ITFG/IPAC Collaboration

BA/BE Technical Team

***Review of In Vivo and In Vitro Tests in FDA's Draft Guidance on
Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal
Sprays for Local Action and Anticipated Forthcoming Guidance for Orally
Inhaled Drugs***

30 August 2000

**[Table of Contents]{.smallcaps}**

**I. EXECUTIVE SUMMARY** 3

**II. BACKGROUND** 4

**III. INTRODUCTION** 5

**IV. ASSUMPTIONS AND OTHER CONSIDERATIONS** 6

1\. Assumptions of BA/BE Technical Team 6

2\. Definitions of BA and BE 6

3\. Factors Relating In Vitro Tests to Deposition and to Biological
Effect 6

**V. TEAM'S POSITION STATEMENTS** 8

1\. In Vitro Tests 8

2\. In Vivo Tests 8

**VI. IN VITRO TESTS IN DRAFT BA/BE GUIDANCE** 9

1\. Overview of In Vitro Tests in Draft BA/BE Guidance 9

2\. BA/BE Team's Analysis 9

> 2A. In Vitro Tests in Draft Guidance are Not Necessarily
>
> More Relevant or Discriminating than Clinical Studies for BE
> Assessment
>
> 2B. Assumption that In Vitro Studies Alone are Sufficient for BE of
> Solutions
>
> is Unfounded
>
> 2C. Utility of Current In Vitro Tests to Demonstrate Clinical
> Equivalence is Limited

**VII. IN VIVO TESTS IN DRAFT BA/BE GUIDANCE** 13

1\. Overview of In Vivo Tests in Draft BA/BE 13

2\. BA/BE Team's Analysis 13

> 2A. Systemic PK/PD Estimates Systemic Exposure But Does Not Estimate
> Local\
> Delivery
>
> 2B. Efficacy Assessments Alone Cannot Establish In Vivo BE
>
> 2C. Lung Deposition Studies
>
> 2D. Reduce Testing Requirements with Validated Models

[**VIII. CONCLUSION** 16]{.smallcaps}

[**IX. REFERENCES** 17]{.smallcaps}

**[I. Executive Summary]{.smallcaps}**

The International Pharmaceutical Aerosol Consortium (IPAC) and the
Inhalation Technology Focus Group (ITFG) of the American Association of
Pharmaceutical Scientists share the FDA\'s goal of assuring the highest
levels of safety, efficacy and quality of orally inhaled and nasal drug
products. The ITFG/IPAC Collaboration has identified several areas in
the draft Guidance for Industry: *Bioavailability (BA) and
Bioequivalence (BE) Studies for Nasal Aerosols and Nasal Sprays for
Local Action*[^1] where scientific rationale can be questioned and where
more scientific discussion and debate are needed.

The ITFG/IPAC Collaboration encourages the Agency to solicit additional
scientific discussion on BA/BE studies before issuing further guidance
in this area. To resolve the outstanding issues expeditiously, the
ITFG/IPAC Collaboration strongly recommends that the Agency pursue
existing avenues for scientific collaboration between the Agency and
outside interested parties, such as the Orally Inhaled and Nasal Drug
Products Subcommittee of the Advisory Committee for Pharmaceutical
Science, the Product Quality Research Institute (PQRI), or another
AAPS/FDA/USP workshop on Regulatory Issues Relating to Drug Products for
Oral Inhalation and Nasal Delivery.

**[II. BACKGROUND]{.smallcaps}**

-   Between October 1998 and June 1999, the FDA issued the following
    draft Guidances for Industry: 1) *Metered Dose Inhaler (MDI) and Dry
    Powder Inhaler (DPI) Drug Products Chemistry, Manufacturing, and
    Controls Documentation*; 2) *Nasal Spray and Inhalation Solution,
    Suspension, and Spray Drug Products Chemistry, Manufacturing, and
    Controls* *Documentation;* and 3) *Bioavailability (BA) and
    Bioequivalence (BE) Studies for Nasal Aerosols and Nasal Sprays for
    Local Action*.

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-   On 3-4 June 1999, the FDA/AAPS/USP sponsored a Workshop on
    Regulatory Issues Relating to Drug Products for Oral Inhalation and
    Nasal Delivery. At the Workshop, the International Pharmaceutical
    Aerosol Consortium (IPAC) proposed the creation of a post-Workshop
    consensus building process to address several issues in the draft
    Guidances for Orally Inhaled and Nasal Drug Products (OINDP).

-   In October 1999,The Inhalation Technology Focus Group (ITFG)
    supported IPAC's proposal at the June Workshop and agreed to
    collaborate with IPAC in order to combine scientific expertise and
    regulatory knowledge and address key issues in the draft OINDP
    Guidance documents. The ITFG/IPAC Collaboration consists of five
    Technical Teams overseen by a Steering Committee. Over one hundred
    individuals from more than twenty companies are participating in the
    ITFG/IPAC Collaboration. The BA/BE Team is formed to address BA/BE
    issues of OINDP.

-   In October 1999, the FDA created the OINDP Expert Panel (currently
    the OINDP Subcommittee of the Advisory Committee for Pharmaceutical
    Science) to facilitate information sharing on scientific, technical,
    compendial and research issues relevant to the draft OINDP
    Guidances. On 26 April 2000, the OINDP Subcommittee held its first
    meeting, during which the ITFG/IPAC Collaboration reported on its
    work and made certain commitments to provide the Agency and OINDP
    Subcommittee with relevant technical reports.

-   At the 26 April 2000 OINDP Subcommittee meeting, the BA/BE Technical
    Team of the ITFG/IPAC Collaboration reported that it has developed
    position statements on in vitro and in vivo testing in the FDA's
    draft BA/BE Guidance.

-   The BA/BE Team's position statement on in vitro testing is: *In
    vitro testing is essential for pharmaceutical product equivalence
    and should be included as part of BA/BE Guidance for all nasal and
    oral inhalation products, but is not currently sufficient for BE
    approval without establishing in vivo BE*.

-   The BA/BE Team's position statement on in vivo testing is: *For BE
    approval, BA/BE Guidance documents for nasal and oral inhalation
    drug products for local action should require use of validated human
    models for in vivo testing for local and systemic exposure, efficacy
    and safety.*

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-   At the 26 April meeting, the BA/BE Team committed to submit to the
    Agency and the OINDP Subcommittee a technical paper on the Team's in
    vitro and in vivo position statements. This is the topic of the
    present report.

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-   The Team also committed to providing the Agency and the OINDP
    Subcommittee with its perspectives on the BA/BE questions presented
    by the Agency during the OINDP Subcommittee meeting. A companion
    paper addressing these questions is being submitted to the Agency
    simultaneously with this technical report.

**[III. Introduction]{.smallcaps}**

The BA/BE Technical Team of the ITFG/IPAC Collaboration has focused on
the in vitro and in vivo tests in the Agency's draft *Guidance for
Industry Bioavailability and Bioequivalence Studies for Nasal Aerosols
and Nasal Sprays for Local Action* (draft BA/BE Guidance). Since January
2000, the BA/BE Technical Team has discussed these issues in depth. The
Team has agreed on several working assumptions and has identified two
main position statements, one for in vitro tests and the other for in
vivo tests in the draft BA/BE Guidance. During the past several months,
Team members have submitted and evaluated data and scientific articles
related to these position statements. The conclusions in this paper are
based upon the Team's working assumptions and currently available
information.

This paper is closely related to the paper which is being co-submitted
by the BA/BE Team to respond to the BA/BE questions presented by the
Agency at the OINDP Subcommittee meeting on 26 April. The paper
presented here is more general in scope and has a broader perspective
than the Team's paper on the Agency's BA/BE questions. There are some
significant areas of overlap between the Team's two papers and therefore
we request that the Agency and OINDP Subcommittee consult both papers
for a complete perspective of the Team's consensus views on BA/BE
issues.

The Team has prepared this paper on in vitro and in vivo tests in the
draft BA/BE Guidance in order to:

-   highlight areas where there are not enough data at present to draw
    conclusions; and

-   review available technical documentation related to BA/BE issues
    addressed by the Team and offer the Team's conclusions based on that
    documentation.

The conclusions of this paper are applicable to the draft BA/BE Guidance
for Nasal Aerosols and Nasal Sprays for Local Action as well as the
Agency's forthcoming draft BA/BE Guidance for orally inhaled drug
products. It is recognized that this paper contains relatively few
examples relating to nasal issues because of the lack of pertinent nasal
data available. Although most of the examples are for pulmonary locally
acting drugs, these data may have general applicability to nasal drugs
and will be directly relevant for the Agency's future guidance on orally
inhaled drug products.

**[IV. Assumptions and Other Considerations]{.smallcaps}**

## 

**1. Assumptions of BA/BE Technical Team**

In preparing this paper, the BA/BE Technical Team has agreed on the
following working assumptions:

-   Our specific BA/BE recommendations apply to locally acting drugs per
    the current draft BA/BE Guidance for nasal aerosols and sprays, and
    should apply, as appropriate, to orally inhaled drug products in the
    anticipated forthcoming BA/BE Guidance for orally inhaled drugs;

-   Our conclusions apply to both orally inhaled and nasal drug
    products, but these dosage forms should be treated in separate
    Guidances;

-   Scientific and clinical bases for developing BA/BE Guidance are
    evolving; and

-   Our BA/BE working propositions reflect only the current state of
    knowledge.

**2. Definition of Bioequivalence (BE)**

As noted in the draft BA/BE Guidance, BA and BE may be established in
vivo by measuring both local delivery and systemic absorption/exposure.
The draft Guidance equates local delivery with efficacy studies and
systemic absorption/exposure with pharmacokinetic (PK) or
pharmacodynamic (PD) studies. The BA/BE Team has discussed situations
where use of in vitro data plus systemic PK/PD studies may be sufficient
to establish BE. This discussion can be found in the BA/BE Team\'s
companion paper which has been submitted to the Agency with this paper.

**3. Factors Relating In Vitro Tests to Deposition and to Biological
Effect**

The biological effect of an inhaled drug is dependent on several
factors. First is the mass of particles in the inhaled air stream
(emitted dose). Particle size distribution, breathing pattern, and the
specific nature of the aerosol delivery from the device are the prime
determinants of the deposition pattern in the body. Other deposition
factors include the geometry of the airways that can be influenced by
disease state. The drug may act locally in the region of deposition, or
at a remote site following absorption of the drug into the blood stream
and systemic delivery. Thus, there are many factors that can influence
biological effect other than the particle size distribution and emitted
dose of the inhaled drug, as has been noted in several reviews
(Schlesinger, 1988; Gonda, 1990; Brain and Blanchard, 1993).

The use of in vitro tests of particle size distribution and emitted dose
as surrogates for deposition or biological effect must be approached
with caution as has been noted previously by individuals and groups
assessing this issue. There have been at least two workshops that have
examined this question in some detail (Clark, 1998; Snell and Ganderton,
1999). The consensus from both meetings was that in vitro/in vivo
comparisons are being developed and in vitro methods are improving to
enhance their in vivo applicability, but that as yet it is not possible
to rely solely on in vitro data as a predictor of clinical use by
patients. The proceedings from these workshops provide in depth
considerations of various aspects of this general question and are
excellent sources for more detailed discussions.

**[V. Team's Position Statements]{.smallcaps}**

The Team's position statements on in vitro and in vivo tests in the
draft BA/BE Guidance are as follows:

**1. In Vitro Tests***:*

> In vitro testing is essential for pharmaceutical product equivalence
> and should be included as part of BA/BE Guidance for all nasal and
> oral inhalation products, but is not currently sufficient for BE
> approval without establishing in vivo BE.

**2. In Vivo Tests*: ***

> For BE approval, BA/BE Guidance documents for nasal and oral
> inhalation drug products for local action should require use of
> validated human models for in vivo testing for local and systemic
> exposure, efficacy and safety.[^2]

**[VI. In Vitro Tests in Draft BA/BE Guidance]{.smallcaps}**

**1. Overview of In Vitro Tests in Draft BA/BE Guidance**

The draft BA/BE Guidance utilizes a large battery of in vitro tests in
order to evaluate drug product quality of nasal and inhaled dosage
forms. In particular, the following tests have been identified in the
draft BA/BE Guidance as part of BA and BE determination:

1.  Dose or Spray Content Uniformity

2.  Droplet and Particle Size Distribution

3.  Spray Pattern

4.  Plume Geometry

5.  Priming and Repriming

6.  Tail Off Profile

Spray content uniformity, particle size distribution, spray pattern and
priming (if part of product labeling) are considered in vitro
determinants of BE utilizing the confidence interval approach. Plume
geometry, tail off profile, and particle size characterization through
light microscopy may be evaluated as supportive characterization of BE.
The draft BA/BE Guidance stresses the importance of conducting in vitro
testing in a randomized, blinded fashion in order to eliminate potential
analyst bias.

In the following sections, we highlight the issues which have been
raised surrounding the use of these tests for the investigation of BE
alone or in combination with an in vivo assessment.

**2. BA/BE Team's Analysis**

> **2A. In vitro tests described in the draft BA/BE Guidance are not
> necessarily more relevant or discriminating than clinical studies for
> BE assessment**

The establishment of BA and BE in nasal products for local action
requires reliance on clinical endpoint studies. The draft BA/BE Guidance
acknowledges that studies of this nature are frequently incapable of
showing a dose-response relationship and may not be consistently
reproducible. However, in vitro tests for demonstration of
bioequivalence also have limitations.

Of the tests utilized for in vitro assessment of nasal and inhalation
drug products, droplet and particle size data have received the most
attention in the literature. According to the draft BA/BE Guidance,
droplet and particle size distribution can be evaluated through several
methods, including optical methods (laser diffraction, light scattering,
time-of-flight), inertial impactor methods (cascade impactor, multistage
liquid impinger), and light microscopy.

Laser diffraction is the suggested method for determination of droplet
size distribution. It is especially useful for nasal sprays, because it
has enough size range to cover large nasal droplets produced by nasal
sprays (Cheng *et al.*, 2000). In general, the method is fast, has good
resolution, a broad particle size range, and can be used for
measurements of pMDIs, DPIs, and liquid atomizers such as nebulizer
systems. The great disadvantage of laser diffraction methods is that
they cannot differentiate components of the formulation. In the case of
pMDI systems, other disadvantages include sampling errors due to
evaporation, overestimation of size distribution due to presence of
propellant s, and dilution requirements (Dolovich, 1991; Clark *et al.*,
1998).

Another optical method currently receiving attention is the
time-of-flight aerodynamic particle size analyzer. Similar to laser
diffraction techniques, this method cannot discriminate between drug and
non-drug particles. This method has been investigated for use with
pMDIs, DPIs and nebulizers. The present state of the art suggests that
this particle sizing method is effective for formulation development and
screening, but cannot replace inertial particle size methods such as
those described in pharmacopoeial compendia (Mitchell *et al.*, 1999).

Inertial particle size techniques, such as cascade impactors and
multistage liquid impingers have a distinct advantage since the methods
are capable of distinguishing drug particles, normally through an assay
technique. However, the limitations of this method have been well
documented. Size distributions among cascade impactors can vary
significantly, and thus any comparisons performed in order to establish
BA or BE must be evaluated with the same equipment (Stein and Olson,
1997; Stein 1999). In addition, there is concern regarding the use of
this equipment for evaluation of nasal products, given that particle
sizing stages have been optimized for oral inhalation products, and not
for nasal delivery, where MMAD exceed 10 m (Harrison, 2000).

The spray pattern/plume geometry including plume angle and speed of the
plume are also important factors on the distribution of deposited
droplets in the nasal airway, and may therefore influence the
bioequivalence of nasal drugs (Cheng *et al.*, 2000). High speed
photography/video is used to determine the plume geometry/spray pattern.
Therefore, we suggest that light microscopy be strictly used as a
supportive method for drug and aggregate particle size and morphology
evaluation, because of its limitations.

We also believe that in vitro tests are important for the establishment
of BA and BE, particularly dose content uniformity and particle size
analysis. However, the predictive limitations of the in vitro tests at
the present time support the need for in vivo studies.

> **2B. The assumption that in vitro studies alone are sufficient for BE
> of solutions is unfounded. The draft BA/BE Guidance should not
> distinguish between nasal suspensions and solutions for in vivo BE**

According to the draft BA/BE Guidance, in vitro tests are sufficient to
support approval of solution nasal products. As documented in this
paper, in vitro tests for use as BE metrics have limitations. Based on
the lack of information on the established relationship between in
vitro/in vivo data for OINDP, it is the consensus of the BA/BE Technical
Team that in vivo BE determinations should be required. As more data
becomes available, removal of in vivo BE testing for solutions could be
considered for certain drug classes.

> **2C. Based on the available literature, current in vitro tests may
> predict lung deposition, but the utility of those tests to demonstrate
> clinical equivalence of inhaled drug products has not been shown**

The clinical relevance of in vitro data to the in vivo environment has
been studied for a variety of products, including inhalation dosage
forms. In particular, in vivo lung deposition has been demonstrated to
be linked to in vitro estimates of fine particle dose in well controlled
studies for cromolyn sodium (Laube *et al.*, 1998). However, such
correlations may not hold true for all cases and classes of drug
substances used in inhalation and nasal dosage forms. In addition, the
ability of in vitro studies to predict clinical effectiveness in general
has not been demonstrated. This is an evolving area with considerable
promise, but there is yet no validated approach of wide-ranging
applicability.

A review of the literature indicates that in certain instances, in vitro
results have failed or inaccurately predicted the in vivo results, which
would have resulted in a false conclusion regarding BE if in vivo
studies had not been conducted. Failure to predict in vivo outcome has
been demonstrated in the following two studies. In a study by Borgström
*et al.* (2000), the in vitro and in vivo performance (lung deposition)
of terbutaline via a pMDI and DPI Turbohaler was evaluated. The
variability in lung deposition could not be attributed solely to in
vitro variability, which is linked mainly to variability in dose leaving
the metering chamber/dosing disk. The interaction of patient geometry
(anatomy) and the actual patient handling of the device had a
significant influence on the overall variability, which could not be
mimicked in the in vitro environment. In another study, two nasal
aerosols with different in vitro properties were generated. Although in
vitro testing concluded significant differences among the two aerosols,
this did not translate into any differences in the in vivo deposition
pattern in the nose (Suman *et al.*, 1999). Similar nasal deposition
patterns with differing particle sizes was also observed by Hughes *et
al.* (1993). The lack of difference in deposition pattern could be a
result of poor power of discrimination in the in vivo test and
emphasizes the difficulty of measuring nasal deposition patterns in
vivo.

Inaccurate predictions of in vivo deposition have also been demonstrated
in several studies. A comparison of 11 scintigraphic studies and fine
particle fraction measurements conducted on MDIs, DPIs and Soft Mist
Inhalers found that in vitro assessment provided an overestimation of
actual lung deposition (Newman, 1998 ) when the standard cut-off
diameter of 4.7 micrometers was used. However, Newman (1998) showed that
there was a much improved correlation of lung deposition with particles
less than 3.3 micrometers. However, it should be noted that this
correlation is in all probability descriptive, not predictive; different
correlations may be obtained if there are variations in the method used
to assess deposition. Another study conducted by Olsson *et al.* (1996)
demonstrated improvement in correlation between lung deposition and fine
particle fraction through modification of the inlet port on the impinger
to mimic the oropharynx. Other recommendations to improve correlations
between in vitro measurements and in vivo deposition include use of a
multistage apparatus in the range of 0.5 -- 5.0 m. and evaluation on a
range of flow rates to mimic the in vivo conditions (Snell and
Ganderton, 1999). A recent study on the AERx inhalation system indicated
good correlation between the in vitro measurement and in vivo deposition
pattern when similar flow rates were utilized (Farr *et al.*, 2000).

The current literature suggests that we can use the available knowledge
on the relationship between in vitro and in vivo outcome to run in vitro
studies during biopharmaceutical development, but we cannot at the
present time use in vitro methods alone to claim in vivo/clinical effect
equivalence as a basis for regulatory approval.

**[VII. In Vivo Tests in Draft BA/BE Guidance]{.smallcaps}**

**1. Overview of In Vivo Tests in Draft BA/BE Guidance**

The BE tests[^3] recommended by the BA/BE Team for all nasal and orally
inhaled drugs fall into the following scheme:

-   Clinical efficacy study to document equivalent drug delivery to the
    local site of action; and

-   Systemic exposure study (PK).

The clinical efficacy study is used to assess local delivery of drug and
efficacy, whereas the systemic exposures are intended to provide a
marker that can be related to safety. Some of the challenges involved in
conducting meaningful in vivo studies are that some endpoints are easier
to measure than others for particular classes of drugs. This means that
it is frequently difficult to assess both local and systemic criteria
adequately for all drugs.

For instance, for nasal drugs, it is difficult to have clinical
responses that can differentiate two products. However, it may be more
difficult to measure systemic exposure of the nasal products considering
the low doses administered. For orally inhaled bronchodilators, good
methods of quantifying bronchodilator response have been identified
(Adams, 1995; Stewart *et al.*, 1999). It is, however, relatively
difficult to ascertain a dose-response relation related to efficacy for
orally inhaled corticosteroids. These difficulties in adequately
assessing BE have been cited frequently (Adams *et al.*, 1994, 1995,
1998; Wong and Hargreave, 1993, Casale *et al.*, 1999; Harrison, 2000).
These complexities and differences between exposure routes, classes of
drugs, and specific drugs, argue for more flexible approaches. Although
the BA/BE Team agrees that the above in vivo BE program should be
recommended in the draft BA/BE Guidance, the Team also recommends that
the BA/BE Guidance urge sponsors to discuss their in vivo BE program for
a specific drug with the Agency.

The following specific issues identified by the BA/BE Technical Team
emphasize that both clinical efficacy and systemic exposure (as an
indicator of adverse effects) need to be evaluated to provide an
adequate assessment of clinical BE.

**2. BA/BE Team's Analysis**

> **2A. Systemic PK/PD estimates systemic exposure (*i.e*., safety) but
> does not estimate local delivery (*i.e*., efficacy and local
> tolerance).**

Blood levels of a particular drug obviously reflect the amount of drug
absorbed systemically. However, for respiratory tract drugs, absorption
can take place from the site of absorption, across tissue and into
blood, and also from drug that is translocated by mucociliary clearance
from nasal or bronchial airway epithelium, swallowed and then absorbed
from the gut. Further, there can be differential rates of absorption
from various sites in the lung. Many data sets show a higher degree of
absorption from the alveolar or pulmonary region than from upper airways
(Oberdorster, 1986) although this is compound dependent and is more
evident for larger than smaller molecules. Available data support the
view that local topical delivery of corticosteroids is responsible for
their clinical efficacy both with nasal delivery (Howland, 1996a, 1996b;
Lindqvist *et al.,* 1989) and for orally inhaled delivery (Toogood *et
al.*, 1990; Lawrence *et al.*, 1997). As a corollary, because the same
systemic blood levels can be achieved by different deposition patterns,
systemic exposure does not necessarily correlate with efficacy. Thus, we
concur with the Agency's position as stated in the draft Guidance.

> **2B. Efficacy assessments alone cannot establish in vivo BE since
> they will not assure comparable safety (systemic exposure)**

Local delivery BE studies are important to assure equivalent efficacy
and local tolerance at the site of action, but the study design does not
assure systemic safety, which is a major concern of a new product.
Literature data clearly indicates that systemic absorption (as measured
by PK) may not correlate with local delivery. Studies comparing oral
administration with either nasal or oral inhalation administration for
fluticasone propionate and budesonide (see references in the previous
section) have shown no correlation between PK and clinical efficacy.
Until a linkage is established for a given drug or drug class, caution
is advised against any modification of the proposed in vivo BE program
that includes both local delivery and systemic absorption/exposure.
Thus, we concur with the Agency's position as stated in the draft
Guidance.

> **2C. Lung deposition studies are a promising new technique, but
> currently cannot replace the local delivery requirement**

Local delivery estimated as total material deposited in the lung is not
likely to be sufficiently discriminating to be predictive of BE. Two
examples are examined to illustrate this point. In a study by Leach
(1998), HFA and CFC formulations of beclomethasone dipropionate were
compared. Although the emitted doses were the same, the fine particle
dose (percent of particle mass \< 4.7 micrometers) was higher for the
HFA formulation compared to the CFC formulation (56% of emitted dose vs
33%,respectively). Deposition was dramatically different, with the HFA
formulation (1.1 m MMAD) resulting in 56% lung deposition vs 6% for the
CFC formulation (3.9 m MMAD). Clinical efficacy studies showed that the
HFA beclomethasone dipropionate formulations did not scale directly with
lung deposition, but required approximately half the emitted dose of the
CFC formulations. In a non-clinical example, Ruffin *et al.* (1978)
compared bronchoconstrictive effects of histamine when inhaled in
different modes. Equal lung doses of histamine were given in one mode
with a central deposition pattern and in the other mode with a
peripheral deposition pattern. Although the total lung doses were equal,
the bronchoconstricting effect of histamine was much greater for the
central deposition pattern.

The Leach and Ruffin papers point out that regional deposition pattern
within the lung is very important for eliciting a biological response,
which can differ even if the total lung dose is the same. For instance,
bronchodilator response to beta-2 agonists appears to be predominantly
related to receptor mediated action on bronchial airway smooth muscle
(Barnes, 1995; Nishikawa *et al.,* 1996). Therefore if two formulations
have the same total lung dose but differing bronchial airway doses,
biological response is likely to differ. Other drugs with different
receptor distributions in the lung and other modes of action will have
to be considered on an individual compound basis. If this is the case,
then knowing total lung dose will not be sufficient to determine
biological response for all pharmacologic agents.

A limitation of the most common lung deposition technique is that the
product must be altered by the sponsor to allow for the addition of a
radiolabeled tag. In order for the radiolabeled material to serve as a
BE standard, data must be provided to show that product properties are
essentially unchanged and remain within specifications. Another
limitation of the radiolabeled lung deposition technique is that at
present, there is no standardized approach to such a study.

**2D. Reduction of testing requirements with validated models**

In vitro data, regional deposition data, PK/PD studies, and clinical
efficacy studies are all likely needed to characterize adequately the
relationships going from inhaler and particle characteristics to relate
to ultimate clinical effects in patients when a new inhaled drug is
developed (Borgström, 1999; Gonda, 1990). (The data derived above for
the new HFA formulation of beclomethasone dipropionate is a good
example). With sufficient data it should be possible to define the
variations around the individual components that results in clinically
similar efficacy. Various linkages among the data sets can be envisaged.

If it is possible to determine that a certain range of regional
deposition values or PK parameters or in vitro test results correlates
with in clinical efficacy within acceptable limits, then future studies
might need only to measure regional deposition or PK or in vitro testing
within these ranges. Further, if these features could be reliably linked
with mathematical models that predict a range of deposition behavior or
PK performance or in vitro test results for given input parameters it
would be possible to reduce or eliminate reliance on carrying out
extensive clinical trials. Until the state of the art improves such that
there is more power among the tests relating in-vitro tests to
ultimately predict clinical effects, it appears a cautious approach is
warranted (Wong and Hargreave, 1993). It is impossible at this time to
completely describe a validated model because it will depend on the
available data for the particular inhaled drug being developed, and so
it is recommended that an approach for each circumstance be negotiated
between the sponsor and regulatory agencies.

**[VIII. Conclusion]{.smallcaps}**

The ITFG and IPAC share the FDA's goal of assuring the highest levels of
safety, efficacy and quality of orally inhaled and nasal drug products
and making these products available to patients in the most expeditious
manner. We recognize and appreciate the considerable efforts put forth
by the Agency in developing guidance on product quality BA and BE
studies for OINDP. The ITFG/IPAC Collaboration also commends the Agency
for addressing key issues in BA and BE studies at the 26 April OINDP
Subcommittee meeting. We are grateful for the opportunity to share with
the Agency and the OINDP Subcommittee our perspectives on in vivo and in
vitro studies in the draft BA/BE Guidance.

Our comments in this paper are intended to highlight areas in the draft
BA/BE Guidance where the scientific rationale can be questioned and
where more scientific discussion and debate are needed. The Agency\'s
comments to the OINDP Subcommittee on 26 April underscore the Agency\'s
concerns with some of the positions in the draft BA/BE Guidance. We
encourage the Agency to solicit further scientific discussion on these
positions before issuing further guidance. In addition, the members of
the ITFG/IPAC Collaboration strongly recommend that the Agency continue
to utilize existing avenues for scientific collaboration, such as the
OINDP Subcommittee of the Advisory Committee for Pharmaceutical Science,
the Product Quality Research Institute (PQRI), or another AAPS/FDA/USP
workshop on Regulatory Issues Relating to Drug Products for Oral
Inhalation and Nasal Delivery to gather all interested parties for a
data-driven scientific review of key BA/BE issues.

**[IX. References]{.smallcaps}**

W. P. Adams. Albuterol MDI In Vivo bioequivalence: FDA's office of
generic drugs dose-response studies. *Drug Information Journal*,
29:935-940 (1995).

W. P. Adams. Albuterol MDI in vivo bioequivalence: FDA's Office of
Generic Drugs' dose-response studies. *Drug Information Journal* 29:
935-94 (1995).

W. P. Adams, G. Poochikian, A. S. Taylor, R. M. Patel, G. P. Burke, R.
L. Williams. Regulatory aspects of modifications to innovator
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[^1]: Draft Guidance for Industry *Bioavailability and Bioequivalence
    Studies for Nasal Aerosols and Nasal Sprays for Local Action*
    available at <http://www.fda.gov/cder/guidance/index.htm> (1999).

[^2]: As addressed in more detail in the BA/BE Team's paper responding
    to the FDA's BA/BE questions, it is appropriate that sponsors be
    given the opportunity to present their case for an abbreviated
    clinical program. If a predictive in vitro/in vivo correlation can
    be documented from the literature or from new well-documented data,
    the sponsor should have the opportunity to request waiving all
    clinical studies.

[^3]: In this paper, BE is assumed to be BE of clinical efficacy and
    safety.