Guidance for Industry

Handling and Retention of BA and BE Testing Samples

**U.S. Department of Health and Human Services**

**Food and Drug Administration**

**Center for Drug Evaluation and Research (CDER)**

**May 2004**

**OGD**

Guidance for Industry

Handling and Retention of BA and BE Testing Samples

*Additional copies are available from:*

*Office of Training and Communication*

*Division of Drug Information, HFD-240*

*Center for Drug Evaluation and Research*

*Food and Drug Administration*

*5600 Fishers Lane*

*Rockville, MD 20857*

*(Tel) 301-827-4573*

*http://www.fda.gov/cder/guidance/index.htm*

**U.S. Department of Health and Human Services**

**Food and Drug Administration**

**Center for Drug Evaluation and Research (CDER)**

**May 2004**

**OGD**

**TABLE OF CONTENTS**

# 

# I. IN[T]{.smallcaps}RODUCTION [1](#introduction) {#i.-introduction-1 .TOC-1}

# II. BACKGROUND [1](#background) {#ii.-background-1 .TOC-1}

# III. SAMPLING TECHNIQUES [2](#sampling-techniques) {#iii.-sampling-techniques-2 .TOC-1}

# IV. RETENTION FOR MULTIPLE STUDIES AND SHIPMENTS [3](#retention-for-multiple-studies-and-shipments) {#iv.-retention-for-multiple-studies-and-shipments-3 .TOC-1}

# V. Quantity of Reserve Samples [4](#quantity-of-reserve-samples) {#v.-quantity-of-reserve-samples-4 .TOC-1}

# VI. RESPONSIBiLITIES IN VARIOUS STUDY SETTINGS [4](#responsibilities-in-various-study-settings) {#vi.-responsibilities-in-various-study-settings-4 .TOC-1}

## A. Studies Conducted at CROs, Universities, Hospitals, or Physicians' Offices [4](#studies-conducted-at-cros-universities-hospitals-or-physicians-offices) {#a.-studies-conducted-at-cros-universities-hospitals-or-physicians-offices-4 .TOC-2}

## B. Studies Involving SMOs [5](#b.-studies-involving-smos) {#b.-studies-involving-smos-5 .TOC-2}

## C. Blinded Studies With Pharmacodynamic or Clinical Endpoints Involving an SMO [6](#c.-blinded-studies-with-pharmacodynamic-or-clinical-endpoints-involving-an-smo) {#c.-blinded-studies-with-pharmacodynamic-or-clinical-endpoints-involving-an-smo-6 .TOC-2}

## D. In-House Studies Conducted by a Study Sponsor and/or Drug Manufacturer [8](#d.-in-house-studies-conducted-by-a-study-sponsor-andor-drug-manufacturer) {#d.-in-house-studies-conducted-by-a-study-sponsor-andor-drug-manufacturer-8 .TOC-2}

## E. In Vitro BE Studies [9](#e.-in-vitro-be-studies) {#e.-in-vitro-be-studies-9 .TOC-2}

# VII. EXCEPTION FOR INHALANT PRODUCTS [9](#exception-for-inhalant-products) {#vii.-exception-for-inhalant-products-9 .TOC-1}

# GLOSSARY [11](#glossary) {#glossary-11 .TOC-1}

# 

**Guidance for Industry**[^1]

**Handling and Retention of BA and BE Testing Samples**

This guidance represents the Food and Drug Administration\'s (FDA\'s)
current thinking on this topic. It does not create or confer any rights
for or on any person and does not operate to bind FDA or the public. You
can use an alternative approach if that approach satisfies the
requirements of the applicable statutes and regulations. If you want to
discuss an alternative approach, contact the FDA staff responsible for
implementing this guidance. If you cannot identify the appropriate FDA
staff, call the appropriate number listed on the title page of this
guidance.

# IN[T]{.smallcaps}RODUCTION 

This guidance is intended to provide recommendations for study sponsors
and/or drug manufacturers, contract research organizations (CROs), site
management organizations (SMOs), clinical investigators, and independent
third parties regarding the procedure for handling reserve samples from
relevant bioavailability (BA) and bioequivalence (BE) studies, as
required by 21 CFR 320.38 and 320.63. The guidance highlights (1) how
the test article and reference standard for BA and BE studies should be
distributed to the testing facilities, (2) how testing facilities should
randomly select samples for testing and material to maintain as reserve
samples, and (3) how the reserve samples should be retained. The
guidance also clarifies and emphasizes points addressed in §§ 320.38 and
320.63. []{.mark}

FDA\'s guidance documents, including this guidance, do not establish
legally enforceable responsibilities. Instead, guidances describe the
Agency\'s current thinking on a topic and should be viewed only as
recommendations, unless specific regulatory or statutory requirements
are cited. The use of the word *should* in Agency guidances means that
something is suggested or recommended, but not required.

# BACKGROUND

# 

Following the generic drug scandal in the 1980s, the FDA issued an
interim rule in the *Federal Register* of November 8, 1990,[^2] on the
retention of BA and BE testing samples. The intent of the interim rule
was to deter possible bias and fraud in BA and BE testing by study
sponsors and/or drug manufacturers. Following public comments, a final
rule was issued in the *Federal Register* of April 28, 1993.[^3]
Implementing regulations are located in 21 CFR 312.57(d),
314.125(b)(17), 314.127(b), 314.150(b)(9), 320.31(d)(1), 320.38, and
320.63.

In the preamble to the final rule, the Agency stated that the study
sponsor and/or drug manufacturer should not separate out the reserve
samples of the test article and reference standard before sending the
drug product to the testing facility.[^4] This is to ensure that the
reserve samples are in fact representative of the batches provided by
the study sponsor and/or drug manufacturer for the testing. The study
sponsor and/or drug manufacturer should send to the testing facility
batches of the test article and reference standard so that the testing
facility can ***randomly select*** samples for testing, and material to
maintain as reserve samples. The drug product should also be maintained
in the sponsor's and/or manufacturer\'s original container (see section
III).

Also in the preamble to the final rule, the Agency noted that reserve
sample retention is the responsibility of the organization that conducts
the BA or BE study.[^5] The intent is to eliminate the possibility of
sample substitution by the study sponsor and/or drug manufacturer, or
prevent the alteration of any reserve samples from a study conducted by
a contractor before release of drug product samples to the FDA.

FDA's Division of Scientific Investigations (DSI) and field
investigators from the Office of Regulatory Affairs (ORA) conduct
inspections of clinical and analytical sites that perform BA and BE
studies for study sponsors and/or drug manufacturers seeking approval of
generic and new drug products. A frequent finding from these inspections
is the absence of reserve samples at the testing facilities where the
studies are conducted. In many cases, DSI finds that testing facilities
return reserve samples to the study sponsors and/or drug manufacturers,
against the direction of the regulations in 21 CFR 320.38 and 320.63. In
other cases, study sponsors and/or drug manufacturers, SMOs, or contract
packaging facilities designate the study test article and reference
standard for each subject, and preclude the testing facilities from
randomly selecting representative reserve samples from the supplies. DSI
also finds that deviations from the regulations more often occur in BE
studies with pharmacodynamic or clinical endpoints in which the studies
are confused with clinical safety or efficacy studies. The
pharmacodynamic or clinical endpoint BE studies are usually multisite,
blinded studies conducted under contract (either directly with the study
sponsor or drug manufacturer or through an SMO) by physicians or
clinical investigators who use their own clinics or offices to conduct
the studies. Moreover, some clinical investigators believe that they are
not CROs and are not required to retain reserve samples. This guidance
clarifies the responsibilities for retention of reserve samples.

# SAMPLING TECHNIQUES 

We recommend that the study sponsor and/or drug manufacturer send to the
testing facility batches of the test article and reference standard
packaged in such a way that the testing facility can randomly select
samples for bioequivalence testing and samples to maintain as reserve
samples. This will ensure that the reserve samples are in fact
representative of the batches provided by the study sponsor and/or drug
manufacturer and that they are retained in the study sponsor's original
container. Because the study sponsor and/or drug manufacturer may
provide a testing facility with a variety of container sizes and
packaging, FDA is flexible in applying the representativeness
requirement described in 21 CFR 320.38. For example, any of the
following random sampling techniques might be used by the testing
facility for the container size and packaging described[^6] (bolded text
is particularly relevant).

**Single Container** -- If a single container of the test article and
reference standard are provided to the testing facility, the testing
facility should remove a sufficient quantity of the test article and
reference standard from their respective containers to conduct the
study; the remainder in each container should be retained as reserve
samples in the original containers.

**Multiple Containers** -- If multiple containers of the test article
and reference standard are provided to the testing facility, the testing
facility should ***randomly select*** enough containers of the test
article and reference standard to conduct the study; the remaining
containers of the test article and reference standard should be retained
as the reserve sample in the original containers. Generally, multiple
open bottles are discouraged. We encourage testing facilities to limit
the number of open containers retained as study reserves.

**Unit Dose** -- If the test article and reference standard are provided
to the testing facility in unit dose packaging, the testing facility
should ***randomly select*** a sufficient quantity of unit doses of the
test article and reference standard to conduct the study; the remaining
unit doses of the test article and of the reference standard should be
retained as the reserve samples in the original unit dose packaging.
***Therefore, it would be inappropriate to provide the study medications
in unit dose packaging and all the reserve samples in bulk
containers.***

**Blinded Study** -- If the study is to be blinded and the test article
and reference standard are provided to the testing facility in unit dose
packaging with each unit dose labeled with a randomization code, ***the
study sponsor and/or drug manufacturer should provide the testing
facility with a labeled set of the test article and reference standard
sufficient to conduct the study and with additional, identically labeled
sets sufficient to retain the "five times quantity" (see section V). The
testing facility should randomly select a labeled set to conduct the
study; the remaining labeled sets would be retained in their unit dose
packaging as the reserve samples***. For a blinded study, we recommend
that the study sponsor and/or drug manufacturer also provide to the
testing facility a sealed code for use by FDA should it be necessary to
break the code. The sealed code should be maintained at the testing
facility.

# RETENTION FOR MULTIPLE STUDIES AND SHIPMENTS

If the same batches of the test articles and reference standards
initially provided to the testing facility are used in performing more
than one study, only one reserve sample of the test article and
reference standard in sufficient quantity need to be retained. The
reserve samples should be identified as having come from the same
batches as used in each study. However, if additional supplies of the
test article and reference standard will be used by a testing facility
to perform the same study or additional studies, the testing facility
should retain a sufficient quantity of reserve samples from the
subsequent shipment. If a CRO with multiple testing facilities conducts
more than one BE study (e.g., fed and fasted studies) for the same drug
product, and the study test article and reference standard are sent to
the testing facilities in different shipments, we recommend that
sufficient quantity of reserve samples be kept for each study at each
testing facility. These approaches are to ensure that the reserve
samples are in fact representative of the batch provided by the study
sponsor and/or drug manufacturer to the testing facility.

# Quantity of Reserve Samples

The quantity of reserve samples should be sufficient to permit the
Agency to perform five times all of the release tests required in the
application or supplemental application. The rationale for requiring the
*five times quantity* is provided in the final rule. The clinical
investigator can obtain the amount that constitutes the five times
quantity from the sponsor and/or drug manufacturer. For solid oral
dosage forms (e.g., tablets, capsules), an upper limit of 300 units each
for the test article and reference standard can be considered sufficient
to meet the five times quantity. Because the Agency has limited
experience with the retention and testing of non-solid oral dosage
forms, the Agency is unable to recommend an upper limit for the
retention of non-solid oral dosage forms at this time. In the case of a
reference standard that is an extemporaneously compounded solution or
suspension or a reconstitutable powder, we recommend that the pure
active ingredient and the unconstituted powder be retained. For a
multisite BA or BE study, we recommend that the total amount of reserve
samples to be retained across ***all*** testing facilities satisfy the
five times quantity requirement. Each site is asked to retain a
reasonable amount of test article and reference standard to be
determined by considering (1) the total number of testing facilities
participating in the study, (2) the number of subjects expected to be
enrolled at each testing facility, and (3) a minimum limit (e.g., 5 dose
units) for each of the test articles and reference standards. If the
reserve samples from more than one testing facility are transferred to
an independent third party for storage, we recommend that the
independent third party segregate the reserve samples from the various
testing facilities so that any given reserve sample can be unambiguously
associated with the testing facility from which it came.

# RESPONSIBiLITIES IN VARIOUS STUDY SETTINGS

Because of the variety of study settings potentially involved in
conducting BA and BE studies, several examples are provided here. These
examples are not the only possible study settings. However, in ***all***
instances, the chain of custody of the reserve samples used in the study
should be preserved. The sponsor and/or manufacturer and any storage
facility should document and maintain the transfer records for Agency
verification. []{.mark}

## Studies Conducted at CROs, Universities, Hospitals, or Physicians' Offices

CROs are the most common study sites. Many BA/BE studies of oral dosage
forms are conducted at CROs to support approval of abbreviated new drug
applications (ANDAs), new drug applications (NDAs), and NDA supplements.
CROs typically conduct single-site, open-label, crossover design studies
with healthy volunteers as participants.

Study sponsors and drug manufacturers sometimes conduct BA and BE
studies through a CRO, university faculty, hospitals, or clinical
investigators in private practice. The testing facilities are usually
clinical study units in universities, hospitals, or clinics run by
physicians.

The responsibilities of the study sponsor and/or drug manufacturer
include:

-   Packaging, distributing, and shipping the test article and reference
    standard to the testing facility

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-   Monitoring the study if it is conducted under an investigational new
    drug application (IND) (rarely needed for most ANDA studies)

The responsibilities of the testing facility are as follows:

-   The clinical investigator or designee (such as the study coordinator
    or research pharmacist of the testing facility) should randomly
    select sufficient test article and reference standard to conduct the
    study from the supplies received from the sponsor and/or drug
    manufacturer, and retain the remaining study samples as study
    reserves.

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-   The testing facility or the pharmacy of the testing facility should
    retain the reserve samples.

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-   If the testing facility does not have adequate storage, or goes out
    of business, the reserve samples can be transferred to an
    independent third party with an adequate facility for storage under
    conditions consistent with product labeling.

***Note***: When studies are conducted at universities, hospitals, or
physicians' offices, the clinical investigator or physician conducting
the study should ***not*** send the reserve samples back to the study
sponsor and/or drug manufacturer. The goal is to eliminate the
possibility for sample substitution by the study sponsor and/or drug
manufacturer, and to preclude the alteration of a reserve sample from a
study conducted by another entity before the release of the reserve
sample to the FDA.

## B. Studies Involving SMOs 

When BA or BE studies are conducted by an SMO, they are frequently
multisite, open-label studies of oral dosage forms in patients, or
multisite, open-label studies of nonoral dosage forms with
pharmacodynamic or clinical endpoints. Often, the study sponsor and/or
drug manufacturer contracts with an SMO to recruit clinical
investigators and to monitor a study. The SMO is involved directly or
indirectly (i.e., by subcontracting to another party) in packaging and
shipping of study test articles and reference standards to the testing
facilities. The testing facilities are usually the clinical study units
of CROs, universities, hospitals, or clinics run by physicians.

The responsibility of the study sponsor or drug manufacturer is to ship
the test article and reference standard to the SMO under contract, or to
the packaging facility under subcontract to the SMO.

The responsibilities of the SMO include:

-   Packaging, distributing, and shipping the test article and reference
    standard to all testing facilities (or subcontracting a packaging
    facility to perform this function)

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-   Monitoring the study at different sites if it is conducted under an
    IND (rarely needed for most ANDA studies)

The SMO should ***not*** randomly select and retain reserve study
samples. As explained in the preamble to the final rule, the Agency
intended that sufficient test article and reference standard to conduct
the study should be randomly selected at each testing facility, and that
each testing facility should retain the remaining study samples as
reserves. [^7]

The responsibilities of the testing facilities are as follows:

-   The clinical investigator or designee (such as the study coordinator
    or the research pharmacist of each testing facility) should randomly
    select sufficient test article and reference standard to conduct the
    study from the supplies received from the SMO under contract, or
    from the packaging facility under subcontract with the SMO, and
    retain the remaining study samples as study reserves.

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-   Each testing facility or the pharmacy of each testing facility
    should retain the reserve samples.

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-   Following the completion of the study, if one or more of the testing
    facilities do not have adequate storage, reserve samples can be
    transferred to an independent third party with an adequate facility
    for storage under conditions consistent with product labeling. The
    reserve samples should not be transferred back to an SMO or any
    other organization that deals with packaging the test articles and
    reference standard for storage. This is to eliminate the possibility
    of commingling reserve samples from packaging activities (21 CFR
    211.84 and 211.170) and bioequivalence studies (21 CFR 320.38 and
    320.63). As stated in subsection VI.A above, the reserve samples
    should ***not*** be shipped back to the sponsor or manufacturer.

## C. Blinded Studies With Pharmacodynamic or Clinical Endpoints Involving an SMO

Blinded BE studies are often conducted at multiple sites and involve
nonoral dosage forms with pharmacodynamic or clinical endpoints. Often,
the study sponsor and/or drug manufacturer contracts with an SMO to
recruit clinical investigators and monitor the study. The SMO is
involved directly or indirectly (i.e., by subcontracting to another
party) in packaging and shipping study test articles and reference
standards to the testing facilities. The testing facilities are usually
the clinical study units of CROs, universities, hospitals, or clinics
run by physicians. In multisite, blinded BE studies, the sponsor and/or
drug manufacturer needs to consider whether the study design will allow
for selection and retention of reserve samples in accordance with 21 CFR
320.38 and 320.63 and the final rule. If the study design is too complex
to meet the regulatory requirements for reserve samples, the study
design may need to be reconsidered. []{.mark}

[]{.mark}

The responsibility of the study sponsor and/or drug manufacturer is to
ship the test article and reference standard to the SMO under contract,
or to the packaging facility under subcontract to the SMO.

The responsibilities of the SMO include:

-   Packaging, distributing, and shipping test article and reference
    standard to all testing facilities (or subcontracting a packaging
    facility to perform this function). We recommend that the SMO
    provide the testing facilities with enough code-labeled sets to
    conduct the study and to retain the five times quantity. Based on
    inspection experience, DSI does not recommend that test article and
    reference standard be prenumbered for subjects, because assigning
    unit doses to a designated subject number precludes the random
    selection of drug used for dosing and drug used for reserve samples
    (see example below for illustration).

-   Monitoring the study at different sites if it is conducted under an
    IND (rarely needed for most ANDA studies)

Note: The SMO should not select reserve samples. In addition, the
reserve samples should not be transferred by the testing facility back
to an SMO or any other organization that deals with packaging the test
articles and reference standard for storage.

The responsibilities of the testing facilities are as follows:

-   The clinical investigator or designee (such as the study coordinator
    or the research pharmacist) of each testing facility should randomly
    select sufficient test article and reference standard to conduct the
    study from the supplies received from the SMO under contract, or
    from the packaging facility under subcontract with the SMO, and
    retain the remaining study samples as study reserves. The clinical
    investigator should be aware of the sampling techniques used for
    blinded studies as described in section III.

-   Each testing facility or the pharmacy of each testing facility
    should retain the reserve samples. Please note that if a placebo is
    used in blinded BE studies, reserve samples for the placebo should
    be retained along with the test article and reference standard
    reserves. The sealed treatment code of the study should be kept at
    the testing facility. This is applicable even if the reserve samples
    are forwarded to an independent third party (see paragraph below).

3\. If one or more of the testing facilities do not have adequate
storage, or go out of business, the reserve samples can be forwarded to
an independent third party with an adequate facility for storage under
conditions consistent with product labeling.

Below is a suggested packaging and random selection plan for a blinded,
multisite study of a dermatological cream product involving a SMO:

> The study enrolls 300 subjects with approximately 60 subjects at five
> testing facilities. The five times quantity for the test article and
> reference standard is 50 tubes for each product. In preparation for
> conducting the study, the SMO prepares 200 boxes that contain one
> code-labeled tube of test article and one code-labeled tube of
> reference standard in each box. The SMO randomly distributes 40 boxes
> to each clinical testing facility. The clinical facility randomly
> selects 30 of the boxes to dose 60 subjects. The remaining 10 boxes
> serve as the reserve samples. In this example, staff (e.g., a
> pharmacist) not involved with the study may be recommended to ensure
> the study remains blinded. This packaging system ensures that an equal
> number of test article and reference standard are administered to the
> subjects at each site, and that an equal number of test article and
> reference standard will be maintained as reserve samples. Since 10
> boxes are kept at each of 5 testing facilities, 50 tubes each of test
> article and reference standard are retained and the five times
> quantity reserve sample requirement is met. In addition, the
> requirement of random selection by each testing facility is also met.

## D. In-House Studies Conducted by a Study Sponsor and/or Drug Manufacturer

Only about 7 percent of all sites inspected by DSI from 1997 to 2002
conducted in-house BA and BE studies. If a study sponsor and/or drug
manufacturer conducts such a study, manufacturing reserve samples (21
CFR 211.170) and BE study reserve samples (21 CFR 320.38 and 320.63)
should be separated. The in-house clinical research unit should operate
as an independent unit for the purposes of sample retention. All matters
(e.g., manufacturing, purchasing, packaging, transfer records)
concerning the test article and reference standard should be clearly
documented and available to FDA investigators during an inspection.
Standard procedures concerning security and accountability of the test
article and reference standard for each study should be established to
eliminate the possibility of sample substitution. Sponsors conducting
in-house studies can engage an independent third party to store reserve
samples. If an independent third party is not used, there should be (1)
a totally segregated and fully compliant in-house storage area; (2)
procedures and policies in place to show that adequate test article and
reference standard are retained; (3) controlled access to the reserve
samples; (4) a rigorous and unbroken chain of custody for the reserve
samples.

The study sponsor and/or drug manufacturer (clinical research
department) should be responsible for packaging and transferring the
test article and reference standard to the in-house clinical study unit.

The testing facility (in-house clinical study unit) should be
responsible for:

-   Documentation of all matters concerning the transfer and receipt of
    the test article and reference standard

-   Random selection of sufficient test article and reference standard
    to conduct the study, and retention of the remaining study samples
    as reserves. The selection is generally made by the clinical
    investigator, study coordinator, or research pharmacist (if
    available) in the clinical study unit. We recommend that a staff
    member (e.g., a study nurse) witness the random selection process
    and dosing.

-   Retention of reserve samples in a secure area. To ensure the
    authenticity of the reserve samples, access to this area should be
    limited. We encourage maintenance of an entry log to the storage
    area.

-   Preparation for adequate storage of reserve samples. If the in-house
    testing facilities do not have adequate storage, or go out of
    business, the reserve samples can be forwarded to an independent
    third party with an adequate facility for secure storage under
    conditions consistent with product labeling.

## E. In Vitro BE Studies

21 CFR 320.63 states:

> The applicant of an abbreviated application or a supplemental
> application submitted under section 505 of the Federal Food, Drug, and
> Cosmetic Act, or, if bioequivalence testing was performed under
> contract, the contract research organization shall retain reserve
> samples of any test article and reference standard used in conducting
> an in vivo or in vitro bioequivalence study required for approval of
> the abbreviated application or supplemental application.

Thus, the regulations for reserve samples apply to in vitro BE studies.
The in vitro BE studies required for approval of nasal aerosols and
nasal sprays for local action are an example of this. Note that in vitro
studies conducted to compare dissolution rates for different strengths
of the same formulation are not subject to the reserve sample
regulations. For an in vitro BE study, the roles of the study sponsor
and/or drug manufacturer and the testing facility are similar to those
described for in vivo BE studies conducted by CROs and in the examples
of in vivo BE studies conducted in-house by a study sponsor and/or drug
manufacturer.

# EXCEPTION FOR INHALANT PRODUCTS

As stated in 21 CFR 320.38(c), each reserve sample shall consist of a
sufficient quantity of samples to permit FDA to perform five times all
of the release tests required in the application or supplemental
application. Dose content uniformity or spray content uniformity release
tests alone usually take 30 units (canisters or bottles) per batch.
Performance of other release tests can suggest a need for additional
units. The number of reserve sample units to be retained for three
batches of test article and reference standard could exceed 1000 units
(up to 250 units for each batch of the test article and reference
standard) based on the five times quantity requirement. The Agency has
determined that in lieu of the "five times quantity" requirement, the
quantity of inhalant (nasal aerosol or nasal spray) test article and
reference standard retained for testing and analyses should be at least
50 units for each batch (see the preamble to the final rule).[^8]

For NDAs, at least 50 units of each of the three batches of nasal
aerosol or nasal spray needed for BA studies should be retained.
However, where the reference standard is another nasal aerosol or nasal
spray, at least 50 units of that batch should also be retained. For
ANDAs, at least 50 units of each of three batches should be retained for
each of the test articles and reference standards used for in vivo or in
vitro BE studies. If multiple testing facilities are used in a BA or BE
study, the total amount of reserves for each product across ***all***
testing facilities would be at least 50 units, and each testing facility
should retain a reasonable amount of test articles and reference
standards (see section V for more details). For NDAs and ANDAs, if the
in vivo or in vitro studies include placebo aerosols or sprays, at least
50 units of each placebo batch should also be retained. These
recommendations apply only to nasal aerosol and nasal sprays for local
action that are to be marketed as multiple dose products, typically
labeled to deliver 30 or more actuations per canister or bottle.

# GLOSSARY

**Clinical Investigator** -- An individual who actually conducts a
clinical investigation (i.e., under whose immediate direction the drug
is administered or dispensed to a subject) (21 CFR 312.3(b)). In this
guidance, when a clinical investigation involves BA or BE studies, the
clinical investigator has the responsibility of retaining the reserve
samples at the testing facility or through an independent third party.

**Contract Research Organization (CRO)** -- An independent contractor of
the sponsor or manufacturer that assumes one or more of the obligations
of a sponsor (e.g., design of a protocol, selection or monitoring of
investigations, evaluation of reports, and preparation of materials to
be submitted to the FDA) (21 CFR 312.3(b)). This guidance addresses BA
and BE studies submitted to support approvals of new and generic drugs.
These studies are usually conducted by CROs under contract to study
sponsors and/or drug manufacturers. Many CROs have their own testing
facilities, with physicians (to serve as clinical investigators) and
clinical support staff (e.g., nurses, medical technologists) to conduct
the BA and BE studies.

**Independent Third Party** -- In this guidance, *independent third
party* indicates a person that has no affiliation with the study sponsor
and/or drug manufacturer.

**Reference Standard** -- In this guidance, *reference standard* refers
to the reference product used in a BE study. It is usually the
innovator's product or a marketed product of the drug under
investigation. For BA studies, the reference standard can be an oral
solution of the drug under investigation.

**Reserve Samples** -- In this guidance, reserve samples and retention
samples are used interchangeably.

**Site Management Organization (SMO)** -- In this guidance, *site
management organization* refers to an organization that manages clinical
study sites on behalf of the sponsor and/or drug manufacturer.

**Sponsor-Investigator** -- An individual who both initiates and
conducts an investigation, and under whose immediate direction the
investigational drug is administered or dispensed. The term does not
include any person other than an individual (21 CFR 312.3(b)).

**Study Sponsor** -- A person who takes responsibility for and initiates
a clinical investigation. The sponsor may be an individual or
pharmaceutical company, governmental agency, academic institution,
private organization, or other organization. The sponsor does not
actually conduct the investigation unless the sponsor is a
sponsor-investigator (21 CFR 312.3 (b)).

In this guidance, the term *study sponsor and/or drug manufacturer* is
used in recognition of the fact that most study sponsors are
pharmaceutical companies that manufacture the drugs under investigation.

**Testing Facility** -- The entity performing the BA or BE (in vivo or
in vitro) study. The testing facility can be a CRO, university,
hospital, clinic of a clinical investigator, or in-house clinical study
unit of a study sponsor and/or drug manufacturer, where dosing and
sampling (i.e., blood, urine, or clinical endpoints) are performed. In
issuing the final rule, the Agency intended that reserve samples should
be kept at the testing facility.

[^1]: This guidance has been prepared by the Division of Scientific
    Investigations in the Center for Drug Evaluation and Research (CDER)
    at the Food and Drug Administration.

[^2]: 55 FR 47034.

[^3]: 58 FR 25918.

[^4]: 58 FR 25918 at 25920.

[^5]: 58 FR 25918 at 25921.

[^6]: 58 FR 25918 at 25920.

[^7]: 58 FR 25918 at 25920.

[^8]: 58 FR 25918 at 25924.