Federal Register / Vol. 74, No. 11 / Friday, January 16, 2009 / Rules and Regulations 2849 

provided in the rule to file their 

substantive responses to the 

Commission because they will be 

devoting the first 30 days of that period 

preparing responses to the Department 

of Commerce. SMA stated that current 

requirements for adequacy comments 

are arduous and that increasing the 

amount of information that must be 

provided while reducing the amount of 

time available to prepare a submission 

is problematic. Kelley asserted that 

domestic producers will put more 

detailed information in a notice of 

review if they are aware that no 

respondent interested parties will 

participate. Notices of appearance need 

not be filed until 21 days after the notice 

of institution, and Kelley asserted that 

nine days would be insufficient time for 

a domestic producer to compile this 

more detailed information. 

The commenters’ objections proceed 

largely from the premise that a domestic 

producer will not begin to prepare its 

responses to either the Commerce notice 

of initiation or the Commission notice of 

institution until these notices are 

published in the Federal Register. The 

Commission does not agree with this 

premise. Interested parties are in a 

position to begin compiling information 

needed for a five-year review well 

before the publication of notices in the 

Federal Register beginning the reviews. 

The parties typically know the date that 

Commerce and the Commission will 

publish their Federal Register notices 

many months in advance. The 

Commission requests standardized 

information in interested parties’ 

responses to notices of institution; the 

information requests are generally 

known prior to publication of the 

Federal Register notice. Similarly, the 

information that Commerce requires to 

be submitted in a notice of intent to 

participate in a sunset review is 

specified by regulation, and thus will be 

known well before initiation of the 

review. Kelley’s assertion that responses 

to the notice of institution contain more 

detailed information in uncontested 

reviews than in contested reviews is not 

consistent with the Commission’s 

experience. 

List of Subjects in 9 CFR Part 207 

Administrative practice and 

procedure, investigations. 

■ For the reasons stated in the preamble, 

the Commission amends 19 CFR part 

207 as follows: 

PART 207—INVESTIGATIONS OF 

WHETHER INJURY TO DOMESTIC 

INDUSTRIES RESULTS FROM 

IMPORTS SOLD AT LESS THAN FAIR 

VALUE OR FROM SUBSIDIZED 

EXPORTS TO THE UNITED STATES 

■ 1. The authority citation for part 207 

continues to read as follows: 

Authority: 19 U.S.C. 1336, 1671–1677n, 

2482, 3513. 

■ 2. Amend § 207.61 by revising 

paragraph (a) as follows: 

§ 207.61 Responses to notice of 

institution. 

(a) When Information Must Be Filed. 

Responses to the notice of institution 

shall be submitted to the Commission 

no later than 30 days after its 

publication in the Federal Register. 

* * * * * 

Issued: January 12, 2009. 

By order of the Commission. 

Marilyn R. Abbott, 

Secretary to the Commission. 

[FR Doc. E9–860 Filed 1–15–09; 8:45 am] 

BILLING CODE 7020–02–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Parts 314 and 320 

[Docket No. FDA–2003–N–0209] (Formerly 

Docket No. 2003N–0341) 

RIN 0910–AC23 

Requirements for Submission of 

Bioequivalence Data; Final Rule 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Final rule. 

SUMMARY: The Food and Drug 

Administration (FDA) is amending its 

regulations on the submission of 

bioequivalence data to require an 

abbreviated new drug application 

(ANDA) applicant to submit data from 

all bioequivalence (BE) studies the 

applicant conducts on a drug product 

formulation submitted for approval. In 

the past, ANDA applicants have 

submitted BE studies demonstrating that 

a generic product meets bioequivalence 

criteria in order for FDA to approve the 

ANDA, but have not typically submitted 

additional BE studies conducted on the 

same drug product formulation, such as 

studies that do not show that the 

product meets these criteria. FDA is 

amending the regulation because we 

now believe that data from additional 

BE studies may be important in our 

determination of whether the proposed 

formulation is bioequivalent to the 

reference listed drug (RLD), and are 

relevant to our evaluation of ANDAs in 

general. In addition, such data will 

increase our understanding of how 

changes in components, composition, 

and methods of manufacture may affect 

product formulation performance. 

DATES: The rule is effective July 15, 

2009. 

FOR FURTHER INFORMATION CONTACT: 

Aida L. Sanchez, Center for Drug 

Evaluation and Research (HFD–650), 

Food and Drug Administration, 7520 

Standish Pl., Rockville, MD 20855, 240– 

276–8782. 

SUPPLEMENTARY INFORMATION: 

I. Background 

In the Federal Register of October 29, 

2003 (68 FR 61640), FDA proposed to 

amend its regulations in parts 314 and 

320 (21 CFR parts 314 and 320) to 

require an ANDA applicant to submit 

data from all BE studies that the 

applicant conducts on a drug product 

formulation submitted for approval. 

Section 505(j)(2)(A)(iv) of the Federal 

Food, Drug, and Cosmetic Act (the act) 

(21 U.S.C. 355(j)(2)(A)(iv)) requires that 

ANDA applicants submit, among other 

things, information showing that the 

applicant’s drug is bioequivalent to a 

drug that has previously been approved 

by FDA. Under the regulations at 

§ 314.3(b), the approved drug product 

identified by FDA as the drug product 

on which an ANDA applicant relies for 

approval is the RLD. The requirement 

that an ANDA applicant submit 

information that shows the proposed 

product is bioequivalent to the RLD is 

described in FDA’s regulations at 

§ 314.94(a)(7). Section 320.24 sets forth 

the types of evidence acceptable to 

establish BE. The most common BE 

studies are those performed on solid 

oral dosage forms of drugs that are 

absorbed into the systemic circulation. 

BE data provide an estimate of the rate 

and extent of drug absorption for a test 

and reference product. These data are 

examined, using statistical procedures, 

to determine whether the test product 

meets BE limits. 

A BE study may fail to show that a 

test product meets BE limits because the 

test product has significantly higher or 

lower relative bioavailability (i.e., 

measures of rate and extent of 

absorption compared to the reference 

product). In some cases, BE will not be 

demonstrated because there are 

inadequate numbers of subjects in the 

study relative to the magnitude of 

intrasubject variability, and not because 


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of either significantly high or low 

relative bioavailability of the product. 

Where the relative bioavailability of a 

product is too low, the concern is that 

not enough of the active ingredient is 

reaching the site of action, and therefore 

the product may not be as 

therapeutically effective as the RLD. 

Where the relative bioavailability of a 

test product is too high, the concern 

with the product is not its therapeutic 

efficacy, but rather its safety relative to 

the RLD. When the variability of the test 

product is high, the concern relates to 

both safety and efficacy. The variability 

may suggest that the test product does 

not perform as consistently as the 

reference product, and the test product 

may be too variable to be clinically 

useful. 

The act and FDA regulations require 

that an ANDA applicant submit 

information demonstrating BE of a 

proposed drug to the RLD, but do not 

specify whether all BE studies must be 

submitted. It has been the practice of 

ANDA applicants to submit evidence of 

bioequivalence consisting of studies 

demonstrating that the rate and extent of 

absorption of the test product meet BE 

limits. Thus, ANDA applicants that 

have conducted multiple studies on a 

final formulation, producing both 

passing and nonpassing results, have 

generally not submitted the results of 

the nonpassing study or studies to FDA. 

Similarly, ANDA applicants that have 

conducted multiple studies on a final 

formulation, producing more than one 

passing result, have generally not 

submitted the results of all of the 

passing studies to FDA. As a result, FDA 

infrequently sees data from such 

additional studies and is generally 

unaware of the existence of such 

studies. In rare instances, ANDA 

applicants have submitted additional BE 

studies, or the agency has learned about 

such studies through other means. 

II. Summary of the 2003 Proposed Rule 

FDA determined that the submission 

of all bioequivalence studies, both 

passing and nonpassing, is necessary for 

the purposes of evaluating a drug 

product submitted for approval under 

an ANDA. Accordingly, the agency 

proposed to amend its regulations in 

parts 314 and 320. Specifically, the 

agency proposed to amend: 

• the ANDA content requirements 

(§ 314.94(a)(7)(i)) 

• the ANDA amendment 

requirements (§ 314.96(a)(1)), and 

• the requirements for submission of 

in vivo bioavailability and 

bioequivalence data (§ 320.21(b)(1)). 

The agency did not propose to amend 

the text of § 320.21(c). However, because 

§ 320.21(c) references the requirements 

of § 320.21(b)(1), the proposed changes 

to § 320.21(b)(1) would also modify the 

requirements of § 320.21(c). In addition, 

FDA explained how it intended to 

interpret two of its current regulations 

to be consistent with the proposal. 

Specifically, FDA explained that it 

intended to interpret the regulation 

applicable to an ANDA submitted under 

an approved suitability petition 

(§ 314.94(a)(7)(ii)) and the 

postmarketing reporting regulation 

(§ 314.81(b)(2)(vi)) to require the 

submission of all BE studies, both 

passing and nonpassing. 

The agency did not propose to amend 

the section heading of § 320.21 

(‘‘Requirements for submission of in 

vivo bioavailability and bioequivalence 

data’’), but after reviewing the public 

comments, the agency believes that the 

section heading of § 320.21 may cause 

confusion. As explained in the proposed 

rule, FDA is requiring the submission of 

all bioequivalence studies conducted on 

a drug product formulation submitted 

for approval. This requirement includes 

both in vivo and in vitro studies that are 

conducted for the purpose of 

establishing bioequivalence. Therefore, 

FDA is changing the section heading of 

§ 320.21 to omit the reference to in vivo 

studies, to more clearly reflect the fact 

that both in vivo and in vitro studies 

must be submitted. 

III. Description of the Final Rule 

We are revising our regulations to 

require applicants to submit data on all 

BE studies, including studies that do not 

meet passing bioequivalence criteria, 

which are performed on a drug product 

formulation submitted for approval 

under an ANDA, or in an amendment or 

supplement to an ANDA that contains 

BE studies. Applicants will also be 

required to submit data in an annual 

report on all postmarketing BE studies 

conducted or otherwise obtained on the 

approved drug product formulation 

during the annual reporting period. 

The provisions of the proposed rule 

stated that BE studies on the ‘‘same drug 

product formulation’’ must be 

submitted. The proposed rule did not 

specifically define the term ‘‘same drug 

product formulation.’’ However, in the 

preamble to the proposed rule, the 

agency stated that ‘‘FDA intends that the 

terminology ‘same drug product 

formulation’ will include formulations 

that have minor differences in 

composition or method of manufacture 

from the formulation submitted for 

approval, but are similar enough to be 

relevant to the agency’s determination 

of bioequivalence. For example, where 

an applicant makes formulation or 

manufacturing changes of the type that 

qualify as level 1 or level 2 changes in 

FDA’s current guidances on scale up 

and postapproval changes (SUPAC) 

listed below, the agency will consider 

the original and modified products to be 

similar enough to constitute the same 

drug product formulation for the 

purposes of the proposed rule’’ (68 FR 

61640 at 61643). The proposed rule then 

listed six SUPAC guidances. 

FDA received a significant number of 

comments indicating that using the 

SUPAC guidances as a way of 

explaining which BE studies must be 

submitted to the agency did not provide 

sufficient clarity. For example, one 

comment on the proposed rule asked if 

the rule will require the submission of 

pilot studies, including pilot 

pharmacokinetic studies in animals, or 

in vitro studies. Another comment 

asked whether it will be necessary to 

submit prior studies—such as a 

pharmacokinetic study on the 

metabolite only, a pharmacokinetic 

study in urine, a pharmacodynamic 

study, a clinical endpoint BE study or 

other clinical study, or a sensitization or 

irritation study for transdermal 

patches—that are not directly relevant 

to the assessment of BE by the current 

criteria. 

The final rule continues to use the 

term ‘‘same drug product formulation.’’ 

However, to eliminate the confusion 

caused by reference to the SUPAC 

guidances, we have added a definition 

of the term ‘‘same drug product 

formulation.’’ As set forth in § 320.1(g) 

of this final rule, the term ‘‘same drug 

product formulation’’ means the 

formulation of the drug product 

submitted for approval and any 

formulations that have minor 

differences in composition or method of 

manufacture from the formulation 

submitted for approval, but are similar 

enough to be relevant to the agency’s 

determination of bioequivalence 

(§ 320.1(g)). This definition is consistent 

with FDA’s intended meaning for the 

term ‘‘same drug product formulation,’’ 

as described in the proposed rule (68 FR 

61640 at 61643), and eliminates the 

need to refer to the SUPAC guidances as 

discussed further in this document. 

In addition, as stated in the preamble 

to the proposed rule, FDA intends to 

make available shortly a draft guidance 

intended to help affected entities better 

understand which BE studies should be 

submitted, as well as the format FDA 

recommends for submission. 

FDA is revising §§ 314.94(a)(7)(i), 

314.96(a)(1), 320.1(g), 320.21 (section 

heading), and 320.21(b)(1), as well as 

modifying § 320.21(c) (which references 

the requirements of § 320.21(b)(1)) to 


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require that an applicant submitting BE 

studies in an ANDA, ANDA 

amendment, or ANDA supplement 

submit: (1) Full reports of BE studies 

upon which the applicant relies for 

approval and (2) either full or summary 

reports of all other BE studies 

conducted on the same drug product 

formulation. In addition to amending 

these provisions, FDA is also clarifying 

its interpretation of two regulations, 

§§ 314.94(a)(7)(ii) and 314.81(b)(2)(vi) as 

follows: 

As currently written, § 314.94(a)(7)(ii) 

requires an applicant submitting an 

ANDA under a petition approved under 

§ 314.93 to submit the results of any 

bioavailability or bioequivalence testing 

required by the agency to show that the 

active ingredients of the proposed drug 

product are of the same pharmacological 

or therapeutic class as those in the RLD, 

and that the proposed drug product can 

be expected to have the same 

therapeutic effect as the RLD. Consistent 

with the regulatory changes described 

above, FDA intends to interpret 

§ 314.94(a)(7)(ii) to require the 

submission of results from all 

bioavailability and BE studies, passing 

and nonpassing, conducted on the same 

drug product formulation. An applicant 

submitting an ANDA under a petition 

approved under § 314.93 will now be 

required to submit complete reports of 

the bioavailability or BE studies upon 

which the applicant relies for approval, 

and a complete or summary report for 

all other bioavailability or BE studies on 

the same drug product formulation. 

As currently written, § 314.81(b)(2)(vi) 

requires an ANDA applicant to submit, 

in an annual report, the results of 

‘‘biopharmaceutic, pharmacokinetic, 

and clinical pharmacology studies 

* * * conducted by or otherwise 

obtained by the applicant’’ during the 

annual reporting period. FDA intends to 

interpret this section to require ANDA 

applicants with approved ANDAs to 

submit reports of all BE studies, both 

passing and nonpassing, conducted or 

obtained by the applicant during the 

annual reporting period on the 

approved drug product. 

IV. Comments on the Proposed Rule 

FDA received 11 comments on the 

proposed rule from manufacturers, trade 

associations, and law firms. On June 11, 

2004, FDA held a meeting to discuss the 

proposed rule with the Generic 

Pharmaceutical Association (GPhA). 

The meeting minutes have been entered 

into the docket, and the comments 

provided by GPhA are included in the 

comments we respond to in this 

document. The majority of the 

comments supported the proposed 

amendments to FDA’s regulations. 

Several comments requested 

clarification on various aspects of the 

rule. The final rule is described in 

section III of this document. 

A. General Comments 

(Comment 1) Several comments, 

including comments from 

manufacturers, law firms, and trade 

associations, commended FDA on the 

proposal. In particular, these comments 

noted the importance of requiring the 

submission of all bioequivalence data to 

assess the safety and effectiveness of 

ANDA products, and to enhance FDA’s 

knowledge concerning bioequivalence. 

(Response) We appreciate the support 

expressed in these comments and agree 

that requiring the submission of these 

data is very important. 

(Comment 2) One comment 

specifically commended FDA for stating 

in the proposed rule that the agency is 

not aware of any adverse public health 

consequences associated with products 

for which studies were not submitted, 

nor of any information on any currently 

marketed generic product suggesting 

that the product is not bioequivalent to 

a reference listed drug to which it has 

been designated as therapeutically 

equivalent. 

(Response) FDA notes that since 

publication of the proposed rule, we 

have not become aware of any such 

information. 

(Comment 3) In the preamble to the 

proposed rule we stated: ‘‘Even when 

additional BE studies are not critical to 

the agency’s bioequivalence 

determination for the specific product 

being reviewed, the data provide 

valuable scientific information that 

increases the agency’s knowledge and 

understanding of bioequivalence and 

generic drug development and promote 

further development of science-based 

bioequivalence policies’’ (68 FR 61640 

at 61641). One comment stated that the 

goal of increasing FDA’s knowledge and 

understanding of bioequivalence should 

not be accomplished by imposing 

regulatory requirements on ANDA 

applicants. This comment suggested 

that the appropriate way to achieve this 

goal will be to hold joint industryagency meetings and conferences. 

(Response) We agree with the 

comment that if the sole purpose of this 

rule was to increase the agency’s 

understanding of BE, there would be 

alternative means for FDA to achieve 

this goal. As stated in the proposal, 

however, the primary purpose of the 

requirement to submit information from 

all BE studies on the same drug product 

formulation is that ‘‘[d]ata contained in 

additional passing and nonpassing BE 

studies can be important to FDA’s 

assessment of bioequivalence for a 

specific product’’ (68 FR 61640 at 

61641). Currently, ANDA applicants are 

only required to submit one BE study 

(or two, if a fed study is required). Based 

on one or two studies, FDA might 

conclude that the product is 

bioequivalent to its RLD. If the agency 

receives other BE studies conducted by 

the applicant, and these studies failed to 

show bioequivalence, the agency might 

make a different decision about whether 

to approve the ANDA than it would 

have if the agency had received only the 

passing study. In such a case, receipt of 

additional BE studies will be critical to 

FDA’s determination as to whether a 

generic product is equivalent to its RLD. 

Unless FDA receives all BE studies on 

the same drug product formulation, it is 

not possible for the agency to make an 

informed, scientifically based decision 

about bioequivalence. Thus, the rule 

requires that all BE studies conducted 

on the same drug product formulation 

be submitted. In other cases, FDA’s 

receipt of additional BE studies might 

not change the agency’s decision that a 

product is bioequivalent to its RLD. In 

both cases, however, review of the 

additional studies will serve the 

ancillary purpose of increasing the 

agency’s understanding of 

bioequivalence, and provide added 

confidence in the agency’s BE 

determination. In setting out the second 

purpose (that of increasing the agency’s 

knowledge of bioequivalence), we note 

in the preamble to the proposed rule 

that this ancillary purpose is served 

even when the additional BE studies do 

not prove to be critical to the agency’s 

bioequivalence determination for the 

specific product being reviewed (68 FR 

61640 at 61641). 

(Comment 4) One comment suggested 

that FDA amend § 314.127(b) of its 

regulations to reflect that failure to 

submit all required BE study reports is 

grounds for receiving an 

‘‘unapprovable’’ letter. 

(Response) FDA generally disagrees 

with the comment. Failure to submit all 

BE studies will be grounds for refusing 

to receive the ANDA under 

§ 314.101(b)(1) of FDA’s regulations 

because the ANDA will not be complete. 

It should be noted that section 505(j)(4) 

of the act describes the grounds for 

refusing to approve an ANDA. Under 

certain circumstances, one or more 

unreported BE studies might provide 

the basis for refusing to approve an 

ANDA under section 505(j)(4)(F) of the 

act (‘‘information submitted in the 

application is insufficient to show that 

the drug is bioequivalent * * *’’). See 

also § 314.127(a)(6). For example, if, 


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while an ANDA is pending, FDA 

discovers that the ANDA omitted one or 

more studies that failed to demonstrate 

BE, FDA might conclude that the BE 

information in the application is 

insufficient. 

(Comment 5) Several comments 

expressed concern about the burden that 

will be imposed on the ANDA review 

process and agency resources (e.g., 

reviewers and inspectors) when the rule 

is implemented. One comment 

expressed concern that the workload 

created by this rule will slow action on 

pending ANDAs. Another comment 

noted that FDA has been trying to 

reduce the time both for BE review and 

response to correspondence by the 

Office of Generic Drug’s (OGD’s) 

Division of Bioequivalence. This 

comment suggested that adequate hiring 

and retention should be established in 

the Division of Bioequivalence before 

implementing the rule. 

(Response) FDA crafted the 

requirements of the rule mindful of 

balancing its need for additional BE 

information with the need to ensure that 

the ANDA review process is not 

unnecessarily burdened. It was the 

desire to achieve this balance that, in 

part, led FDA to require only the 

submission of BE studies conducted 

with the ‘‘same drug product 

formulation’’ as that submitted for 

approval, rather than requiring the 

submission of all BE studies conducted 

with all developmental formulations, as 

some comments suggested. FDA 

appreciates, however, that the final rule 

will increase the number of studies 

reviewed by the Division of 

Bioequivalence, and the agency is 

working on hiring additional staff to 

handle this increase. FDA is also 

developing databases that will help 

decrease the amount of correspondence 

received by OGD. We believe these steps 

will ensure that the ANDA review 

process continues to be efficient. 

(Comment 6) In the preamble to the 

proposed rule, FDA stated that an 

applicant ‘‘will rarely, if ever, conduct 

a postmarketing BE study other than one 

required for an ANDA supplement’’ (68 

FR 61640 at 61643). One comment 

suggested that requiring applicants to 

submit failing BE studies will create an 

additional disincentive to perform 

postmarketing BE studies, which may 

discourage applicants from considering 

ways to improve their manufacturing 

processes. 

(Response) FDA believes that the 

concern expressed in the comment is 

unfounded. The major disincentives to 

performing postmarketing BE studies 

are the financial costs and resource 

expenditures for the applicant. That is 

why such studies are rarely performed, 

except when required for an ANDA 

supplement. In any event, FDA believes 

that any potential disincentive created 

by requiring that such studies be 

submitted to the agency will be 

negligible. Moreover, FDA believes that 

industry will agree that because the 

drug will already be on the market, in 

the event that a postmarketing study 

fails to demonstrate bioequivalence, it 

would be particularly important for the 

agency and the applicant to examine the 

reason for the failure. 

(Comment 7) One comment stated 

that if ANDA holders are going to be 

required to submit failed studies 

performed in accordance with the 

SUPAC guidances, new drug 

application (NDA) holders should also 

be required to submit such studies. 

(Response) NDA applicants and NDA 

holders are already required to submit 

failed BE studies. Section 314.50(d)(3) 

of FDA regulations requires an NDA to 

contain a description of all 

bioavailability and pharmacokinetic 

studies in humans performed by or on 

behalf of the applicant. The requirement 

to submit bioavailability studies 

includes reports of any bioequivalence 

studies performed by or on behalf of the 

applicant. 

B. Same Drug Product Formulation 

(Comment 8) Several comments 

requested clarification of the term 

‘‘same drug product formulation.’’ One 

comment stated that clarification of the 

language was important to ensure that it 

was not subject to varying 

interpretations by ANDA applicants. 

(Response) The final rule adds in 

§ 320.1(g) a definition of the term ‘‘same 

drug product formulation’’ to mean the 

formulation of the drug product 

submitted for approval and any 

formulations that have minor 

differences in composition or method of 

manufacture from the formulation 

submitted for approval, but are similar 

enough to be relevant to the agency’s 

determination of bioequivalence. FDA’s 

draft guidance on the submission of BE 

data, when available, will expand on 

this definition by providing specific 

examples of formulations that FDA 

considers to be the same drug product 

formulation. For example, FDA 

considers two drug products that use 

different ingredients intended to affect 

the color or flavor of the drug product, 

or use a different technical grade and/ 

or specification of an excipient, to be 

the same drug product formulation. If an 

applicant has questions that are not 

answered by the draft guidance on 

submission of BE data, the applicant 

should contact OGD for assistance in 

applying the term ‘‘same drug product 

formulation.’’ 

(Comment 9) Two comments asked 

FDA to revise the concept ‘‘same drug 

product formulation.’’ One comment 

requested that the term be limited to 

‘‘studies which are statistically powered 

correctly and have a batch size of at 

least 100,000 packaged units.’’ Another 

comment asked that the term be broadly 

interpreted to require the submission of 

all BE studies performed on the various 

formulations of a drug for which an 

ANDA is ultimately submitted. For 

example, the comment suggested that 

ANDA applicants should be required to 

submit BE studies performed on 

formulations that differ by SUPAC level 

3 changes from the formulation 

submitted for approval. The comment 

suggested that failure to broadly 

interpret ‘‘same drug product 

formulation’’ will result in ANDA 

applicants making certain SUPAC level 

3 changes (such as changing the 

manufacturing site) in an attempt to 

avoid submitting failed study results. In 

addition, the comment noted that the 

submission of all BE data on all 

formulations could serve the ancillary 

purposes of helping FDA to: (1) Refine 

the SUPAC levels and (2) establish 

chemistry, manufacturing, and controls 

specifications. 

(Response) FDA disagrees with both 

of these comments. The term ‘‘same 

drug product formulation’’ is intended 

to balance competing concerns. To limit 

the definition to require only the 

submission of studies that are 

statistically powered correctly and have 

a particular batch size could undermine 

the goals of the rule. Such a limitation 

will result in FDA failing to receive 

results from pilot studies. As discussed 

in greater detail below, FDA appreciates 

that if a pilot study is underpowered, it 

cannot be expected to satisfy BE criteria. 

Nevertheless, such studies provide 

valuable information that is relevant to 

FDA’s bioequivalence determination. 

Therefore, FDA declines to limit the 

scope of the term ‘‘same drug product 

formulation’’ as suggested in the 

comment. 

FDA also declines to broadly interpret 

the definition to include all 

formulations tested during the drug’s 

development program. Such an 

interpretation would: (1) Increase the 

burden on ANDA applicants, (2) likely 

result in the submission of data 

irrelevant to the agency’s determination 

of bioequivalence, and (3) potentially 

slow the ANDA review process without 

enhancing FDA’s ability to analyze 

whether the formulation submitted for 

approval is bioequivalent to the RLD. 

Moreover, FDA believes that the 


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comment’s concern about ANDA 

applicants making SUPAC level 3 

changes to a formulation to avoid 

submitting failing results is not relevant 

to the final rule. As discussed above, the 

final rule does not use the SUPAC 

guidances to interpret the term ‘‘same 

drug product formulation.’’ Moreover, if 

a formulation failed to demonstrate 

bioequivalence, it is unlikely that 

manufacturing the same or very similar 

formulation at a different site would 

result in a passing BE study for 

submission in an ANDA. (Note that the 

issue of a change in manufacturing site 

is also discussed in the response to 

comment 15.) In addition, FDA believes 

that the intended goals of the rule are 

best served by focusing the agency’s 

review on data relevant to the 

formulation submitted for approval. 

Therefore, the agency believes that the 

disadvantages of employing such a 

broad interpretation of ‘‘same drug 

product formulation’’ outweigh the 

theoretical benefits. Overall, FDA 

believes that its definition of ‘‘same 

drug product formulation’’ strikes an 

appropriate balance. 

(Comment 10) One comment 

suggested that FDA’s definition of 

‘‘same drug product formulation’’ 

resulted in an inconsistency between 

how FDA treats changes pre- and 

postapproval. Specifically, the comment 

suggested that because a BE study will 

not be required for a SUPAC level 1 or 

2 change postapproval, FDA should not 

require that BE data be submitted 

preapproval for a formulation that 

differs only by a SUPAC level 1 or 2 

change from the formulation submitted 

for approval. 

(Response) This comment reflects the 

confusion created by our proposal to 

rely on SUPAC guidance concepts to 

determine when a drug has the same 

formulation for purposes of this rule. 

The SUPAC guidances provide 

recommendations for when FDA will 

require the conduct of a BE study to 

support a formulation or manufacturing 

change submitted in an amendment or 

supplement. In short, they provide 

guidance for when new data will be 

required to support a change to the drug 

product. 

In contrast, this rule does not address 

when data are required to support a 

product application or product change. 

It does not require that a new study be 

conducted under any circumstances. 

The rule merely addresses situations 

where an applicant has conducted BE 

studies in addition to those it seeks to 

rely on in its ANDA or ANDA 

amendment or supplement. It also 

indicates when the results from those 

additional studies must be submitted to 

FDA, because they were conducted on 

a drug product formulation that is the 

same as, or similar to, that covered by 

the application. While SUPAC is 

focused on determining what product 

changes will trigger the need for new 

data to support the change, this rule 

focuses on when existing data must be 

submitted to FDA, because they are 

relevant to the drug product with the 

same formulation. 

FDA had initially proposed to refer to 

the SUPAC guidances to determine 

when drug products with minor changes 

are considered to be the same 

formulation. Under SUPAC, level 1 or 2 

changes to a drug product formulation 

do not require a manufacturer to 

conduct BE testing or submit BE data in 

order to market the drug product with 

those changes. Level 3 changes are fairly 

significant and require a manufacturer 

to conduct a BE test to demonstrate the 

equivalence between the new and old 

formulations before it may market the 

new formulation. However, under this 

rule, BE test data on a product that is 

three SUPAC levels different from the 

approved or marketed formulation 

would not need to be submitted if that 

formulation is not, and will not, be 

marketed. In the proposed rule, we 

suggested that BE data on products 

reflecting modest changes, described as 

SUPAC level 1 and 2 changes, are 

relevant to the marketed formulation 

and would need to be submitted. As a 

result, reference to the SUPAC concepts 

created confusion, because the instances 

where SUPAC recommends that 

manufacturers conduct and submit BE 

test data to support product changes 

were the exact situations where this rule 

would not require submission of 

existing BE data, because the data are of 

limited applicability to the formulation 

subject to the application. Accordingly, 

we are no longer referring to the SUPAC 

guidances in the final rule. Instead, we 

have included a definition of ‘‘same 

drug product formulation’’ in § 320.1(g) 

of the final rule, in order to provide 

assistance in determining when this rule 

requires submission of BE data on a 

similar formulation. 

C. Bioequivalence Studies That Must Be 

Submitted 

(Comment 11) Several comments 

requested clarification about the types 

of studies that will be required to be 

submitted under the rule. In particular, 

several comments questioned whether 

‘‘pilot studies’’ or studies that were 

designed not to evaluate BE, but to 

generate BE data, will have to be 

submitted under the rule. Such studies 

could be performed to: (1) Obtain 

information related to the performance 

of prototype drug formulations, (2) 

estimate the appropriate number of 

subjects necessary for the definitive BE 

study, (3) determine the appropriate 

plasma concentration time curves, or (4) 

determine whether a drug entity can be 

reliably measured in the media chosen. 

Some comments suggested that such 

studies should not be required to be 

submitted because they may not be 

powered to pass BE statistical criteria 

and, as a result, are arguably not ‘‘BE 

studies.’’ 

(Response) The term ‘‘all other 

bioequivalence studies’’ is used in the 

rule without limitation. It is intended to 

capture all studies generating BE data, 

including pilot studies. Therefore, 

complete or summary reports of pilot 

studies conducted with formulations 

that are the ‘‘same drug product 

formulation’’ as that submitted in the 

ANDA must be submitted under the 

rule. FDA believes that the submission 

of pilot studies is important because 

they may provide valuable BE 

information. For example, they may 

provide FDA information about the 

assay used in the BE study relied on for 

approval. FDA appreciates the concern 

raised in the comments about pilot 

studies potentially being underpowered 

and not designed to evaluate 

bioequivalence. The agency will fully 

consider these issues when reviewing 

pilot studies. If a pilot study is not 

properly powered, FDA will not expect 

it to demonstrate bioequivalence. 

(Comment 12) One comment asked if 

the rule will require submission of pilot 

pharmacokinetic studies in animals or 

in vitro studies. 

(Response) The final rule does not 

require the submission of animal 

studies. In vitro studies must be 

submitted when in vitro testing is 

conducted to demonstrate 

bioequivalence (§ 320.24(b)(5)). 

Examples include in vitro testing for 

nasal sprays and resin binding testing 

for bile acid sequestrants. When an in 

vivo study is submitted to show 

bioequivalence of a formulation, all 

other in vivo and in vitro 

bioequivalence data, both passing and 

nonpassing, for that formulation must 

be submitted as well. Similarly, when 

an in vitro study is submitted to show 

bioequivalence of a formulation, all 

other in vivo and in vitro 

bioequivalence data, both passing and 

nonpassing, for that formulation must 

be submitted. The data from in vitro 

dissolution studies conducted for 

purposes other than to show 

bioequivalence need not be submitted 

under this rule, but may be required by 

other regulations (for example, 

§ 314.94(a)(9)). In the proposed rule, 


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FDA cited § 320.24 as the regulatory 

requirement which ‘‘sets forth the types 

of evidence acceptable to establish 

bioequivalence.’’ According to 

§ 320.24(a), bioavailability may be 

demonstrated by several in vivo and in 

vitro methods. Section 320.24 makes it 

clear that bioequivalence studies may 

consist of either in vivo or in vitro 

studies. 

Since reviewing the comments to the 

proposed rule, FDA has become aware 

that the language of the proposed rule 

may cause confusion regarding the 

requirement that all in vitro 

bioequivalence studies must be 

submitted. In particular, the section 

heading of § 320.21, ‘‘Requirements for 

submission of in vivo bioavailability 

and bioequivalence data,’’ may lead to 

this misinterpretation. Thus, in this 

final rule, FDA is changing the section 

heading of § 320.21 so that it removes 

the specific reference to in vivo data. 

(Comment 13) One comment asked if 

prior studies that are not directly 

relevant to the assessment of BE by the 

current criteria must be submitted. For 

example, if the current BE 

recommendation for a particular 

product specifies a pharmacokinetic 

study on the parent drug in plasma, will 

the following types of studies have to be 

submitted: A pharmacokinetic study on 

the metabolite only, a pharmacokinetic 

study in urine, a pharmacodynamic 

study, a clinical endpoint BE study or 

other clinical study, a sensitization or 

irritation study for transdermal patches, 

etc.? 

(Response) Yes, all studies on the 

same drug product formulation as 

defined in this final rule must be 

submitted regardless of what FDA’s 

current criteria for BE testing for the 

product are. Otherwise, the agency 

might not be aware of a study that is 

relevant to our determination of 

whether two products are bioequivalent. 

For example, if a firm conducted a 

pharmacodynamic study that failed to 

show BE, and then conducted a 

pharmacokinetic study that 

demonstrated BE, we would want to 

know about the pharmacodynamic 

study. 

(Comment 14) One comment noted 

that the SUPAC guidance states that for 

narrow therapeutic index (NTI) drugs, 

biostudies are required for all 

formulation changes except level 1 

changes. The comment asked whether 

this means that biostudies on any 

formulations differing by more than 

SUPAC level 1 for NTI drugs will not 

need to be submitted under the new 

rule. 

(Response) As discussed in section III 

of this document, the final rule does not 

use the SUPAC guidances to explain 

what the regulation means by ‘‘same 

drug product formulation.’’ Instead, the 

final rule defines ‘‘same drug product 

formulation’’ as the formulation of the 

drug product submitted for approval 

and any formulations that have minor 

differences in composition or method of 

manufacture from the formulation 

submitted for approval, but are similar 

enough to be relevant to the agency’s 

determination of bioequivalence. Under 

the final rule, all biostudies on the same 

drug product formulation must be 

submitted, regardless of the level of 

change under SUPAC. 

(Comment 15) One comment asked if 

a change in manufacturing site alone (a 

SUPAC level 3 change) will make the 

products at the original and new sites 

not the same drug product formulation 

even if the formulations and 

manufacturing processes were otherwise 

identical. 

(Response) No. Manufacturing site 

changes are not relevant to the 

definition of ‘‘same drug product 

formulation.’’ Studies conducted for 

products that are considered the ‘‘same 

drug product formulation’’ must be 

submitted whether the products are 

manufactured at the same or different 

manufacturing sites. 

(Comment 16) One comment stated 

that in some cases, it may be impossible 

to determine whether a particular older 

formulation on which a biostudy had 

been conducted falls within the scope of 

a SUPAC level 2 change from the 

approved or submitted formulation. For 

example, the older formulation has only 

single point dissolution data, precluding 

an f2 comparison; or multiple 

dissolution conditions were used, some 

of which yield f2 factors greater than 50 

and some less than 50. In such cases, 

how is an applicant to decide whether 

or not a biostudy on an older 

formulation needs to be submitted? 

(Response) If a biostudy was 

conducted on a product that is the same 

drug product formulation as defined in 

the final rule, it must be submitted. 

Dissolution testing is not a criterion for 

submission. 

(Comment 17) One comment stated 

that the language defining the ‘‘final 

formulation’’ may not capture all 

relevant bioequivalence data. For 

example, formulations containing an 

active ingredient with a particle size or 

morphic form that differs from the drug 

for which the ANDA is submitted would 

not be considered the ‘‘final 

formulation’’ of the drug. Thus, ANDA 

sponsors would not be required to 

submit bioequivalence data performed 

on these formulations, although such 

differences might affect the drug’s 

pharmacokinetic profile, safety, and 

effectiveness. 

(Response) FDA disagrees. The term 

‘‘same drug product formulation,’’ as 

defined in § 320.1(g) of this rule, 

includes formulations that differ in 

particle size and morphic form; thus, 

studies on such formulations would 

need to be submitted to FDA. 

Section 505(j)(2) of the act specifies 

that an ANDA must contain, among 

other things, information to show that 

the active ingredient in the generic drug 

product is the ‘‘same as’’ that of the 

RLD. Section 314.92(a)(1) of FDA 

regulations provides that the term 

‘‘same as’’ means, among other things, 

‘‘identical in active ingredient(s).’’ In 

the discussion of ‘‘sameness’’ of active 

ingredient(s) in the preamble to the final 

rule adopting the ANDA regulations, 

FDA specifically rejected a proposal that 

would have required an ANDA 

applicant to show that the active 

ingredient in its generic drug product 

and the active ingredient in the RLD 

‘‘exhibit the same physical and 

chemical characteristics, that no 

additional residues or impurities can 

result from the different manufacture or 

synthesis process and that the 

stereochemistry characteristics and 

solid state forms of the drug have not 

been altered’’ (57 FR 17950 at 17958, 

April 28, 1992). Differences in particle 

size and polymorphic forms of a drug 

substance are not differences in 

chemical structure, but only in internal 

solid-state structure. 

(Comment 18) One comment 

questioned whether FDA’s 

interpretation of § 314.81(b)(2)(vi) will 

require an applicant to submit studies 

performed by someone other than the 

applicant. For example, will the 

applicant be required to submit a study 

performed by a competitor (a ‘‘challenge 

study’’)? The comment noted that a 

complete or summary report may not be 

available to the applicant. Another 

comment asked if it will be necessary to 

conduct literature searches to find BE 

studies conducted by third parties. 

(Response) Section 314.81(b)(2)(vi) 

requires the submission of data from 

‘‘biopharmaceutic, pharmacokinetic, 

and clinical pharmacology studies 

* * * conducted by or otherwise 

obtained by the applicant.’’ This 

language clearly contemplates that if an 

applicant obtains the results of a study 

conducted by a third party, the results 

must be submitted in the annual report. 

It will not be necessary to conduct 

literature searches to find BE studies 

conducted by third parties. However, if 

an applicant obtains a complete or 

summary report, that report must be 

submitted. If the applicant obtains study 


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results in a form other than a complete 

or summary report, those results must 

be submitted in the annual report. 

(Comment 19) One comment asked 

whether the rule requires applicants to 

contact previous owners of the ANDA to 

obtain BE studies. 

(Response) Section 314.72 of FDA 

regulations concerns change in 

ownership of an application. Section 

314.72(a)(2)(iii) requires the new owner 

of an application either to submit to 

FDA a statement that the new owner has 

a complete copy of the approved 

application, or to request a copy of the 

application from FDA. In addition, FDA 

believes it is incumbent upon the 

purchaser of an ANDA to request from 

the owner all biostudies conducted on 

the drug product, even if they were not 

submitted to the ANDA. 

D. Summary and Complete Reports 

(Comment 20) One comment stated 

that FDA should clarify the appropriate 

content of complete and summary 

reports to ensure that FDA receives the 

information necessary to fully evaluate 

bioequivalence. 

(Response) FDA believes that 

applicants are aware of the appropriate 

content of a complete BE study report, 

as they are currently required to submit 

such a report for the study relied on for 

ANDA approval. The draft guidance on 

the submission of BE data, when 

available, will discuss the content of 

summary reports in greater detail. 

(Comment 21) One comment 

suggested that the submission of 

complete or summary reports of all 

other BE studies is unnecessary. Instead, 

the comment suggested, the product 

development report submitted as part of 

the ANDA may be the most appropriate 

place to put a small summary of the 

results of all bioequivalence studies 

performed on the product prior to 

ANDA submission. 

(Response) FDA disagrees with this 

comment. While FDA agrees that the 

product development report provides 

helpful information for the ANDA 

review process, a small summary of all 

bioequivalence studies in the product 

development report will be insufficient 

to satisfy the objectives of the rule. The 

agency is requesting complete or 

summary reports of the studies in order 

to be able to evaluate the study design 

and the resulting data. A small summary 

in the product development report will 

likely provide insufficient information 

for the agency to adequately evaluate 

why certain studies failed and others 

passed. 

(Comment 22) One comment stated 

that in many cases, an applicant may 

request only a summary report from a 

contract research organization (CRO) 

when a test product has failed to meet 

standard BE criteria. Therefore, if after 

the applicant submits the summary 

report, FDA requests a complete report, 

the applicant will need additional time 

and will incur additional costs for the 

CRO to generate a complete report. 

(Response) FDA appreciates that 

industry’s current practice may be to 

request only summary reports from 

CROs for failing studies. As noted in the 

preamble to the proposed rule, FDA 

foresees that in the majority of cases, a 

summary report will be sufficient to 

satisfy the rule. For example, in the case 

of a pilot study that was not powered to 

demonstrate bioequivalence, the agency 

does not foresee the need for a complete 

report. However, in light of the new 

submission requirements, the agency 

encourages applicants to consider 

whether there is a clear reason, such as 

failure to properly power the study, for 

a study’s failure to demonstrate 

bioequivalence. In cases where the 

reason the study failed is unclear, the 

applicant may want to consider 

requesting a complete report rather than 

a summary report from the CRO to assist 

the applicant in evaluating the study. 

E. FDA Criteria for Evaluating Studies 

In the preamble to the proposed rule, 

FDA listed the following four factors as 

examples of criteria it will use to 

evaluate BE studies when at least one 

study failed to demonstrate 

bioequivalence: (1) The statistical power 

of the studies, (2) minor differences in 

the formulation used in each study, (3) 

whether the product was administered 

consistently with the RLD’s labeling in 

every study, and/or (4) various other 

study design issues (68 FR 61640 at 

61641). 

(Comment 23) While recognizing that 

it is impossible for FDA to prospectively 

identify all potential issues, two 

comments requested clarification about 

the criteria FDA plans to use to: (1) 

Determine when to require the 

submission of a complete report of a 

study when a summary report has been 

previously submitted and (2) evaluate 

bioequivalence when at least one of the 

studies submitted by the applicant 

failed to demonstrate bioequivalence. In 

particular, the comments requested 

clarification about: (1) What additional 

data will be required to demonstrate to 

FDA that a drug is bioequivalent to the 

RLD, (2) whether FDA will be primarily 

concerned with the conditions under 

which the drug was administered or the 

rationale for the selection of certain 

types of study design characteristics, 

and (3) whether decisions about 

bioequivalence will be at the sole 

discretion of the reviewer. Another 

comment asked how conflicting results 

from two or more BE studies will be 

assessed. In particular, the comment 

asked if FDA will perform a metaanalysis on pooled studies. One 

comment expressed concern that if 

criteria were not provided, it could 

increase the costs associated with 

compliance with the rule. 

(Response) Generally, the criteria FDA 

reviewers will use to evaluate BE 

studies submitted in response to the 

rule are the same as the criteria they 

currently use to evaluate BE studies 

relied on for ANDA approval. Those 

criteria have been discussed in detail in 

various FDA guidances (available on the 

Internet at http://www.fda.gov/cder/ 

guidance/index.htm under 

Biopharmaceutics). When an applicant 

is submitting both passing and 

nonpassing studies, it should include its 

own analyses of the data and any 

potential explanations for nonpassing 

results. The decision tree used by the 

applicant will likely be similar to that 

used by FDA. While it is impossible to 

prospectively state which issues will be 

most relevant in any particular case, 

examples of likely questions that should 

be included in that decision tree are: 

• Was the study correctly powered? 

• Was the assay appropriate? 

• Was the formulation inappropriate, 

and if so, how has the formulation been 

changed? 

• Was the drug properly administered 

in the failing study? 

• Were there technical flaws in the 

way the study was conducted? 

The applicant’s explanations for 

failing results will likely be a reviewer’s 

first step in evaluating whether to 

request the submission of a complete 

report of any particular study. FDA 

anticipates that, in most cases, a 

summary report will be sufficient. The 

applicant’s explanations will also likely 

be a reviewer’s first step in evaluating 

how to weigh conflicting BE data. 

However, the reviewer will also 

undertake an independent scientific 

analysis of the study reports submitted. 

FDA will not rely on a meta-analysis of 

pooled studies. 

As the comments recognize, it is 

difficult to predict what type of 

information FDA may request to assure 

the agency that the drug is bioequivalent 

to the RLD. For example, FDA may 

choose to inspect the site where a 

submitted study was conducted, or FDA 

may request additional data. As 

discussed in the proposed rule, the 

responsibility to demonstrate that the 

ANDA product is bioequivalent to the 

RLD rests with the applicant. Therefore, 

it will ultimately be the applicant’s 


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responsibility to demonstrate why the 

nonpassing study or studies should not 

affect a determination that the ANDA 

product is bioequivalent to the RLD. 

(Comment 24) One comment stated 

that the four examples provided by FDA 

in the preamble to the proposed rule 

regarding the criteria for evaluating BE 

studies submitted (i.e., statistical power, 

minor differences in formulations, 

product administration, and other study 

design issues) are so critical that FDA 

should require the submission of all BE 

studies conducted on all formulations of 

the drug, rather than only requiring the 

submission of studies conducted on the 

‘‘same drug product formulation.’’ As an 

example, the comment stated that 

requiring the submission of all studies 

conducted on all formulations will 

allow FDA to identify situations where 

an applicant used increasingly larger 

sample sizes in their bioequivalence 

studies. Similarly, the comment notes 

that, by listing ‘‘minor differences in 

formulation’’ as an evaluation factor, 

FDA has acknowledged that formulation 

changes are relevant to analyzing 

bioequivalence. The comment states 

that this underscores the need to require 

the submission of passing and 

nonpassing studies on all formulations. 

(Response) As discussed in greater 

detail in response to comment 5, the 

decision to require the submission of BE 

studies conducted on the ‘‘same drug 

product formulation’’ as that submitted 

for approval was based on a need to 

balance competing concerns. Requiring 

the submission of all studies conducted 

on all formulations, regardless of their 

relationship to the formulation 

submitted for approval, will 

unnecessarily burden applicants and the 

review process without a resulting 

benefit. Therefore, FDA declines to 

adopt this suggestion. 

(Comment 25) Several comments 

requested information about the dispute 

resolution procedure that will be used if 

both passing and nonpassing studies are 

submitted. In particular, the comments 

highlighted the need for prompt 

resolution when the applicant and the 

agency disagree about how study results 

should be interpreted. The comments 

suggested that the dispute resolution 

procedure should be efficient to ensure 

a timely review process. One comment 

questioned whether a new 

administrative procedure is going to be 

developed for the resolution of potential 

disputes. 

(Response) FDA does not believe that 

a new procedure will be necessary to 

resolve any potential disputes arising 

from the submission of additional BE 

studies. If FDA has questions about an 

applicant’s explanation as to why a 

particular study failed or needs 

additional information to continue its 

review of the application, FDA will 

communicate with the applicant in the 

same manner as it does to resolve any 

other ANDA issue. FDA also notes there 

are dispute resolution procedures 

available to resolve differences between 

applicants and FDA. See 21 CFR 10.75 

and 21 CFR 314.103, as well as Center 

for Drug Evaluation and Research/ 

Center for Biologic Evaluation and 

Research guidance for industry entitled 

‘‘Formal Dispute Resolution: Appeals 

Above the Division Level.’’ 

F. Enforcement 

(Comment 26) One comment 

questioned how FDA intends to enforce 

and monitor compliance with the rule. 

In particular, the comment suggested 

that FDA should not rely on its 

preapproval inspection authority to 

monitor compliance with the rule. The 

comment expressed concern that 

investigators may not have the 

opportunity to look for failed studies 

during preapproval inspections or, at a 

minimum, may not be focused on 

looking for them. The comment also 

points out that Compliance Program 

Guidance Manual 7346.832 states that 

preapproval inspections are not 

mandated for narrow therapeutic range 

index drugs or the top 200 prescribed 

drugs. The comment suggested that 

rather than relying on investigators to 

examine studies, OGD scientists are the 

most appropriate personnel for 

determining whether study results affect 

FDA’s bioequivalence determination. 

(Response) As discussed in the 

response to comment 7, § 314.50(d)(3) of 

FDA regulations already requires NDA 

applicants to submit a description of all 

bioavailability and pharmacokinetic 

studies in humans performed by or on 

behalf of the applicant. That regulation 

does not contain a specific enforcement 

provision, and FDA believes it is not 

necessary to provide a specific 

enforcement mechanism for this final 

rule, which imposes similar duties on 

ANDA applicants. Moreover, in certain 

circumstances, noncompliance with this 

final rule could be considered a 

violation of 18 U.S.C. 1001, which 

prohibits knowingly and willfully 

falsifying or concealing a material fact 

from a branch of the Federal 

government. 

FDA agrees that it is not appropriate 

to rely solely on preapproval 

inspections of manufacturing facilities 

to look for BE studies. However, the 

agency has a variety of different 

enforcement and oversight mechanisms 

that we use to ensure compliance with 

data submission requirements. 

FDA agrees with the comment’s 

suggestion that OGD’s scientists are the 

most appropriate personnel to 

determine how BE study results should 

affect a bioequivalence determination. 

Any studies identified by FDA will be 

forwarded to OGD scientists for 

consideration. 

FDA’s initiative ‘‘Pharmaceutical 

cGMPs for the 21st Century’’ promotes 

a science and risk-based approach to 

product quality regulation. Compliance 

Program Guidance Manual 7346.832 

was revised to reflect the approach 

described in the 21st Century initiative. 

(Comment 27) In the preamble to the 

proposed rule, FDA stated that it may 

inspect sites where BE studies were 

conducted to determine whether there 

were technical flaws in the way they 

were performed (68 FR 61640 at 61641). 

Two comments questioned whether 

such inspections, particularly of sites in 

foreign countries, will slow down the 

ANDA review process. One comment 

focused on pilot studies performed by 

CROs in foreign countries and 

questioned whether the inspection of 

such sites could lead to approval delays. 

(Response) FDA appreciates the 

concern expressed in the comments. 

FDA’s inspection resources are limited, 

and the agency does not anticipate 

routinely inspecting every site for every 

BE study submitted. The agency may, 

however, inspect any study sites it 

determines appropriate in order to 

assess whether a generic drug is 

bioequivalent to its RLD. 

(Comment 28) One comment stated 

that FDA should not rely on field 

investigators to discover the existence of 

BE studies. 

(Response) FDA expects that most, if 

not all, applicants will comply with this 

final rule and submit the appropriate BE 

studies of which they are aware. The 

agency will not comment on its methods 

of investigation with respect to 

enforcement of the final rule. However, 

the agency agrees that field investigators 

should not be the only source for 

discovering the existence of BE studies. 

G. Miscellaneous 

(Comment 29) One comment asked 

what event determines the date the 

study was conducted for purposes of 

deciding whether a biostudy needs to be 

submitted. 

(Response) The event that should be 

considered to determine whether a BE 

study must be submitted under this 

regulation is the date the first dose in 

the study was administered. This date 

should be readily identifiable by the 

applicant and FDA. 

(Comment 30) Two comments 

questioned whether it was necessary for 


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applicants to retain samples for studies 

other than the BE study relied on for 

approval. 

(Response) It is not necessary to retain 

such samples. Applicants are only 

required to retain samples for the BE 

study relied on for approval. 

(Comment 31) Two comments asked 

whether FDA will apply the Freedom of 

Information Act (FOIA) to failed BE 

studies submitted to FDA under the 

rule. The comments expressed concern 

that if such studies are made available 

to the public, confidence in generic 

drugs could be undermined, and 

companies may use this information to 

disparage other companies and their 

products. 

(Response) Information submitted on 

passing and nonpassing bioequivalence 

studies will be available for public 

release after approval of the application 

or supplemental application, consistent 

with FDA’s disclosure regulations in 21 

CFR part 20 and § 314.430, and with the 

FOIA. While FDA appreciates the 

concern expressed in the comment, the 

agency notes that in addition to the 

study results, the applicant’s 

explanations concerning failed studies 

and the agency’s determination and the 

basis for its determination of 

bioequivalence will also be publicly 

available. We believe the availability of 

this information should assuage the 

comments’ concerns. 

H. Economics 

(Comment 32) Two comments 

suggested that FDA’s estimate that the 

rule will result in a 10 percent increase 

in the number of BE studies submitted 

to the agency was too conservative. One 

comment stated that, based on its 

informal survey of generic drug 

companies, the number will be larger. 

The other comment noted that, because 

the number of ANDA applications and 

correspondence documents has risen in 

recent years, the 10-percent estimate is 

not reflective of recent trends. 

(Response) FDA recognizes that the 

number of ANDAs and related 

submissions has increased in recent 

years. However we are not able to 

accurately predict the number or pattern 

of future submissions. Due to this 

uncertainty, the agency assumed, for the 

reasons discussed in the preamble to the 

proposed rule, that the number of BE 

studies submitted annually will increase 

by approximately 10 percent. This 

estimate is based on information 

suggesting that approximately 20 

percent of all BE studies conducted 

produce results that do not meet 

bioequivalence limits, and that 

approximately 50 percent of these 

studies are conducted on formulations 

that are not submitted for approval. The 

comments appear to acknowledge the 

uncertainty of trying to predict the exact 

increase in the number of studies 

submitted, because neither comment 

suggests an alternative number to FDA’s 

estimate of 10 percent. Therefore, FDA 

continues to estimate that the increase 

in the number of studies submitted will 

be approximately 10 percent. The 

economic analysis in the proposed rule, 

however, relied on year 2000 data for 

the number of submissions received by 

the agency. To ensure that the economic 

analysis reflects current trends, FDA has 

revised the economic analysis (section 

VIII of this document) to reflect the most 

current data available on the number of 

submissions received by the agency. 

(Comment 33) One comment 

suggested that the compliance 

requirements and cost analysis in the 

preamble to the proposed rule were 

flawed because they failed to consider 

costs in addition to staff time. The 

comment noted that companies often 

employ CROs to conduct activities 

related to the design, initiation, 

conduct, and report generation of BE 

studies. The comment suggested that 

companies may routinely request 

complete reports from CROs, as opposed 

to summary reports, in the event FDA 

requests a complete report. The 

comment also questioned FDA’s 

estimate that summary reports will be 

required approximately 80 percent of 

the time and complete reports will be 

required approximately 20 percent of 

the time. 

(Response) FDA acknowledges that it 

is impossible to predict precisely how 

often a complete report will be 

requested in the future. However, the 

agency’s estimate that a complete report 

will be required only 20 percent of the 

time was based on its belief that, in 

most cases, the reason a study failed 

will be evident from the information 

provided in the summary report and the 

applicant’s explanations. FDA does not 

believe that the use of a CRO to conduct 

a study affects its economic analysis. 

When a company contracts with a CRO, 

it may stipulate the reporting format for 

the study. FDA does not believe that 

stipulating a report format for BE 

studies in accordance with this rule will 

create a significant burden for any 

affected entity. 

(Comment 34) One comment noted 

that FDA cited its desire to increase the 

agency’s knowledge and understanding 

of bioequivalence as an objective of the 

rule. The comment questioned whether 

the costs associated with the submission 

of ‘‘all other bioequivalence studies,’’ 

and the resolution of why various 

studies failed, were justified by this 

objective. 

(Response) As discussed in greater 

detail in section VIII of this document, 

FDA believes the costs of the rule are 

justified by the multiple objectives we 

hope to achieve through this final rule. 

The objective cited by the comment is 

a secondary objective of the rule. In 

addition to increasing FDA’s 

knowledge, the submission of all BE 

studies is necessary because the data 

contained in passing and nonpassing BE 

studies provide information that can be 

important to FDA’s assessment of the 

bioequivalence for a specific product. 

V. Legal Authority 

Section 701(a) of the act (21 U.S.C. 

371(a)) authorizes FDA to issue 

regulations for the efficient enforcement 

of the act. Under section 505(j)(2)(A)(iv) 

of the act, an ANDA applicant must 

submit ‘‘information to show that the 

new drug is bioequivalent to the 

[reference] listed drug * * *.’’ If this 

requirement is not met because 

information submitted in the 

application is insufficient to show that 

the drug is bioequivalent to the listed 

drug referred to in the application, FDA 

may deny approval of an ANDA (section 

505(j)(4)(F) of the act; § 314.127(a)(6)(i) 

and (a)(6)(ii)). FDA believes that an 

application may not be complete if a BE 

study that is conducted by an applicant 

on the same drug product formulation is 

not submitted for review, because the 

agency is being asked to make a 

bioequivalence determination based on 

a review of only part of the available 

bioequivalence data. The agency’s 

experience with additional 

bioequivalence data on the same drug 

product formulation has shown that 

such data can be important, and even 

critical, to the agency’s bioequivalence 

determination. 

Requiring the reporting of all BE 

studies is consistent with the act’s 

requirement that applications must not 

contain untrue statements of material 

fact (section 505(j)(4)(K) of the act; 

§ 314.127(a)(13)). FDA believes that 

failure to report all BE studies 

conducted on the same drug product 

formulation as that submitted for 

approval in an ANDA, amendment, or 

supplement may constitute selective 

reporting of a material fact, which can 

result in withdrawal of approval of an 

application under § 314.150(b)(6). 

Selective reporting refers to reports that 

contain certain passing results only. It 

may not include nonpassing results 

and/or the scientific justification for 

rejecting the nonpassing data (see FDA’s 

notice describing selective reporting of 


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stability tests (60 FR 32982 at 32983, 

June 26, 1995)). 

VI. Effective Date 

Revised §§ 314.94(a)(7)(i), 

314.96(a)(1), 320.1(g), 320.21 (section 

heading), and 320.21(b)(1), as well as 

§ 320.21(c) (which references the 

requirements of § 320.21(b)(1)) and 

§ 314.94(a)(7)(ii) (as interpreted in 

section III of this document), apply to 

ANDAs, amendments, or supplements 

submitted on or after the effective date. 

Thus, with respect to ANDAs, 

amendments, or supplements submitted 

prior to the effective date, applicants are 

not required to report additional BE 

studies that were conducted in 

conjunction with their applications. 

However, when an ANDA has been 

approved or submitted prior to the 

effective date of the final rule, and a 

supplement or amendment to the ANDA 

containing a BE study or studies is 

submitted on or after the effective date, 

the applicant is required under 

§§ 314.96(a)(1) and 320.21(b)(1), as well 

as § 320.21(c) (which refers to the 

requirements of § 320.21(b)(1)), to 

submit all BE studies, both passing and 

nonpassing, conducted in conjunction 

with the supplement or amendment. In 

addition, on and after the effective date, 

all applicants with approved ANDAs, 

including ANDAs that were approved or 

submitted for approval prior to the 

effective date, are required to comply 

with § 314.81(b)(2)(vi), as interpreted by 

FDA in section III of this document. As 

stated in response to comment 6, in the 

event that a postmarketing study of an 

approved and marketed drug fails to 

demonstrate bioequivalence, it would be 

particularly important for the agency 

and the applicant to examine the reason 

for the failure. Therefore, any annual 

report submitted on or after the effective 

date by an applicant with an approved 

ANDA must include reports of all BE 

studies on the approved drug product, 

both passing and nonpassing, conducted 

or obtained by the applicant during the 

annual reporting period, including those 

studies conducted before the effective 

date but within the applicant’s annual 

reporting period. 

VII. Environmental Impact 

The agency has determined under 21 

CFR 25.30(h) that this action is of a type 

that does not individually or 

cumulatively have a significant effect on 

the human environment. Therefore, 

neither an environmental assessment 

nor an environmental impact statement 

is required. 

VIII. Analysis of Economic Impacts 

FDA has examined the impacts of the 

final rule under Executive Order 12866 

and the Regulatory Flexibility Act (5 

U.S.C. 601–612), and the Unfunded 

Mandates Reform Act of 1995 (Public 

Law 104–4). Executive Order 12866 

directs agencies to assess all costs and 

benefits of available regulatory 

alternatives and, when regulation is 

necessary, to select regulatory 

approaches that maximize net benefits 

(including potential economic, 

environmental, public health and safety, 

and other advantages; distributive 

impacts; and equity). The agency 

believes that this final rule is not a 

significant regulatory action under the 

Executive order. 

The Regulatory Flexibility Act 

requires agencies to analyze regulatory 

options that would minimize any 

significant impact of a rule on small 

entities. Based on our economic analysis 

and review of comments submitted in 

response to the proposed rule, the 

agency certifies that the final rule will 

not have a significant economic impact 

on a substantial number of small 

entities. 

Section 202(a) of the Unfunded 

Mandates Reform Act of 1995 requires 

that agencies prepare a written 

statement, which includes an 

assessment of anticipated costs and 

benefits, before proposing ‘‘any rule that 

includes any Federal mandate that may 

result in the expenditure by State, local, 

and tribal governments, in the aggregate, 

or by the private sector, of $100,000,000 

or more (adjusted annually for inflation) 

in any one year.’’ The current threshold 

after adjustment for inflation is $130 

million, using the most current (2007) 

Implicit Price Deflator for the Gross 

Domestic Product. FDA does not expect 

this final rule to result in any 1-year 

expenditure that would meet or exceed 

this amount. 

A. Background 

Under current regulations, ANDA 

applicants are required to submit 

information demonstrating that a 

generic product is bioequivalent to an 

RLD. In the past, firms have submitted 

only the results of those BE studies that 

demonstrate that the rate and extent of 

absorption of the test product meets 

bioequivalence limits. Firms have not 

typically submitted the results of any 

additional BE studies that were 

conducted on the same product 

formulation submitted for approval. The 

agency now believes that data and 

information from additional BE studies, 

both passing and nonpassing, are 

important for determining whether the 

proposed formulation is bioequivalent 

to the RLD. Therefore, this final rule 

requires ANDA applicants to submit the 

results of all BE studies, passing and 

nonpassing, on the same drug product 

formulation submitted for approval 

under an ANDA, amendment or 

supplement. 

As discussed in response to comment 

6, the agency also believes that it is 

important to clarify that the 

responsibility to submit the results of all 

BE studies, passing and nonpassing, 

continues after approval under the 

annual report submission requirements. 

However, the agency believes that it will 

be highly unusual for an ANDA 

applicant to conduct a postmarketing BE 

study. In particular, the agency believes 

that an applicant will rarely, if ever, 

conduct a postmarketing BE study other 

than one required for an ANDA 

supplement. 

B. Affected Entities 

This final rule will affect 

establishments that submit ANDAs 

containing BE studies. FDA does not 

know the precise number of entities, 

either large or small, that will submit 

ANDAs in the future. In the year 2006, 

there were 511 BE studies submitted by 

177 applicants in 622 original ANDAs, 

amendments, and supplements. FDA 

estimates that this final rule will result 

in a 10-percent increase in the total 

number of BE studies submitted 

annually, or 51 (511 x 0.10) additional 

studies. As stated in the proposed rule, 

this estimate is based on information 

suggesting that approximately 20 

percent of all BE studies conducted 

produce results that do not meet 

bioequivalence limits, and that 

approximately 50 percent of these 

studies are conducted on formulations 

that are not submitted for approval. 

Because we did not receive any 

comments suggesting specific 

alternative figures that would be more 

appropriate, we continue to rely on 

these assumptions for the economic 

analysis of this final rule. 

C. Compliance Requirements and Costs 

The main cost of complying with this 

final rule will be staff time. The analysis 

in the proposed rule assumed a 

weighted average wage rate of $40 per 

hour. The current, comparable figure for 

2006 assumed in this analysis is $47 per 

hour (Ref. 1). FDA estimates it will 

require approximately 120 hours of staff 

time to prepare and submit each 

additional complete BE study report, 

and approximately 60 hours of staff time 

for each additional BE study summary 

report. The agency believes that a 

complete report will be required 


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approximately 20 percent of the time, 

while a summary will suffice 

approximately 80 percent of the time. 

Based on a weighted-average 

calculation using the information 

presented above, the submission of each 

additional BE study is expected to cost 

$3,384 ([120 x $47 x 0.2] + [60 x $47 x 

0.8]). Thus, the overall impact on the 

industry of reporting an additional 51 

BE studies per year will be about 

$173,000 ($3,384 x 51 = $172,584). 

Assuming it equally likely that each of 

the 51 additional BE studies will be 

conducted by any of the 177 applicants, 

a binomial distribution can be used to 

predict how many firms will submit 

additional studies. Based on this 

distribution, 38 firms will incur costs of 

$3,384 for 1 additional BE study, 6 firms 

will incur costs of $6,768 (2 x $3,384) 

for 2 additional studies, and 1 firm will 

incur costs of $10,152 (3 x $3,384) for 

3 additional studies (the total number of 

studies in the calculation does not equal 

51 because of rounding). Thus, the 

maximum expected annual cost burden 

associated with this final rule for any 

one firm is $10,152. Approximately 75 

percent (132 of 177, or 74.6 percent) of 

all firms are expected to incur no 

additional annual costs under the final 

rule. 

D. Impact on Small Entities 

FDA recognizes that some of the 

establishments required to submit 

additional BE study reports under this 

final rule will be small entities with 

limited resources. In the proposed rule, 

the agency acknowledged the 

uncertainty of its estimates with respect 

to the number of additional BE studies 

that will be submitted, their distribution 

among large and small entities, and the 

number of small entities affected. We 

also requested detailed comments on 

these important issues. After revising 

our Initial Regulatory Flexibility 

Analysis in response to the public 

comments received, FDA has 

determined that this final rule will not 

have a significant economic impact on 

a substantial number of small entities. 

FDA also recognizes that requiring 

submission of all BE study results may 

result in a longer total application 

review time if these additional BE study 

results suggest that a generic product is 

not bioequivalent to the RLD. In these 

situations, firms will be required to 

submit additional data that demonstrate 

bioequivalence in order to obtain 

marketing approval. Marketing approval 

may be denied if evidence from the 

additional BE studies fails to establish 

bioequivalence. The agency does not 

know how frequently these situations 

might occur. 

According to standards established by 

the Small Business Administration, a 

small pharmaceutical preparation 

manufacturer (North American Industry 

Classification System (NAICS) Code 

325412) employs fewer than 750 

employees (Ref. 2). An FDA review of 

ANDA records submitted during the 3- 

year period from October 1996 to 

September 1999 found that 32 percent 

of the applications (322 of 1,007) were 

from small entities, and that 39 percent 

of ANDA applicants (64 of 164) were 

small entities. (Resource limitations 

prevented the agency from being able to 

perform a similar, labor intensive 

manual search of similar records for a 

more recent time period.) Thus, the 

majority of ANDAs are not submitted by 

small entities. Assuming these 

proportions continue to hold, there will 

be about 69 small entities (0.39 x 177) 

submitting ANDAs annually. FDA also 

assumes that this group of small entities 

will submit 16 of the additional 51 BE 

studies (0.10 x 0.32 x 511) per year. 

Assuming it is equally likely that each 

of the 16 additional BE studies will be 

reported by any of the 69 small entities, 

a binomial distribution can be used to 

predict how many of these firms will 

submit additional studies. Based on this 

distribution, 13 small entities will incur 

costs of $3,384 for one additional BE 

study, and two firms will incur costs of 

$6,768 (2 x $3,384) for two additional 

BE studies. Thus, the maximum 

expected burden of this final rule for 

any one small entity is $6,768. Nearly 

80 percent (55 of 69, or 79.5 percent) of 

all small entities are expected to incur 

no additional annual costs under the 

final rule. 

In the proposed rule, FDA relied on 

information indicating that the cost of 

preparing and submitting an ANDA was 

between $300,000 and $1 million (68 FR 

61640 at 61645). Because we were 

unable to identify any similar, more 

recent cost estimates, we have adjusted 

these earlier figures for inflation to 

estimate the economic impact of this 

final rule. Our inflation adjustment was 

made based on percent changes in the 

Biomedical Research and Development 

Price Index (BRDPI) (Ref. 3). Based on 

these inflation adjustments, FDA 

estimates that the cost to prepare and 

submit an ANDA is now between 

$361,500 and $1.24 million. The details 

of our inflation adjustment calculations 

are summarized in table 1 of this 

document. 

TABLE 1.—DETAILS OF INFLATION ADJUSTMENT

ANDA Cost Estimate Base Year Percent Change in the BRDPI 

from Base Year 

Inflation Adjusted ANDA Cost 

Estimate 

$300,000 2001 20.5% $361,500 

$1 million 2000 24.4% $1.24 million 

Based on this information, the 

maximum expected cost burden of this 

final rule on any one firm will be 

between 0.8 percent ($10,152 for three 

additional BE studies / $1.24 million) 

and 2.8 percent ($10,152 / $361,500) of 

the total cost of preparing and 

submitting an ANDA. The maximum 

expected cost burden for any one small 

entity will be between 0.6 percent 

($6,768 for two additional BE studies / 

$1.24 million) and 1.9 percent ($6,768 / 

$361,500) of the total cost of preparing 

and submitting an ANDA. 

A year 2000 survey of 26 public 

generic drug companies revealed 15 

firms with fewer than 750 employees (as 

described in the proposed rule, 68 FR 

61640 at 61645). Because FDA was 

unable to identify a similar, more recent 

survey available in the public domain, 

we have relied on this information to 

estimate the impact of the final rule on 

small entities. The 15 small entities 

identified in the survey had an average 

of 331 employees and average annual 

revenues of $115 million. The 

maximum expected burden of this final 

rule for any one of these small entities 

is therefore expected to be only 0.006 

percent ($6,768 / $115 million) of 

average annual revenues. The agency 

believes this cost could be recovered 

through drug sales after marketing 

approval. 

In recognition of the potential 

economic impact on small entities, the 

agency has structured the rule to 

minimize the reporting burden. For 

example, the agency believes that 

summary reports of additional BE 

studies will suffice 80 percent of the 


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time, provided that complete results are 

available to FDA upon request. The 

agency believes that a summary report 

will require only 60 hours of staff time 

per BE study, or half the time and 

expense required to prepare and submit 

a complete report. This provision 

should prove particularly beneficial for 

small entities. 

Furthermore, no specific educational 

or technical skills are required to 

complete and submit the additional BE 

study reports. Trained and qualified 

employees of an establishment who are 

involved in normal operations generally 

complete similar activities. Also, FDA 

has reviewed related Federal rules and 

has not identified any rules that 

duplicate, overlap, or conflict with the 

final rule. 

FDA has evaluated only two 

regulatory options: (1) Continuing the 

current practice of requiring the 

submission of only pivotal BE study 

results, or (2) requiring the submission 

of results from all BE studies conducted 

by an applicant on a final drug product 

formulation. Under the first option, 

firms will incur no additional reporting 

costs, although some firms might 

experience significant costs if their 

product was initially approved and 

subsequently recalled, or had approval 

withdrawn because the product is found 

not to be bioequivalent to the RLD. The 

agency believes that the second option, 

requiring that results from all BE studies 

conducted on the final drug product 

formulation be submitted for approval, 

is important for assessing 

bioequivalence. The final rule requires 

reporting of all BE studies, but also 

permits summary reports for BE studies 

other than those the applicant relies on 

for approval, except where full reports 

are specifically requested by the agency. 

The agency believes that the final rule 

therefore addresses the perceived 

regulatory need in the least intrusive 

and most cost effective way. 

E. Benefits of the Final Rule 

The final rule will generate economic 

benefits both for individuals and for 

society as a whole, to the extent that the 

reporting of data from all BE studies on 

the same drug product formulation as 

that submitted for approval prevents 

product discontinuation and adverse 

health effects. Also, the data from 

additional BE studies may provide 

valuable scientific information, thereby 

increasing the agency’s understanding 

of bioequivalence and generic drug 

development issues, and improving the 

drug approval process. Therefore, this 

final rule will permit FDA to make more 

informed BE determinations in the 

future. 

IX. Paperwork Reduction Act of 1995 

This final rule contains information 

collection requirements that are subject 

to review by the Office of Management 

and Budget (OMB) under the Paperwork 

Reduction Act of 1995 (44 U.S.C. 3501– 

3520). The title, description, and 

respondent description of the 

information collection requirements are 

shown below with an estimate of the 

annual reporting burden. Included in 

this estimate is the time for reviewing 

instructions, searching existing data 

sources, gathering and maintaining the 

data needed, and completing and 

reviewing each collection of 

information. 

Title: Requirements for Submission of 

Bioequivalence Data; Final Rule 

Description: FDA is amending the 

requirements for certain ANDAs, ANDA 

amendments, and ANDA supplements 

submitted under §§ 314.94, 314.96, and 

314.97. Specifically, FDA is amending 

§§ 314.94(a)(7)(i), 314.96(a)(1), and 

320.21(b)(1), as well as modifying the 

requirements of § 320.21(c) (which 

refers to § 320.21(b)(1)), to require an 

ANDA applicant to submit information 

from all BE studies, both passing and 

nonpassing, conducted by the applicant 

on the same drug product formulation 

as that submitted for approval under an 

ANDA, amendment, or supplement. 

In addition, FDA is announcing its 

intention to interpret § 314.94(a)(7)(ii) as 

requiring that ANDA applicants who 

submit ANDAs under a petition 

approved under § 314.93 submit 

information on all bioavailability or BE 

studies conducted on the same drug 

product formulation submitted for 

approval. 

FDA is also clarifying through this 

rulemaking that it intends to interpret 

§ 314.81(b)(2)(vi) as requiring the 

submission of postmarketing reports of 

all BE studies conducted or otherwise 

obtained by ANDA applicants in the 

applicant’s annual report. However, 

FDA believes an applicant will rarely, if 

ever, conduct a postmarketing BE study, 

other than one required for an ANDA 

supplement. 

Description of Respondents: Persons 

and businesses, including small 

businesses and manufacturers. 

Burden Estimate: Table 2 of this 

document provides an estimate of the 

annual reporting burden under the rule. 

The rule will affect establishments 

that submit ANDAs. FDA does not know 

the precise number of entities, either 

large or small, that will submit ANDAs 

in the future. In the year 2006, 177 

applicants submitted 511 BE studies in 

622 original ANDAs, amendments, and 

supplements. FDA estimates that this 

rule will result in a 10-percent increase 

in the number of BE studies submitted 

annually, or 51 (511 x 0.10) additional 

studies. This estimate is based on the 

assumptions that approximately 20 

percent of all BE studies conducted 

produce results that do not meet 

bioequivalence limits, and that about 

half of these studies are conducted on 

formulations that are not submitted for 

approval. 

FDA estimates it will require 

approximately 120 hours of staff time to 

prepare and submit each additional 

complete BE study report, and 

approximately 60 hours of staff time for 

each additional BE summary report. The 

agency believes that a complete report 

will be required approximately 20 

percent of the time, while a summary 

will suffice approximately 80 percent of 

the time. Based on a weighted-average 

calculation using the information 

presented above, the submission of each 

additional BE study is expected to take 

72 hours of staff time ([120 x 0.2] + [60 

x 0.8]). 

In table 2 of this document, FDA has 

estimated the reporting burden 

associated with each section of the rule. 

FDA believes that the vast majority of 

additional BE studies will be reported in 

ANDAs (submitted under § 314.94) 

rather than supplements (submitted 

under § 314.97), because it is unlikely 

that an ANDA holder will conduct BE 

studies with a drug after the drug has 

been approved. Moreover, drugs 

approved under an ANDA prior to the 

effective date of the final rule will only 

be required to report additional BE 

studies conducted after the effective 

date, which should not result in the 

submission of many BE study reports in 

supplements. With respect to the 

reporting of additional BE studies in 

amendments (submitted under 

§ 314.96), this should also account for a 

small number of reports, because most 

BE studies will be conducted on a drug 

prior to the submission of the ANDA 

and will be reported in the ANDA itself. 


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Federal Register / Vol. 74, No. 11 / Friday, January 16, 2009 / Rules and Regulations 2861 

TABLE 2.—ESTIMATED ANNUAL REPORTING BURDEN1

21 CFR 

Section 

No. of 

Respondents 

Annual Frequency 

per Response 

Total Annual 

Responses 

Hours per 

Response Total Hours 

314.94(a)(7) 49 1 49 72 3,528 

314.96(a)(1) 1 1 1 72 72 

314.97 1 1 1 72 72 

Total 3,672 

1There are no capital costs or operating and maintenance costs associated with this collection of information. 

The information provisions of this 

final rule have been submitted to the 

Office of Management and Budget 

(OMB) for review, as required by section 

3507(d) of the Paperwork Reduction Act 

of 1995. The requirements were 

approved and assigned OMB control 

number 0910–0630. This approval 

expires November 30, 2011. An agency 

may not conduct or sponsor, and a 

person is not required to respond to, a 

collection of information unless it 

displays a currently valid OMB control 

number. 

X. Federalism 

FDA has analyzed this final rule in 

accordance with the principles set forth 

in Executive Order 13132. FDA has 

determined that the rule does not 

contain policies that have substantial 

direct effects on the States, on the 

relationship between the National 

Government and the States, or on the 

distribution of power and 

responsibilities among the various 

levels of government. Accordingly, the 

agency has concluded that the rule does 

not contain policies that have 

federalism implications as defined in 

the Executive order and, consequently, 

a federalism summary impact statement 

is not required. 

XI. References 

The following references have been 

placed on display in the Division of 

Dockets Management (HFA–305), Food 

and Drug Administration, 5630 Fishers 

Lane, rm. 1061, Rockville, MD 20857, 

and may be seen by interested persons 

between 9 a.m. and 4 p.m., Monday 

through Friday. (FDA has verified the 

Web site addresses, but FDA is not 

responsible for any subsequent changes 

to the Web sites after this document 

publishes in the Federal Register.) 

1. U.S. Department of Labor, Bureau of 

Labor Statistics, Table 11. Employer costs per 

hour worked for employee compensation and 

costs as a percent of total compensation: 

Private industry workers, by occupational 

group and full-time and part-time status, 

December 2006, Management, professional, 

and related series. 

2. U.S. Small Business Administration, 

Office of Size Standards, Table of Size 

Standards, available online at http:// 

www.sba.gov/idc/groups/public/documents/ 

sba_homepage/serv_sstd_tablepdf.pdf. 

3. National Institutes of Health, Office of 

Science Policy Analysis, Biomedical 

Research and Development Price Index 

(BRDPI), available online at http:// 

officeofbudget.od.nih.gov/PDF/ 

BRDPI_2_5_07.pdf (viewed April 20, 2007). 

List of Subjects 

21 CFR Part 314 

Administrative practice and 

procedure, Confidential business 

information, Drugs, Reporting and 

recordkeeping requirements. 

21 CFR Part 320 

Drugs, Reporting and recordkeeping 

requirements. 

■ Therefore, under the Federal Food, 

Drug, and Cosmetic Act and under 

authority delegated to the Commissioner 

of Food and Drugs, 21 CFR parts 314 

and 320 are amended as follows: 

PART 314—APPLICATIONS FOR FDA 

APPROVAL TO MARKET A NEW DRUG 

■ 1. The authority citation for 21 CFR 

part 314 continues to read as follows: 

Authority: 21 U.S.C. 321, 331, 351, 352, 

353, 355, 356, 356a, 356b, 356c, 371, 374, 

379e. 

■ 2. Amend § 314.94 by revising 

paragraph (a)(7)(i) to read as follows: 

§ 314.94 Content and format of an 

abbreviated application. 

(a) * * * 

(7) Bioequivalence. (i) Information 

that shows that the drug product is 

bioequivalent to the reference listed 

drug upon which the applicant relies. A 

complete study report must be 

submitted for the bioequivalence study 

upon which the applicant relies for 

approval. For all other bioequivalence 

studies conducted on the same drug 

product formulation as defined in 

§ 320.1(g) of this chapter, the applicant 

must submit either a complete or 

summary report. If a summary report of 

a bioequivalence study is submitted and 

FDA determines that there may be 

bioequivalence issues or concerns with 

the product, FDA may require that the 

applicant submit a complete report of 

the bioequivalence study to FDA; or 

* * * * * 

■ 3. Amend § 314.96 by adding four 

sentences at the end of paragraph (a)(1) 

to read as follows: 

§ 314.96 Amendments to an unapproved 

abbreviated application. 

(a) * * * 

(1) * * * Amendments containing 

bioequivalence studies must contain 

reports of all bioequivalence studies 

conducted by the applicant on the same 

drug product formulation, unless the 

information has previously been 

submitted to FDA in the abbreviated 

new drug application. A complete study 

report must be submitted for any 

bioequivalence study upon which the 

applicant relies for approval. For all 

other bioequivalence studies conducted 

on the same drug product formulation 

as defined in § 320.1(g) of this chapter, 

the applicant must submit either a 

complete or summary report. If a 

summary report of a bioequivalence 

study is submitted and FDA determines 

that there may be bioequivalence issues 

or concerns with the product, FDA may 

require that the applicant submit a 

complete report of the bioequivalence 

study to FDA. 

* * * * * 

PART 320—BIOAVAILABILITY AND 

BIOEQUIVALENCE REQUIREMENTS 

■ 4. The authority citation for 21 CFR 

part 320 continues to read as follows: 

Authority: 21 U.S.C. 321, 351, 352, 355, 

371. 

■ 5. Amend § 320.1 by adding paragraph 

(g) to read as follows: 

§ 320.1 Definitions. 

* * * * * 

(g) Same drug product formulation 

means the formulation of the drug 

product submitted for approval and any 

formulations that have minor 

differences in composition or method of 


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2862 Federal Register / Vol. 74, No. 11 / Friday, January 16, 2009 / Rules and Regulations 

manufacture from the formulation 

submitted for approval, but are similar 

enough to be relevant to the agency’s 

determination of bioequivalence. 

■ 6. Amend § 320.21 by revising the 

section heading and paragraph (b)(1) to 

read as follows: 

§ 320.21 Requirements for submission of 

bioavailability and bioequivalence data. 

* * * * * 

(b) * * * 

(1) Evidence demonstrating that the 

drug product that is the subject of the 

abbreviated new drug application is 

bioequivalent to the reference listed 

drug (defined in § 314.3(b) of this 

chapter). A complete study report must 

be submitted for the bioequivalence 

study upon which the applicant relies 

for approval. For all other 

bioequivalence studies conducted on 

the same drug product formulation, the 

applicant must submit either a complete 

or summary report. If a summary report 

of a bioequivalence study is submitted 

and FDA determines that there may be 

bioequivalence issues or concerns with 

the product, FDA may require that the 

applicant submit a complete report of 

the bioequivalence study to FDA; or 

* * * * * 

Dated: January 13, 2009. 

Jeffrey Shuren, 

Associate Commissioner for Policy and 

Planning. 

[FR Doc. E9–884 Filed 1–15–09; 8:45 am] 

BILLING CODE 4160–01–S 

DEPARTMENT OF LABOR 

Wage and Hour Division 

29 CFR Parts 3 and 5 

Protecting the Privacy of Workers: 

Labor Standards Provisions Applicable 

to Contracts Covering Federally 

Financed and Assisted Construction, 

Effectiveness of Information Collection 

Requirements 

AGENCY: Department of Labor, 

Employment Standards Administration, 

Wage and Hour Division. 

ACTION: OMB approval of information 

collection requirements. 

SUMMARY: The Office of Management 

and Budget (OMB) has approved under 

the Paperwork Reduction Act (PRA) 

information collection requirements 

contained in recently revised final 

regulations published by the 

Department of Labor in the Federal 

Register on December 19, 2008. The 

PRA requires this notice to set forth the 

effectiveness of information collection 

requirements contained in a final rule. 

DATES: The amendments to §§ 3.3(b) and 

5.5(a)(3)(ii)(A) and (B)(1) published in 

the Federal Register on December 19, 

2008 (73 FR 77504) have been approved 

by OMB and are effective January 18, 

2009. 

ADDRESSES: Written comments 

regarding the burden-hour estimates or 

other aspects of the information 

collection requirements contained in 29 

CFR parts 3 and 5 may be submitted to: 

Administrator, Wage and Hour Division, 

Room S3502, 200 Constitution Avenue, 

NW., Washington DC 20210. 

FOR FURTHER INFORMATION CONTACT: 

Richard M. Brennan, Director, Division 

of Interpretations and Regulatory 

Analysis, Wage and Hour Division, 

Employment Standards Administration, 

U.S. Department of Labor, Room S– 

3506, 200 Constitution Avenue, NW., 

Washington, DC 20210; telephone: (202) 

693–0051. 

Questions of interpretation and/or 

enforcement of regulations referenced in 

this notice may be directed to the 

nearest Wage and Hour Division (WHD) 

District Office. Locate the nearest office 

by calling the WHD toll-free help line at 

(866) 4US–WAGE ((866) 487–9243) 

between 8 a.m. and 5 p.m. in your local 

time zone, or log onto the WHD’s Web 

site for a nationwide listing of WHD 

District and Area Offices at: http:// 

www.dol.gov/esa/whd/america2.htm. 

This notice is available through the 

printed Federal Register and 

electronically via the http:// 

www.gpoaccess.gov/fr/index.html Web 

site. 

Copies of this notice may be obtained 

in alternative formats (Large Print, 

Braille, Audio Tape or Disc), upon 

request, by calling (202) 693–0023. 

TTY/TDD callers may dial toll-free (877) 

889–5627 to obtain information or 

request materials in alternative formats. 

SUPPLEMENTARY INFORMATION: On 

December 30, 2008, the Office of 

Management and Budget (OMB) 

approved under the PRA the 

Department of Labor’s information 

collection request for requirements in 29 

CFR 5.5(a)(3)(ii)(A), and 

5.5(a)(3)(ii)(B)(1), as published in the 

Federal Register on December 19, 2008. 

See 73 FR 77504. The current expiration 

date for OMB authorization for this 

information collection is December 31, 

2011. The regulations implement DavisBacon and Related Acts and the 

Copeland Anti-Kickback Act 

requirements, and the regulatory 

changes reduce respondent burden and 

improve privacy protections for laborers 

and mechanics employed on federally 

financed or assisted construction 

contracts by lessening the transmission 

of personal information regarding 

individuals who work on contracts 

subject to Davis-Bacon Act labor 

standards. The preamble to the new 

regulations stated a general effective 

date of January 18, 2009; however, the 

OMB had not yet provided a PRArequired approval for the revised 

information collection requirements 

contained in 29 CFR 3.3, 5.5(a)(3)(ii)(A), 

and 5.5(a)(3)(ii)(B)(1) at the time of their 

publication. 44 U.S.C. 3507(a)(2). An 

agency may not conduct an information 

collection unless it has a currently valid 

OMB approval; therefore, in accordance 

with the PRA, the effective date of the 

information collection requirements in 

the revised regulations was delayed 

until the OMB approved them under the 

PRA. 44 U.S.C. 3506(c)(1)(B)(iii)(V). On 

December 30, 2008, the OMB approved 

the Department’s information collection 

request under Control Number 1215– 

0149; thus, giving effect to the 

requirements, as announced and 

published in the Federal Register on 

December 18, 2008, under the PRA. The 

current expiration date for OMB 

authorization for this information 

collection is December 31, 2011. 

Dated: January 9, 2009. 

Victoria A. Lipnic, 

Assistant Secretary, Employment Standards 

Administration. 

Alexander J. Passantino, 

Acting Administrator, Wage and Hour 

Division. 

[FR Doc. E9–675 Filed 1–15–09; 8:45 am] 

BILLING CODE 4510–27–P 

DEPARTMENT OF LABOR 

Wage and Hour Division 

29 CFR Part 825 

The Family and Medical Leave Act of 

1993, Effectiveness of Information 

Collection Requirements 

AGENCY: Department of Labor, 

Employment Standards Administration, 

Wage and Hour Division. 

ACTION: OMB approval of information 

collection requirements. 

SUMMARY: On December 14, 2008, the 

Office of Management and Budget 

(OMB) approved under the Paperwork 

Reduction Act (PRA) the Department of 

Labor’s information collection request 

for requirements regarding Family and 

Medical Leave Act regulations, as 

published in the Federal Register on 

November 17, 2008. The PRA requires 

this notice to set forth the effectiveness 


sroberts on PROD1PC70 with RULES