaneously while receiving protocol-specified medication(s), and for (specify)
months after stopping the medication(s).

Study volunteers who are not of reproductive potential (girls who have not reached menarche or women who have
been post-menopausal for at least 24 consecutive months or have undergone hysterectomy and/or bilateral
oophorectomy or prepubescent boys or men who have documented azoospermia) are eligible without requiring the
use of a contraceptive method. Acceptable documentation of sterilization, menopause and a child’s reproductive
potential is specified in the Appendix.
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TRP Protocol Eligibility Criteria Templates for Pregnancy Prevention
APPENDIX
Acceptable Contraception Methods and Documentation of Sterilization, Menopause and Child’s
or Adolescent’s Reproductive Potential
1. Acceptable Contraception Methods; Please also refer to the FDA Birth Control Guide found at
http://www.fda.gov/ForConsumers/ByAudience/ForWomen/ucm118465.htm
Category X Medications
Contraception requirements as
directed by drug package insert,
medical alert, or investigator’s
brochure.
Category Da Medications
Category C Medications
A Combination of TWO of the
following methods:
At least one of the following methods
MUST be used:
 Condoms (male or female) with or
without a spermicidal agent.
 Diaphragm or cervical cap with
spermicide
 IUD
 Tubal ligationb
 Hormone-based contraceptive
 Condoms (male or female) with or
without a spermicidal agent
 Diaphragm or cervical cap with
spermicide
 IUD
 Hormone-based contraceptive
Footnotes:
a. Exceptions for Some Drugs: Additional or specific requirements may be found in the package insert, medical alert, or
investigator’s brochure, e.g. the labeling for efavirenz, a Category D drug, specifies that only the female study volunteer
must use two reliable contraceptive methods, one of which must be a barrier method. In such cases, all the relevant
instructions must be included in the protocol.
b. Tubal Ligation is considered a form of sterilization for Category C drugs. For Category D and X, if not otherwise
specified in the package insert or IB, it is considered a form of contraception.
Note: Some protocol-specified medications (e.g., PI’s, NNRTI’s) alter the metabolism of hormone-based methods. This
interaction may make hormone-based methods less effective. Therefore, alternative or an additional contraception method
may be required.
2. Acceptable documentation of hysterectomy and bilateral oophorectomy, tubal ligation, tubal micro-inserts,
vasectomy and menopause
 For participants receiving protocol-specified Category C medications:
 Patient-reported history
 Confirmation of the lack of reproductive potential is REQUIRED for participants receiving protocol-specified
Category X and D medications:
 Written documentation or oral communication from a clinician or clinician’s staff documented in source
documents of one of the following:
 Physician report/letter
 Operative report or other source documentation in the patient record
 Discharge summary
 Laboratory report of azoospermia (is required to document successful vasectomy)
 FSH measurement elevated into the menopausal range as established by the reporting laboratory.
Note 1: The female study volunteer may not be able to provide written proof of a male partner’s vasectomy
status since he is not usually enrolled in the same study to provide consent for release of this information.
The verbal report from the female study volunteer of her partner’s status should be written into the
source documents.
Note 2, for EFV only: If the female study volunteer reports a history of infertility based on one of the above
categories but written documentation is not obtainable, or she states that her partner has had a vasectomy, the
female study volunteer must agree to use at least one barrier method with a possible second method required
at the discretion of the site study physician. Documentation of the study volunteer's statement should be
entered into the source document.
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TRP Protocol Eligibility Criteria Templates for Pregnancy Prevention
3.
Acceptable Documentation of a child’s or adolescent’s reproductive potential:

Assess the child’s reproductive potential:
 Participant /caregiver-reported history: in males: the onset of puberty or; in females: onset of menarche.
 Physical exam: Tanner stage.

If the participant is pre-pubescent:
 Document the assessment that the participant has not reached reproductive potential (e.g., Tanner 1 or less for
class X drugs in some protocols).
 Protocol-directed contraception and pregnancy testing are not necessary.

If the onset of puberty has occurred or physical exam shows evidence of reproductive potential:
 Document the assessment that the participant has reached reproductive potential (e.g., onset of menarche in
girls).
 Contraception counseling, contraception and pregnancy testing are required as specified by the protocol, if the
subject is participating in sexual activity that could lead to pregnancy.
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