DECIDING WHETHER TO CONDUCT A PHARMACOKINETIC STUDY IN PREGNANT WOMEN
Ethical issues are important when considering studying
drugs in pregnant women. Given the large number of pregnant women who need
prescription medicines to maintain their health, some have argued that it is
unethical not to obtain dosing information in this subpopulation (Faden
2000). Others recommend that only pregnant women who need a drug for
therapeutic reasons be included in clinical studies, citing that drug studies
cannot be done in “normal pregnant volunteers” (Stika 2001).
All studies in pregnant women must conform to all
applicable regulations, including human subject protection.[4]
The Agency recommends that all studies in pregnant women have Institutional
Review Board (IRB) review and informed consent for all study participants.
Pregnant women may be involved in PK studies if the
following conditions are met (45 CFR Subpart B 46.204):
·
Preclinical studies, including studies on pregnant animals, and
clinical studies, including studies on nonpregnant women, have been conducted
and provide data for assessing potential risk to pregnant women and fetuses; and
·
The risk to the fetus is not greater than minimal and the purpose
of the research is the development of important biomedical knowledge which
cannot be obtained by any other means.
The definition of minimal risk is broad. The fetal risk
is considered minimal when the estimated risk to the fetus is no more than that
from established procedures routinely used in an uncomplicated pregnancy or in a
pregnancy with complications comparable to those being studied.[5]
Although PK studies in pregnancy can be considered in Phase 3
development programs depending on anticipated use in pregnancy and the results
of reproductive toxicity studies, the FDA anticipates that most PK studies in
pregnant women will occur in the postmarketing period and will be conducted
using pregnant women who have already been prescribed the drug as therapy by
their own physician.
An example of a minimal risk study would be one to
determine PK/PD of an antihypertensive medication in pregnant women who are
taking that medication to treat hypertension during pregnancy. The decision to
use the antihypertensive medication is made by the patient and her physician
independent of participation in the PK/PD study.
Information on human pregnancy experiences and exposures
will emerge during the postmarketing phase for virtually all drug products.
Sponsors are requested to explicitly address positive or negative experiences
during pregnancy or lactation as one of the safety issues in the Overall Safety
Evaluation section of the Periodic Safety Update Report.[6]
This source of information is valuable in determining whether to
conduct PK studies in pregnant women. Other important sources of information
include publications concerning safety (e.g., reports that describe the use of
the drug in pregnancy) or efficacy in pregnancy and information from medical
specialty groups. These types of postmarketing exposure and safety data on drug
products provide the basis for determining the need for PK assessment of a drug
in pregnant women.
This guidance recommends that PK studies be conducted
in pregnant women in any of the following situations:
·
The drug is known to be prescribed in or used by
pregnant women, especially in the second and third trimesters.
·
For a new drug or indication, if there is anticipated or actual
use of the drug in pregnancy.
·
Use is expected to be rare, but the consequences of
uninformed dosages are great (e.g., narrow therapeutic range drugs, cancer
chemotherapy). Drugs of this type can normally be studied in pregnant patients.
·Pregnancy is likely to alter significantly the PK of a drug (e.g.,
renally excreted drug) and any of the above apply.
PK studies in pregnant women are not recommended if the
drug is not used in pregnant women or the drug has known or highly suspect fetal
risk.
For approved products, consider whether a study in
pregnant women must be conducted under the investigational new drug (IND)
regulations (21 CFR 312.2). If there is a concern for significantly increasing
the risk (or decreasing the acceptability of the risks) in a patient population
(i.e., the mother or fetus), an IND would be needed (21 CFR 312.2(b)(iii)).
Also, according to the IND regulations, if a different route of administration
or dosage level is used, an IND would be needed.
|
