**October 22, 1999**

**Dockets Management Branch (HFA-305)**

**Food and Drug Administration**

**5630 Fishers Lane**

**Room 1061**

**Rockville, Maryland 20852**

**Re: Draft FDA Guidance on Bioavailability and Bioequivalence Studies
for Nasal Aerosols and Nasal Sprays for Local Action**

> **Docket No. 99D-1738**

Dear Sir/Madam:

Enclosed, please find our comments on this guidance document. We hope
that these comments will help the agency in designing its final guidance
for industry.

The draft guidance according to the Notice issued at the time of the
publication is intended to provide guidance for industry on planning
studies to measure bioavailability and bioequivalence studies in support
of new drug applications (NDA\'s) or abbreviated new drug applications
(ANDAs) for nasal aerosols (metered-dose inhalers) and nasal sprays
(metered-dose spray pumps) for local action.

Thank you for the opportunity to evaluate and respond to this draft
guidance.

Sincerely,

> Debra Hackett Associate Director

North America Regulatory Affairs

**Draft FDA Guidance on Bioavailability and Bioequivalence Studies for
Nasal Aerosols and Nasal Sprays for Local Action**

**Docket No. 99D-1738**

***[General Comments]{.underline}***

1.  [Population and Individual BE]{.underline}: The guidance is confused
    by reference throughout, when discussing in vitro BE, to the
    concepts of population and individual bioequivalence which are
    themselves the subject of a draft guidance yet to be finalised (and
    then only in the context of *in vivo* BE studies). It would simplify
    this guidance enormously to simply cross-refer to currently accepted
    bioequivalence guidelines, making it clear that new bioequivalence
    guidelines may be applied in this context when they are finalised.

***[Specific Comments]{.underline}***

**INTRODUCTION**

[p.2. para 1:]{.underline} The guidance is very specific about the
classes of intranasal product covered and is not applicable for other
classes of intranasal drugs which will be developed in the future.

**BACKGROUND**

[p.4, 1. Local Delivery BA/BE Concepts, para 1]{.underline}: The
sentence beginning "An *in vivo* systemic exposure.." should make it
clear that this is only expected if a drug assay is achievable.

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**IV. DOCUMENTATION OF BIOAVAILABILITY & BIOEQUIVALENCE**

[p.7, 3. Suspension Formulations without PK Systemic Exposure
Data:]{.underline} It is indicated that equivalence in a clinical study
will not be sufficient proof of therapeutic equivalence if the results
of the *in vitro* study don\'t meet the equivalence criteria. However,
this doesn\'t appear to make sense, since it is the clinical performance
that is the meaningful end-point. Normally, the *in vivo* performance is
taken as the determinant of whether different formulations are
bioequivalent or not. In the case of drugs intended for local action, it
would seem that this judgement should be based on clinical end-point
rather than PK, since effect is not directly related to systemic
exposure.

[pp.11-12, 2. Droplet and Drug Particle Size Distribution]{.underline}:
It is not clear how particle size distribution (PSD) and drug and
aggregate PSDs are differentiated. Also, it appears somewhat incongruous
that 'Droplet Size Distribution' appears under the sub-heading a)
Particle size distributions.

[p.12, Laser Diffraction, para 1]{.underline}: Taken in the context of
cross-reference to Section IX Statistical Analysis - *In Vitro* BA data
(p.22 ), which refers to measures on the log scale, it is not clear
whether the summary statistics mentioned are on the linear or log
scales. This point should be clarified and consistency maintained
between these sections. It is suggested that geometric means (if not
already implied by log scale), and possibly medians, be added.

[p.14, Light Microscopy]{.underline}: The term \"geometric standard
deviation\" should be defined.

**V. BIOAVAILABILITY & BIOEQUIVALENCE: IN VITRO STUDIES**

[P.16, 6. Tail Off Profile:]{.underline} In this section, there should
be a distinction between drugs used for a fixed period and those used to
the end of the spray or canister; for the former, the tail-off period
will be irrelevant as long as the number of doses delivered is adequate
to reach the end of the regimen.

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**VI. BIOAVAILABILITY & BIOEQUIVALENCE: CLINICAL STUDIES FOR LOCAL
DELIVERY**

[p.17, B. Clinical Study Endpoints]{.underline}: Statistical analysis of
change from baseline measurements should be avoided in favour of
analysis of covariance using the absolute values of each measure.

[p.18, 1. Traditional Treatment Study]{.underline}: The definition needs
to be more clearly laid out with respect to which formulations are being
evaluated in this study design and what is the purpose of the two-week
run-in period. Since the efficacy endpoint of total nasal symptom scores
(TNSS) will be determined at least twice daily, clarification is
required as to how these measures should be combined to assess
bioequivalence (this comment applies also to other study designs).

[p.18, 2. Days in Park Study]{.underline}: How variation in response
rate between individuals etc. is accounted for in this design requires
clarification. Also, some clarification is required as to whether all
subjects are to be studied on the same day. If not, then the study
design needs to ensure that subjects on studied on similar days (with
respect to allergen exposure) and that there is a balance between the
groups of subjects being studied on each day.

[pp.19, 3. Environmental Exposure Unit]{.underline}: With an adequate
wash-out period e.g. 14 days, the EEU allergen challenge study could be
conducted to a cross-over design, with the anticipated benefit of
reducing sample size.

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**VII BIOAVAILABILITY AND BIOEQUIVALENCE**

[p.19, PK Systemic Exposure Studies, para 1:]{.underline} The primary
endpoints for BE assessment (presumably Cmax and AUC) should be stated.

[pg 20, B. BE Study Endpoints for corticosteriods :]{.underline} Since
the endpoint may be serum cortisol levels collected every 4 hours over a
24 hour period, there could be six actual values for each asessment
period. It should be clarified how these are to be summarised/collapsed
into one endpoint.

[p.20, PK Systemic Exposure Studies, para 2, last sentence]{.underline}:
It should state "A pilot study or [data from previous
studies]{.underline} is recommended\..."

[p.21, B. BE Study Endpoints for Corticosteroids, last
sentence]{.underline}: Clarification is required regarding the method of
baseline adjustment prior to statistical analysis. SB recommend ANCOVA
rather than analysis of change from baseline.

[p.21, D. Clinical Study Designs and Subject Inclusion
Criteria]{.underline}: A double-dummy approach be considered for
incorporation in these designs.

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**IX STATISTICAL ANALYSIS**

[p.22, IX.A. *In Vitro* BE Data]{.underline}: Are the \"percent CV\'s\"
to be reported derived on the arithmetic scale or on the log scale? (ii)
The proposed analysis makes sense, being that for a nested design for
each formulation. Assuming:

> b (=3) batches;
>
> c (=10) canisters per batch;
>
> s (=3) lifestages per canister;

then the ANOVA table would be:

> [Degrees of freedom]{.underline} [Expected Mean Squares]{.underline}
>
> Between batches (b-1) 2 LT2 + s.CT2 + sc.BT2
>
> Between canisters within batches b(c-1) 27 LT2 + s.CT2
>
> [Between lifestages within canisters bc(s-1) 60]{.underline} LT2
>
> TOTAL bcs-1 89

As well as the overall mean, the following mean values are also
requested:

+-----------------+-----------------+-----------------+-----------------+
|                 |                 | > Lifestages    |                 |
|                 |                 | > (from:)       |                 |
+-----------------+-----------------+-----------------+-----------------+
| > Batch         | > Beginning     | > Middle        | > End           |
+-----------------+-----------------+-----------------+-----------------+
| > 1             | > x             | > x             | > x             |
+-----------------+-----------------+-----------------+-----------------+
| > 2             | > x             | > x             | > x             |
+-----------------+-----------------+-----------------+-----------------+
| > 3             | > x             | > x             | > x             |
+-----------------+-----------------+-----------------+-----------------+
| > Overall       | > x             | > x             | > x             |
+-----------------+-----------------+-----------------+-----------------+

[p.22, IX.B In vitro BE Data: Nonprofile Analyses using a confidence
interval approach:]{.underline} It is not clear in section 2, how the BE
criterion described under IX.B applies to the multinomial situation, ie
how Rd is calculated from MN(100,PR), FBR and FCR for the reference data
(and similar definition for test data). Further comments for the
derivation of Rd based on the chi-square \'triplet\' approach, which is
described in more detail, are given below under Appendix A.

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[p.28, E. *In vivo* BE Data: Categorical Endpoints]{.underline}: SB
would like to see the wording of this section before the guidance is
finalised.

[p.28, *In vivo* BE PK Systemic Exposure Studies]{.underline}: For
completeness, there should be a sub-heading here with a brief statement
simply cross-referring to existing bioequivalence guidelines.

[p.32 Decision Tree for Product Quality:]{.underline} The mention in the
flow chart of \"Clinical study for systemic absorption\" is confusing,
since this guidance is intended to cover [only]{.underline} intranasal
products for local action.

[p.32, Decision Tree for Product Quality :]{.underline} The order of the
studies in the final 2 boxes of the flow chart are a little misleading
as \"In vitro studies\" appear last in the list when in fact they will
probably be conducted before \"Clinical study for local delivery
\....\".