22 August 2008

Division of Dockets Management (HFA-305)

Food and Drug Administration

5630 Fishers Lane, rm. 1061

Rockville, MD 20852

**Re: Docket No. FDA-2006-N-0515, RIN 0910-AF11, Content and Format
Labeling for Human Prescription Drug and Biological Products;
Requirements for Pregnancy and Lactation Labeling, Proposed Rule**

To whom it may concern:

First DataBank, a subsidiary of Hearst Corporation, would like to thank
the Food and Drug Administration for the opportunity to provide public
comment on the proposed rule for changes to pregnancy and lactation
prescription product labeling. We strongly support the FDA's efforts,
and would like to provide comment and feedback. Furthermore, we would
like to recommend the addition of some suggested formatting that will
make clinician review efficient and more accurate as well as providing
ease of codification for knowledge base companies. Specifically, we are
recommending continued codification of pregnancy severity warnings and
believe that this is invaluable and absolutely necessary for clinicians
as well as for use in the computable electronic healthcare record. We
also are recommending the addition of a succinct "clinician summary"
section for prescribers, and again believe this to be absolutely
necessary in the fast paced practice of medicine. As the author of a
computable and integrateable drug knowledge base, we at First DataBank
are very glad to see that the FDA is advocating increased
standardization of drug information reporting by manufacturers.

**Comments Pertaining to the Newly Proposed Pregnancy Section:**

-   We assume that the enhanced pregnancy/lactation section structure
    for the final rule will be implemented in the next version of SPL.

-   We would like to propose a new pregnancy section titled "Clinician
    Summary" in addition to the information included in the proposed
    rule. A succinct presentation of the drug data is what we believe
    most clinicians will find the most useful for making efficient
    clinical decisions. Most clinicians will likely not have the
    adequate time to read the detail of pregnancy research data
    presented by a manufacturer.

**New Section Example: Clinician Summary**

-   This new section could utilize standardized statements for human
    data when available that describe the "fetal risk." We propose six
    example "fetal risk summary statements" below. This or some other
    schema would ideally be tested clinically for clinician acceptance
    and completeness of coverage of the risk continuum for pregnancy
    outcomes.

> Below are six possible examples of standardized "Fetal Risk Summary
> Statements" used to describe sufficient, insufficient or unavailable
> human data.

1.  **Contraindicated**: Known risk of human developmental
    abnormalities. (This category includes former FDA pregnancy category
    X drugs).

2.  **Warning**: Known human developmental abnormalities, consider
    maternal benefit of treatment versus fetal risk. (This category
    includes former FDA pregnancy category D drugs).

3.  **Limited Human Data:** Limited human data suggests **possible fetal
    risk**. Based on animal data, the likelihood that (name of drug)
    increases the risk of developmental abnormalities is predicted to be
    (low, moderate or high).

4.  **Limited Human Data:** Limited human data suggests **unclear fetal
    risk**. Based on animal data, the likelihood that (name of drug)
    increases the risk of developmental abnormalities is predicted to be
    (low, moderate or high).

5.  **No human data currently available.** Based on animal data, the
    likelihood that (name of drug) increases the risk of developmental
    abnormalities is predicted to be (low, moderate or high).

6.  **Safe:** No known risk of human developmental abnormalities (This
    category includes former FDA pregnancy category A drugs).

-   Data details for these statements could be presented in the data
    section.

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-   Additionally, a brief one to two sentence "Clinical Considerations"
    summary of the major clinical considerations following the "Fetal
    Risk Summary" statement would also be beneficial.

-   The "Fetal Risk Summary" statement and "Clinical Considerations"
    summary should be added to the "Highlights" section of the SPL.

-   Additionally, we recommend the addition of a data summary table (see
    complete example below in section: **Presentation format of newly
    proposed section- Clinician Summary**).

-   Many providers are familiar with and rely upon the current FDA
    Pregnancy categories for decision making. Inclusion of the
    clinically relevant categories, specifically A, D, and X by
    referencing them in appropriate fetal risk standardized statements
    as shown above would be very valuable and allows for recognition and
    consistency between the new labeling requirements and the historical
    format that will continue for many older FDA approved drugs. New
    category "fetal risk summary statements" such as those presented
    above could be very helpful for clinicians needing to make efficient
    clinical decisions.

-   Categories B and C typically provide little information for the
    clinician regarding a drugs use in pregnancy, and are sometimes
    wrongly interpreted. We agree with elimination of these categories.
    Replacing pregnancy categories B and C with standardized statements
    would be more helpful in these instances.

-   Where human data is insufficient or unavailable, incorporating the
    appropriate, FDA proposed standardized statements for animal data
    could be helpful for a clinician.

**Presentation Format of Newly Proposed Section- Clinician Summary:**

-   Highlighting the risk using one of the six example standardized
    statements from above could quickly alert a clinician to the most
    pertinent information.

-   Addressing all developmental abnormalities and other risks serves as
    a complete information source for the clinician, leaving less
    ambiguity regarding the risks. These types of data should be
    presented in a more detailed data section for review by clinicians
    if they should choose to do so.

-   A tabular format would be a very concise way of presenting risk
    summary data.

**Complete Example Format for the "Clinician Summary":**

**Clinician Summary:** Seizurol ® (Fictitious drug)

> **Fetal Risk Summary Statement: Warning**: Known human developmental
> abnormalities, consider maternal benefit of treatment versus fetal
> risk. (This category includes former FDA pregnancy category D drugs)
>
> **Clinical considerations**: Treatment benefits for a mother with
> epilepsy often outweigh the risk of fetal developmental abnormalities
> from this drug.

**Complete Example Format for the "Clinician Summary": continued**

**Data Summary**:

+---------------+---------+--------------+--------------+--------------+
| **Fetal       | **Tr    | **Rev        | **Known or   | **           |
| Risk**        | imester | ersibility** | Possible     | Drug-related |
|               | N       |              | Adverse      | risk         |
|               | umber** |              | effects in   | compared to  |
|               |         |              | the          | background   |
|               |         |              | fet          | risk**       |
|               |         |              | us/neonate** |              |
+---------------+---------+--------------+--------------+--------------+
| Structural    | 1       | Surgical     |              | 30 in 100    |
| Anomaly:      |         | i            |              | treated      |
|               |         | nterventions |              | mothers, 10  |
| Cleft Palate  |         | to correct   |              | in 100       |
|               |         | palate       |              | without      |
|               |         | malformation |              | treatment    |
|               |         | may be       |              |              |
|               |         | required.    |              |              |
+---------------+---------+--------------+--------------+--------------+
| Physiologic   |         |              |              |              |
| a             |         |              |              |              |
| bnormalities- |         |              |              |              |
| none known    |         |              |              |              |
+---------------+---------+--------------+--------------+--------------+
| Alterations   |         |              |              |              |
| to growth-    |         |              |              |              |
| none known    |         |              |              |              |
+---------------+---------+--------------+--------------+--------------+
| Fetal and     |         |              |              |              |
| infant        |         |              |              |              |
| mortality-    |         |              |              |              |
| none known    |         |              |              |              |
+---------------+---------+--------------+--------------+--------------+
| Other Risks   |         |              |              |              |
| (t            |         |              |              |              |
| ransplacental |         |              |              |              |
| ca            |         |              |              |              |
| rcinogenesis) |         |              |              |              |
| none known    |         |              |              |              |
+---------------+---------+--------------+--------------+--------------+

Below we present comments on each of the following sections based on the
FDA supplied example templates for the Pregnancy section; General
Information, Fetal Risk Summary, Clinical Considerations, and Data.

**FDA Proposed General Information Section (comments):**

-   We support requesting the manufacturers to list pregnancy registry
    information which is a valuable tool for clinicians. This may also
    pave the way for improved registry use by clinicians leading to
    better documentation of drug effects and use during pregnancy.

-   We support background risk statements and acknowledge that they are
    important facts to consider when reviewing risks of drugs.
    Clinicians will certainly find this useful when explaining the
    comparative fetal risks associated with and without treatment.
    However, background risks of pregnancy can vary by demographics,
    location, ethnicity and several other variables. The FDA should
    provide industry guidance for describing background risk. Providing
    manufacturers with a guidance document could help keep these
    descriptions uniform and standardized, so that clinicians can easily
    make comparisons between products.

**FDA Proposed Fetal Risk Summary Section (comments):**

-   Again we reiterate our support for comprehensive drug information
    for drug use in pregnancy, since the current category system can
    often be misleading.

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-   Animal Data Presentation

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-   We support presentation of animal data secondary to human data when
    insufficient or unavailable.

-   Extrapolation of animal data to humans may be very complicated, and
    difficult to interpret by clinicians. A standardized statement
    indicating the possible correlation between animal and human data
    would be useful when interpreting animal data. This should be
    clearly stated by the manufacturers.

-   We support the standardized statements regarding the likelihood that
    a drug will increase the risk for a known developmental abnormality.

**FDA Proposed Clinical Considerations Section (comments):**

-   Clinical guidance provided by this section will be highly regarded
    and utilized by clinicians.

-   We support addressing maternal toxicities and adverse effects in
    this section. It will serve as a useful tool in weighing the
    benefits of treatment versus risk to fetus.

**FDA Proposed Data Summary Section (comments):**

-   This section contains very useful information, and could serve as a
    great supplement to the summary table we recommend above in our
    comments.

-   In addition to the proposed content, references for the data cited
    could serve as potentially useful information to the clinicians, and
    other multidisciplinary health care workers interested in
    researching a pregnancy issue further.

**Comments Pertaining to the Newly Proposed Lactation Section:**

> We appreciate that the content proposed for the lactation label
> section is very thorough and detailed.

**Comments:**

-   In addition to the proposed content, we would like to propose a new
    section titled Clinician Summary. This section would incorporate
    standardized statements based on human data for the following:
    Compatibility with breastfeeding, excretion information, and if
    available any adverse effects that may be known or predicted for the
    infant.

-   Highlighting these three subjects at the beginning of the section as
    a summary section will serve as a simplified but effective method
    for communicating the bottom line message to clinicians.

-   The use of succinct standardized statements could provide key
    information for efficient clinical decision making.

**New Section Example: Clinician Summary**

-   **Compatibility:**

> The following compatibility statements are conceptually similar to
> those that the American Academy of Pediatrics (AAP) and the World
> Health Organization (WHO) use as a classification system for drugs
> used during breastfeeding. (1, 2)
>
> Examples of standardized statements that could be implemented:

1.  "Drug X" is Compatible with breastfeeding, based on known human
    data.

2.  "Drug X" is probably compatible with breastfeeding, with close
    monitoring for any adverse effects. Discontinuation of breastfeeding
    has associated risks. AAP recommends exclusive breastfeeding up to 6
    months of age for protection against diseases. (3)

3.  "Drug X" is contraindicated with breastfeeding. Alternative
    prescription medications may be considered if breastfeeding is to be
    continued. Discontinuation of breastfeeding has associated risks.
    AAP recommends exclusive breastfeeding up to 6 months of age for
    protection against diseases. (3)

-   **Excretion (**examples of standardized statements that could be
    implemented)**:**

    1.  "Drug X" is excreted in breast milk, based on known human data.
        Based on breast milk excretion data, an infant would be
        estimated to consume "Y" mg/24 hours or "Z"% of the 24 hour
        weight-adjusted dose for an infant. Discontinuation of
        breastfeeding has associated risks. AAP recommends exclusive
        breastfeeding up to 6 months of age for protection against
        diseases. (3)

    2.  It is not know if "Drug X" is excreted into breast milk. Limited
        or no human data is available. Discontinuation of breastfeeding
        has associated risks. AAP recommends exclusive breastfeeding up
        to 6 months of age for protection against diseases. (3)

    3.  "Drug X" is not excreted into breast milk, based on known human
        data.

    -   **Effect on infant**

> Either or both of the statements below could provide clear, concise
> information in this section:

1.  (If excretion and effects on the infant are documented) The
    following effects on the infant have been documented: ...

2.  (If excretion is not known) Based on the known pharmacology of drug
    "X", and if breastfeeding is to be continued, monitor for the
    following adverse effects in the infant: ...

**Complete Example Format for the "Clinician Summary":**

**Clinician Summary:** Seizurol ® (Fictitious drug)

> **Compatibility:** Seizurol ® is probably compatible with
> breastfeeding, with close monitoring for adverse effects, based on
> limited human data. Discontinuation of breastfeeding has associated
> risks. AAP recommends exclusive breastfeeding up to 6 months of age
> for protection against diseases (3)
>
> **Excretion:** It is not know if Seizurol ® is excreted into human
> breast milk. Limited human data is available. Discontinuation of
> breastfeeding has associated risks. AAP recommends exclusive
> breastfeeding up to 6 months of age for protection against diseases.
> (3)
>
> **Effect on Infant:** Based on the known pharmacology of Seizurol ®,
> and if breastfeeding is to be continued, monitor for the following
> adverse effects in the infant: somnolence and irritability.

Data detail for these statements could be presented in the data section.

The **Clinician Summary** section: compatibility, excretion, and effect
on infant should be added to the "Highlights" section of the SPL.

Below we present comments on each of the following sections based on the
FDA supplied example templates for the proposed Lactation section: Fetal
Risk Summary, Clinical Considerations, and Data.

**FDA Proposed Risk Summary (comments)**

-   We support the use of standardized statements when a drug is not
    systemically absorbed.

-   We support including (if available) the information below for drugs
    that are systemically absorbed.

-   **Presence of drug in milk**

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-   To reduce ambiguity, avoiding predictions and relying on clinical
    data only may better assist providers.

-   Standardizing the approach to presenting drug concentrations in
    breast milk will ensure that uniform data is presented by all
    manufacturers, allowing for easy comparisons between prescription
    products.

-   Providing a guidance document highlighting the value of breast milk
    AUC concentrations, providing standardized ways of calculating
    weight-normalized drug doses and average breast milk consumption
    could better guide manufacturers, and help create a unified approach
    to describing drug concentrations in breast milk.

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-   **Drugs impact on breast milk**

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-   Information regarding quality and composition may not be clinically
    relevant for the nursing infant.

-   Discussing drug effect on the quantity of breast milk produced could
    be of little value also, since data is very limited and poorly
    relates to prolactin levels. If data exists, it should be presented.

**FDA Proposed Clinical Considerations (comments)**

-   For drugs that may have serious potential adverse effects, or are
    considered contraindicated in breastfeeding, a standardized
    statement should be included by the manufacturer to emphasize the
    important benefits of breastfeeding and risks of discontinuation of
    breastfeeding.

    -   Example: Discontinuation of breastfeeding has associated risks.
        AAP recommends exclusive breastfeeding for 6 months for
        protection against diseases. (3)

-   Presentation of methods to reduce nursing infant exposure to drug
    during lactation, based on pharmacokinetic principles may be
    valuable to clinicians only if the presentation of pharmacokinetic
    data is minimized and the clinical relevance and rationale is
    clearly explained.

-   The proposals reference to dose adjustment information is unclear.
    Does this refer to dosage level adjustments or dose timing relative
    to nursing times? We feel the most likely dose adjustment would be
    timing of a drug dose to breastfeeding.

**FDA Proposed Data Section (comments)**

-   We support evidence for the lactation section being presented in
    this section.

-   Stating the fact that no evidence exists is valuable information to
    clinicians.

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-   Only human data should be presented when it is available.

-   Extrapolation of animal data to humans may not be helpful without
    the manufacturers stating the human clinical correlation if it is
    known.

We would like to thank the FDA once again for providing this opportunity
for First DataBank to comment on the proposed changes to the pregnancy
and lactation sections. We appreciate and commend the FDA's efforts
toward improving drug information availability to medical professionals
as well as the general public. Our goal in providing comment and
suggestion is to increase the awareness of a practicing clinicians need
for succinct and meaningful information that is easily interpretable and
easily used in the daily workflow. Additionally, the presentation of
these data must be standardized as much as possible with applicable
coding schema for ease of implementation in databases and electronic
health record system checking algorithms. We hope our recommendations
will provide useful insights into further improvements that can be made
to the proposed changes to the pregnancy and lactation labeling
sections.

Respectfully Submitted,

Usha Desiraju, Pharm.D.

Clinical Pharmacist, Disease Decisions Support

Jeff Bubp, Pharm.D.

Clinical Pharmacist, Disease Decision Support

Joan Kapusnik-Uner, Pharm.D., FCSHP

Manager, Disease Decision Support

**References:**

1\. Eleventh Model List of Essential Drugs. In: *The Use of Essential
Drugs.* Ninth report of the WHO Expert Committee (including the revised
Model List of Essential Drugs). World Health Organization (Technical
report Series No. 895), Geneva 2000.

2\. American Academy of Pediatrics, Committee on Drugs. The Transfer of
Drugs and Other Chemicals Into Human Milk. Pediatrics, 108:776-789, 2001

3.Gartner LM, Morton J, Lawerence RA, Naylor,AJ, O'Hare D, Schanler RJ,
Eidelman AI; American Academy of Pediatrics Section on Breastfeeding.
Breastfeeding and the use of human milk. Pediatrics. 2004
Nov;114(5):1365.