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.  INTRODUCTION................................................................................................................. 1
 
II.  BACKGROUND ...................................................................................................................1
 
III.  SAMPLING TECHNIQUES ............................................................................................... 2 

IV.  RETENTION FOR MULTIPLE STUDIES AND SHIPMENTS..................................... 3 

V.  QUANTITY OF RESERVE SAMPLES............................................................................. 4 

VI.  RESPONSIBILITIES IN VARIOUS STUDY SETTINGS............................................... 4 

A.  Studies Conducted at CROs, Universities, Hospitals, or Physicians Offices...........................4
 
B.  Studies Involving SMOs ................................................................................................................5
 
C.  Blinded Studies With Pharmacodynamic or Clinical Endpoints Involving an SMO..............6
 
D.  In-House Studies Conducted by a Study Sponsor and/or Drug Manufacturer .......................8
 
E.  In Vitro BE Studies........................................................................................................................9
 
VII.  EXCEPTION FOR INHALANT PRODUCTS.............................................................. 9 

GLOSSARY................................................................................................................................. 11
  Contains Nonbinding Recommendations 
1
 
Guidance for Industry
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. 
I.   INTRODUCTION 
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. 
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. 
II.   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 
                                                
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.
  Contains Nonbinding Recommendations 
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 sponsors 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. 
FDAs 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. 
III.   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 
                                                
3 58 FR 25918. 
4 58 FR 25918 at 25920. 
5 58 FR 25918 at 25921. 
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  Contains Nonbinding Recommendations 
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 
sponsors 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 described6 (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. 
IV.   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 
                                                
6 58 FR 25918 at 25920. 
3
  Contains Nonbinding Recommendations 
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. 
V.   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. 
VI.   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. 
A.   Studies Conducted at CROs, Universities, Hospitals, or Physicians Offices 
4
  Contains Nonbinding Recommendations 
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 
	   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. 
	   The testing facility or the pharmacy of the testing facility should retain the reserve 
samples. 
	   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. 
5
  Contains Nonbinding Recommendations 
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) 
	   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. 
	   Each testing facility or the pharmacy of each testing facility should retain the reserve 
samples. 
	   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. 
                                                
7 58 FR 25918 at 25920. 
6
  Contains Nonbinding Recommendations 
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. 
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: 
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  Contains Nonbinding Recommendations 
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 
8
  Contains Nonbinding Recommendations 
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. 
VII.   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  
                                                
8 58 FR 25918 at 25924. 
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  Contains Nonbinding Recommendations 
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. 
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  Contains Nonbinding Recommendations 
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 innovators 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. 
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  Contains Nonbinding Recommendations 
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. 
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