August 27, 2008

Division of Dockets Management (HFA-305)

Food and Drug Administration

5630 Fishers Lane

Room 1061

Rockville, MD 20852

Re: Content and Format of Labeling for Human Prescription Drug and
Biological Products: Requirements for Pregnancy and Lactation Labeling
(Docket No. FDA-2006-N-0515)

To whom it may concern:

Public Citizen submits the following comments in response to the Food
and Drug Administration's (FDA's) Proposed Rule on pregnancy and
lactation labeling for drugs and biologics. While the Proposed Rule
contains many improvements over the current haphazard approach to risk
disclosure, we are concerned that the heightened emphasis on human
studies, many of which are poorly designed and/or underpowered, might
provide false reassurance regarding the safety of these products. We
provide comments only on the pregnancy section of the Proposed Rule.

The current system of pregnancy labeling consists of five
letter-categories (A, B, C, D, and X, in order of increasing risk) based
primarily on animal studies, but also on human studies and theoretical
considerations. The FDA now proposes replacing this system with "Fetal
Risk Summaries" that include a one-sentence fetal risk conclusion,
followed by a separate narrative explanation of the human and animal
data underlying the Summary. The new label would give primary importance
to human studies, if they exist, while downgrading the emphasis on
animal data.

*Limitations of Human Data*

Of course, if the human data are of good quality, such data would be
central to the evaluation of the risk posed by these products. But the
essential problem is that, for a large proportion of drugs, the quality
and statistical power of the human data fall well short of the
desirable. Consequently, human data must be accompanied by clear
acknowledgment of their deficiencies. It is important to remind readers
that, unlike animal studies, these are not randomized, controlled
trials, that they usually include only small numbers of women, and have
limited follow-up. Very often the available studies conflate different
doses and durations of use of the drug and do not clearly state when
exposure occurred, even though these are critical to evaluating risk.
Moreover, while prospective studies typically do an adequate job of
determining the presence or absence of particular teratogenic effects,
registries and retrospective cohort studies are much less certain to
have done so. Very few studies include follow-up long enough to rule out
late-manifesting effects such as behavioral abnormalities. Thus, while
the human studies have obvious advantages (and attractiveness to those
intimidated by animal studies), they bring with them deficiencies not
associated with animal studies.

Of the problems with human reproductive studies mentioned above, the
most concerning is that such studies are typically underpowered. Most
studies have fewer than 300 subjects, yet with a baseline birth defect
incidence of 3% (and this is for all defects, not particular ones), such
a study has only 85% power to detect a relative risk of 2 (alpha = 0.05,
one-sided). Most patients will find little solace in knowing that all
that has been excluded is a more than doubling of their risk. It is
worth recalling that cigarette smoking, an accepted risk factor in
pregnancy, is associated with "only" a 1.34-fold increase in the risk of
birth defects.[^1] (Of course, smoking has other adverse effects on the
fetus.) Societal and medical admonitions against smoking during
pregnancy are very strong.

The solution to this problem is to make clear the limitations of any
human studies cited. These should include mention that the study was not
randomized, that there may have been problems of ascertainment
(especially for registries), how long the follow-up was and whether the
study combined exposures of different doses, durations and weeks of
gestation. Most important, for studies that fail to find an elevated
risk associated with the drug, a sentence with the following formulation
should be included: "While a study of XXX human exposures to the drug
did not show an elevated risk of birth defects compared to background
rates, this study only excludes a YYY-fold increase in the rate of birth
defects due to the drug."

The FDA also seeks comment on the degree of detail to be included the
animal studies section of the data component of the label. Details on
numbers of species, consistency of the findings and the extent of the
elevated risk for the most important defects should all be provided. The
level of detail should be similar to that provided for the human
studies. To not do so prevents those with sufficient expertise from
properly weighing the animal data, particularly when in many cases human
data will be missing or deficient.

Finally, companies are unlikely on their own to seek better human data.
It is therefore incumbent on the FDA to make the collection of human
data on fetal damage a more common element of pre- or post-approval
studies.

*Clinical Aspects*

The FDA proposes boilerplate language that asserts "All pregnancies have
a background risk of birth defect, loss, or other adverse outcome
regardless of drug exposure." Under Clinical Considerations, it provides
fairly detailed reasons why the use of the drug may be justified in
pregnancy (e.g., "Asthma complicates approximately 1 percent of all
pregnancies resulting in higher perinatal mortality, low birth weight
infants, preterm births, and pregnancy-induced hypertension compared to
outcomes for nonasthmatic women. Because of the risks of even mild
maternal hypoxia to the developing fetus, asthma should be clinically
well-controlled during pregnancy.") The inclusion of such statements is
deeply ironic, for the FDA has long held to the claim that it does not
engage in the practice of medicine. Yet here, in the *pregnancy* section
of the label, it makes a spirited case for the usefulness of the drug.
The agency has repeatedly presented itself as simply a provider of data
clinicians can use to make informed decisions; we recommend that the
agency adhere to that role in this case.

The agency would also use such vague terms as "low," "moderate," and
"high" risk of developmental abnormalities (see p. 30842 of Federal
Register notice). We do not believe that these terms are precise or that
individual clincians or patients would interpret them similarly.
Finally, while it is certainly true that a decision to use a drug during
pregnancy should be made in the context of the effectiveness of the drug
and the seriousness of the condition being treated, the Proposed Rule
does not consider whether an alternative drug may be less likely to be
teratogenic.

*Procedural Considerations*

Because the new label will consist largely of narrative descriptions of
studies, a critical part of the process will be who decides which data
sources get cited, how critically they are analyzed, and what weight
they are given. The majority of published human analyses of safety done
by Teratology Information Services (e.g., OTIS and Motherisk) conclude
that most drugs are without risk.

The synthesis of the new label will be a time-consuming process. It is
not clear who will be responsible for writing/reviewing: industry or the
FDA. Who will choose which studies to include and make the judgments as
to the seriousness, reversibility, and correctability of an abnormality?
Will the FDA provide training for staff to analyze the literature,
adverse event databases (U.S. and international), pregnancy registers,
and animal studies? Will these staff have the expertise to critically
evaluate statistics, medicine, physiology, and toxicology? Will the FDA
call on outside experts, and who will identify them?

*Problems concerning the sample labels provided by the FDA*

Example 2: Drug for which only animal data are available; lack of
developmental toxicity findings

The Fetal Risk Summary that the drug "is not predicted to increase the
risk of developmental abnormalities" is based on a study in rats and
rabbits treated at doses only 1.5 times the maximum adjusted human dose.
There is no information to alert the reader that the use of doses this
low does not constitute a valid test, and, thus, in addition to no human
data, there are also no valid animal data.

Example 3: Drug for which animal and some human (insufficient) data are
available

The Fetal Risk Summary states that "the risk of major congenital
abnormalities or spontaneous abortions is low," a conclusion based on
less than three weeks of exposure in the first trimester in an unknown
number of women. Only if one takes the time to go the data section below
does one find the reference and learn the power of the study. Will
readers make this effort in practice? Will the reader be able to
interpret the conclusions presented? Finally, how does one interpret the
statement that, based on animal data, the risk of developmental
abnormalities is predicted to be "moderate"? Do physicians and patients
have similar interpretations of this term?

Example 4: Drug for which sufficient human data are available

The Fetal Risk Summary states that "Human data do not indicate that
DELTAMAN increases the overall risk of major congenital malformations or
neural tube defects." This conclusion is based on a pregnancy exposure
registry and a retrospective cohort study of a group of women using this
drug and "pharmacologically similar drugs." Although the label states
that the registry has a 90% power to detect a 2.5-fold increase in major
malformations and only an 80% power to detect a 10-fold increase in the
rate of neural tube defects, we do not know doses, duration of use, or
when exactly exposure occurred during the first trimester. Exclusion of
a 2.5-fold increased risk does not merit a conclusion that there is no
risk, the conclusion most will draw from the Fetal Risk Summary.

Completely ignored in the Summary are the data from three animal species
(rats, mice, and monkeys), all of which demonstrated a dose-dependent
increase in neural tube and skeletal anomalies. Webster and Freeman
state that where there is "an increased incidence of one or more birth
defects in two animal species and evidence of a dose-effect ... \[s\]uch
findings are treated as though the drug would cause birth defects in the
human regardless of the pharmacokinetic data."[^2] The proposed FDA
algorithm states that human data outrank animal data, apparently even
where there are compelling data from animals that contradict those from
humans. Finally, this is a drug for gastro-esophageal reflux disease
(GERD), for which changes in diet and behavior might be all that are
needed.

*Conclusion*

Predicting the safety of drug use in pregnancy is a very inexact
science, particularly due to the relative absence of well-designed and
--conducted human studies. Using cryptic Fetal Risk Summary statements,
basing safety on a potentially selected set of human studies, and
downplaying the usefulness of animal data, fails to provide pregnant
women and their health care providers with the information the FDA is
required to provide by law.

Yours sincerely,

Elizabeth Barbehenn, PhD

Research Analyst

Peter Lurie, MD, MPH

Deputy Director

Sidney M. Wolfe, MD

Director

Health Research Group at Public Citizen

[^1]: Shepard TH, Brent RL, Friedman JM. Update on new developments in
    the study of human teratogens. Teratology 2002;65:153-161.

[^2]: Webster WS, Freeman JAD. Is this drug safe in pregnancy?
    Reproductive Toxicology 2001;15:619-629.