Comments from Lori A. Dostal, PhD, DABT

Consultant, Aptuit Consulting, Inc.

I appreciate the opportunity to comment on the Proposed change in
regulations concerning format and content of the "Pregnancy", "Labor and
delivery" and "Nursing mothers" sections of labeling for human drugs.
The following are my own opinions and questions based on \~20 years of
experience in the conduct and management of reproductive and
developmental toxicology studies in animals to support drug development.

I agree with the efforts to change the labeling since the previous
designations (Categories A, B, C, D, and X) are too broad, not helpful,
and have potentially negative consequences to pregnant women with
inadvertent exposure to their fetus.

**Specifically in response to the statement "FDA seeks comment on
whether these standardized statements can adequately communicate
different levels of risk based on animal data and their potential
relevance to human fetal effects, or whether these statements are likely
to generate confusion among prescribers."**

**B. Pregnancy Subsection**

[Fetal Risk Summary]{.underline}:

I believe that for new drugs and those that are not widely used in women
of childbearing potential, human pregnancy data will be minimal or
nonexistent. Therefore animal data obtained from studies conducted in
accordance with ICH guidelines, under GLPs, should play a key role in
predicting the safety of use during human pregnancy. Placing more
emphasis on minimal human data (such as case reports) than on strong
animal data can easily misrepresent the fetal risk of a drug. FDA should
develop an overall approach to characterize the risk based on all of the
data since conflicts between animal and human data will be frequent.

The terminology proposed for use in the animal data section is
appropriate except for the term "developmental abnormalities" to
encompass all types of developmental effects. This term is likely to be
interpreted as malformations and not the more general term as intended.
The term "developmental effects" would be better and more common. The
terminology used in the Appendix: Sample Pregnancy Subsection Labeling
does not match the proposed terminology in this section. In the samples,
terms like teratogenicity, embryocidal, embryolethal, etc. are used,
especially for the animal data.

I believe the proposed Conclusion categories of "Low", Medium", and
"High" risk based on animal data are confusing and subject to variable
interpretations. It will be very difficult to categorize the results of
multiple studies conducted for a single drug into these categories. The
categories of Medium and High will overlap or be highly debatable in
many situations. A drug that produces "more than one fetal developmental
abnormality in more than one animal species" would arguably fit both the
Moderate and High categories depending on one's perception of "low
exposures compared with anticipated human exposure". A 5-fold margin
might be a large safety margin to one person and a small safety margin
to another. Animal data are often very complex and difficult to place
into categories even with the examples given. A narrative summary of the
animal data and an overall evaluation of the database in terms of the
potential for harm to humans is a more appropriate approach.

In fact most of the examples are more confusing than helpful. For
example, the example DELTAMAN inaccurately describes a set of animal
data as "low" risk when the data describe markedly adverse fetal
effects. The example ALPHATHON is a poor example because it describes
fairly high developmental toxicity but the last bullet point is not
realistic. "The effects of ALPHATHON on fetal growth, labor, or
postnatal complications were not evaluated" is virtually impossible
given the 2 preceding bullets since the animal data described would most
likely be obtained from ICH guideline EmbryoFetal Development studies,
which necessarily include an evaluation of fetal growth. It is highly
unlikely that a drug for asthma would have no human data and would not
have a pre/postnatal development study conducted according to ICH
Guidelines. The example KAPPAATE would be "low" risk in my opinion.

The proposed Fetal Risk Conclusions will inappropriately result in the
same mis-interpretations that the current A, B, C etc categories
produce. Is "Medium" risk actually safer than "High" risk? Will most new
drugs fall in the "Moderate" risk category? Since most animal studies
are conducted up to Maternally Toxic doses as required by ICH
guidelines, there are frequently fetal growth and development effects as
a result of toxicity.

I suggest that the exposure levels in animal studies that produced no
effects should be described relative to multiples of the clinical doses
or exposures. Also, effects in animals at high exposure multiples with
significant maternal toxicity should be of less concern than effects at
therapeutic exposures.