September 22, 1999

Dockets Management Branch

HFA-305, Room 1061

Food and Drug Administration

5630 Fishers Lane

Rockville, MD 20852

**SUBJECT: RESPONSE TO DOCKET NO. 99D-1738**

Dear Sir/Madam:

Enclosed herein are our comments to the "Draft Guidance for Industry on
Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal
Sprays for Local Action."

Schering Corporation has addressed bioequivalence requirements for
Beclomethasone Dipropionate Nasal spray products with FDA, beginning in
December of 1996 (SP to Dr. Janet Woodcock) and additionally with Mr.
Douglas Sporn ( Office of Generic Drugs ) in March of 1997. Although we
find many of our previous comments addressed in this "Draft Guidance"
and generally are in agreement, please take note of the following
comments :

*[Solution Products Reliance on In-Vitro Methods-- Page 3]{.underline}*

> Schering-Plough agrees that the most critical factors for delivery to
> the upper respiratory tract are release of drug substance from the
> product and delivery to the mucosa. While in-vitro methods seem
> appropriate to characterize the delivery of drug substance from the
> product, there is, according to Schering-Plough's knowledge, no
> adequate evidence suggesting that in-vitro methods can predict
> clinical performance. A number of the *in-vitro* assessments which are
> suggested to replace clinical trials for solution products have been
> developed for oral inhalation and will according to Schering-Plough's
> assessment not be able to adequately characterize products intended
> for nasal delivery. Schering Plough believes that the results of
> clinical studies are indispensible element of establishing therapeutic
> equivalence between two formulations.

Dockets Management Branch September 22, 1999

Response to Docket No. 99D-1738 Page 2

> Relatively little is known about the delivery of pharmaceuticals to
> the mucosa of the upper respiratory tract. Methods to characterize
> deposition without major alterations of the product and enabling
> three-dimensional imaging of drug deposition in relation to anatomical
> structures are in development, but substantial further progress is
> necessary before a more thorough understanding of nasal delivery is
> possible. At the same time, relevant indications include diseases with
> major alterations of the anatomical structures such as polyposis and
> claims on effects, which are probably related to delivery to the
> sinuses and the internal entrance of the Eustachian tube. Based on the
> somewhat limited knowledge about nasal delivery and facing different
> indications and claims there is no agreement about an appropriate
> target for particle size distribution.

The methodology currently used for the characterization of particle size
distribution is in Schering-Plough's view insufficient to establish
therapeutic equivalence between two solution products:

-   The multistage cascade impactor (CI) and the multistage liquid
    impinger (MSLI) are optimized for products intended for oral
    inhalation. This includes the dimensions of the test inlet serving
    as "throat", the flow rate and the particle size spectrum covered.
    The concept of the test inlet has to be fundamentally different for
    nasal products, the relevant flow rate is lower for nasal products
    and the method should allow an adequate coverage and precision to
    assess particles larger than 10 micron.

-   In line with the Draft Guideline, laser diffraction and light
    microscopy may only provide supportive evidence for the
    characterization of particle size distribution; both have major
    limitations, which are widely acknowledged.

# Suspension Formulations with PK Systemic Exposure Data -- Page 7

> Schering-Plough agrees with the Draft Guideline that a pharmacokinetic
> approach for the establishment of comparable safety is only valid, if
> the nasal administration results in sufficiently high plasma or blood
> concentrations to produce meaningful AUC-data. In Schering's
> experience, potential issues with some commonly used drugs are:

-   tissue concentrations may be substantially higher than blood or
    plasma concentrations and small changes in blood or plasma
    concentrations may reflect relatively large changes in individual
    tissues which are relevant to safety.

Dockets Management Branch September 22, 1999

Response to Docket No. 99D-1738 Page 3

-   If the mean concentration or a substantial number of individual
    concentrations are below or close to the limit of quantitation, the
    sensitivity of a pharmacokinetic comparison may become undesirably
    low .

> In our view, major active metabolites have to exhibit comparable blood
> concentrations as well. This should be at least the case for compounds
> for which a metabolite is more active than the parent compound.
> Corresponding changes are suggested for Section VII, Bioavailability
> and Bioequivalence, PK Systemic Exposure Studies to address the
> characterization of major active metabolites.

# Suspension Formulations without PK Systemic Exposure Data -- Page 7

> The Draft Guideline states that for products intended for local
> action, which produce blood or plasma levels too low for adequate
> measurement, a BE study with a clinical endpoint to establish
> equivalent local delivery to nasal sites and a study with a
> pharmacodynamic or clinical endpoint to establish systemic absorption
> are recommended.
>
> Our suggestion is to add 'sensitive' before 'pharmacodynamic or
> clinical endpoint to establish systemic absorption.... This addition
> would be in line with the paragraph "BE Study Endpoints for
> Corticosteroids" on page 20.

# Clinical BE study Designs and Subject Inclusion Criteria --Page 18

> The Draft Guidance proposes that the three study designs outlined in
> the draft will cover all indications. In our opinion there should be
> individual justification that other indications of the originator
> product may not be associated with substantially different drug
> delivery issues.

# Bioavailability and Bioequivalence: PK Systemic Exposure Studies -- Page 20

> If several actuations from the drug in each nostril are needed, the
> increase in bioavailability across doses may or may not be dose
> proportional, in particular, if a relatively large volume is
> administered which may partially trickle out of the nasal cavity
> either into the throat or out of the nares. In our view it is
> debatable, whether this approach (without evidence supporting dose
> proportionality) will result in a reliable and sensitive estimate of
> systemic exposure.

Dockets Management Branch September 22, 1999

Response to Docket No. 99D-1738 Page 4

# 

# 

# BE Study Endpoints for Corticosteroids -- Page 20

> As discussed in the 1998 Advisory Board Meeting with respect to New
> Chemical Entities and New Formulations, assessments of HPA-axis
> function may be less sensitive than the assessment of growth. This
> appears to be particularly relevant if the product labeling includes
> pediatric use and if an effect on growth has been shown for the
> originator product or if the effect on growth is unknown. In the
> interest of a similar safety standard for originator and generic
> products a growth study, preferably intermediate term (one-year)
> stadiometry data, should be provided for corticosteroids indicated for
> the use in children. In our view, this should apply always if the
> originator product is indicated for the use in children, since a
> labeling restriction for the generic product may be impractical and
> growth data are a sensitive indicator for systemic effects in the
> absence of other data such as bone densitometry.
>
> Sincerely,

Joseph F. Lamendola, Ph.D.\
Vice President\
U.S. Regulatory Affairs