[Federal Register Volume 68, Number 238 (Thursday, December 11, 2003)]
[Rules and Regulations]
[Pages 69009-69020]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-30641]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 314 and 601

[Docket No. 2000N-1652]
RIN 0910-AB91


Requirements for Submission of Labeling for Human Prescription 
Drugs and Biologics in Electronic Format

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending its 
regulations governing the format in which certain labeling is required 
to be submitted for review with new drug applications (NDAs), certain 
biological license applications (BLAs), abbreviated new drug 
applications (ANDAs), supplements, and annual reports. The final rule 
requires that certain labeling content be submitted electronically in a 
form that FDA can process, review, and archive. Submitting the content 
of labeling in electronic format will simplify the drug labeling review 
process and speed up the approval of labeling changes.

DATES: The rule is effective June 8, 2004.

FOR FURTHER INFORMATION CONTACT:
    Randy Levin, Center for Drug Evaluation and Research (CDER) (HFD-
001), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 
20857, 301-827-7756, or
    Robert A. Yetter, Center for Biologics Evaluation and Research 
(HFM-10), Food and Drug Administration, 1401 Rockville Pike, Rockville, 
MD 20852, 301-827-0373.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of May 3, 2002 (67 FR 22367), FDA published 
a proposed rule to require the submission of the content of labeling 
for human prescription drugs and certain biologics in electronic format 
in a form that FDA can process, review, and archive. This electronic 
submission requirement would necessitate the amendment of FDA's 
regulations under Sec. Sec.  314.50(l) (21 CFR 314.50(l)), 
314.81(b)(2)(iii) (21 CFR 314.81(b)(2)(iii)), 314.94(d)(1) (21 CFR 
314.94(d)(1)), and the addition of Sec.  601.14 (21 CFR 601.14).
    Under current regulations, as noted in the preamble to the proposed 
rule, labeling for the archival copy of an NDA must be submitted to the 
agency on paper, labeling for the archival copy of an ANDA may be 
submitted in any form that FDA and the applicant agree upon, and the 
current regulations for BLA labeling do not specify a format for 
submission to the agency. The term ``labeling'' used in Sec. Sec.  
314.50, 314.94, 314.81, and Sec.  601.12 is defined in section 201(m) 
of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 
321(m)) to mean both labels\1\  and other written, printed, or graphic 
matter upon any article or any of its containers or wrappers, or 
accompanying such article. Thus, requiring the submission of 
``labeling'' entails submission of the label (i.e., the label on the 
immediate container) and labeling. Labeling consists of the 
comprehensive prescription drug labeling directed to health care 
practitioners (i.e., the labeling required under Sec.  201.100(d)(3) 
(21 CFR 201.100(d)(3)), commonly referred to as the ``package insert'' 
or

[[Page 69010]]

``professional labeling'')\2\  and other labeling. This final rule 
applies to the electronic submission of the content of labeling, 
defined as the contents of the package insert or professional labeling, 
including all text, tables, and figures.
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    \1\ Under section 201(k) of the act, the term ``label'' means a 
display of written, printed, or graphic matter upon the immediate 
container of any article.
    \2\ Section 201.100(d) requires that any labeling distributed by 
or on behalf of the manufacturer, packer, or distributor of the 
drug, that furnishes or purports to furnish information for use of 
the drug, or which prescribes, recommends, or suggests a dosage for 
the use of the drug, must meet the content and format requirements 
in 21 CFR 201.56 and 201.57.
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    Each year FDA conducts a word-for-word comparison of the labeling 
as part of the review process for more than 1,000 proposed labeling 
changes for approved NDAs and BLAs, and more than 2,600 proposed 
original and supplemental labeling changes for ANDAs.\3\  Because 
reviewers currently conduct these comparisons manually using two paper 
copies of the labeling, the process is slow and subject to error. 
Requiring the electronic submission of labeling for NDAs, certain BLAs, 
ANDAs, supplements, and annual reports will greatly enhance the 
accuracy and speed of labeling review. This will result in increased 
protection of the public health because electronic review and 
comparison of labeling files will provide a higher degree of certainty 
that all sections of prescription drug labeling are correct.
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    \3\ We also conduct a word-for-word comparison of the labeling 
for the proposed generic drug product and the reference listed drug 
to verify that any differences in labeling have been correctly 
annotated and explained by the ANDA applicant under Sec.  
314.94(a)(8)(iv).
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    Although FDA has not previously required regulatory submissions in 
electronic format, we have issued several guidances describing how to 
make voluntary electronic submissions to the agency. In the Federal 
Register of January 28, 1999 (64 FR 4433), we (FDA) issued a guidance 
on general considerations for electronic submissions entitled 
``Providing Regulatory Submissions in Electronic Format--General 
Considerations'' (general considerations guidance). In the general 
considerations guidance, we included a description of the types of 
electronic file formats that we are able to accept for processing, 
reviewing, and archiving electronic documents. In the Federal Register 
of January 28, 1999 (64 FR 4432), we announced the availability of a 
guidance entitled ``Providing Regulatory Submissions in Electronic 
Format--NDAs,'' which provided information on how to submit a complete 
archival copy of an NDA in electronic format. In November 1999, we 
published a guidance to assist applicants in submitting documents in 
electronic format for review and archive purposes as part of a BLA, 
product license application (PLA), or establishment license application 
(ELA) (64 FR 61647, November 12, 1999). Most recently, we published a 
guidance for ANDAs entitled ``Providing Regulatory Submission in 
Electronic Format--ANDAs'' (67 FR 43331, June 27, 2002). In addition, 
part 11 (21 CFR part 11), concerning electronic records and electronic 
signatures, describes certain controls for electronic regulatory 
submissions and states that we are prepared to accept those regulatory 
submissions that have been identified in the public docket (62 FR 
13430, March 20, 1997).
    FDA received 13 comments (which raised 21 issues) on the proposed 
rule and addresses each of those comments in section III of this 
document. The majority of the comments supported the proposed 
amendments to FDA's regulations. After careful consideration of the 
comments, the agency is adopting this final rule without any changes 
from the proposed rule. The final rule is described in section II of 
this document.

II. Description of the Final Rule

    We are revising our regulations to require the electronic 
submission of the content of labeling (i.e., the content of the package 
insert or professional labeling, including all text, tables, and 
figures) for NDAs, certain BLAs, ANDAs, supplements, and annual 
reports. This requirement is in addition to existing requirements, 
found elsewhere in our regulations, that copies of the label and 
labeling and specimens of enclosures be submitted.
    Under the amended regulations that we are adopting in this final 
rule, Sec. Sec.  314.50(l), 314.81(b)(2)(iii), and 314.94(d)(1) are 
revised to require applicants to submit the content of labeling in 
NDAs, ANDAs, supplements, and annual reports electronically in a form 
that we can process, review, and archive.\4\  Under new Sec.  
314.94(d)(1), ANDA applicants are required to submit in electronic 
format the content of labeling for the proposed drug product (i.e., the 
content of the generic drug product labeling). As previously stated in 
the preamble to the proposed rule, ANDA applicants are not required to 
submit in electronic format the content of labeling for the reference 
listed drug product. Section 601.14 is added to require applicants for 
biological products subject to the requirements of Sec.  201.100(d)(3) 
to submit the content of labeling in BLAs, supplements, and annual 
reports electronically in a form that we can process, review, and 
archive.\5\
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    \4\ The submission of labeling for the archival copy of an NDA 
is required under Sec.  314.50(e)(2)(ii). Section 314.71(b) (21 CFR 
314.71(b)) requires that supplements to approved applications 
submitted to the agency under Sec.  314.70 (21 CFR 314.70) follow 
the procedures described in Sec.  314.50. Section 314.81(b)(2)(iii) 
(21 CFR 314.81(b)(2)(iii)) requires that annual reports include 
``currently used professional labeling, patient brochures, or 
package inserts.'' With respect to the archival copy of an ANDA, 
Sec.  314.94(a)(8)(ii) requires copies of the label and all labeling 
for the drug product. Under Sec.  314.97 (21 CFR 314.97), 
supplements and other changes to approved ANDAs must be submitted to 
the agency under the requirements of Sec. Sec.  314.70 and 314.71. 
Under Sec.  314.98(c) (21 CFR 314.98(c)), annual reports for ANDAs 
must be submitted as required in Sec.  314.81(b)(2)(iii).
    \5\ Section 601.2 (21 CFR 601.2) describes the requirements for 
submission of a BLA, which include the requirement that specimens of 
enclosures and Medication Guides for a product, if any, be 
submitted. Section 601.12 (21 CFR 601.12) describes the requirements 
to make changes to an approved BLA, including labeling changes.
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    At this time, portable document format (PDF) is the only type of 
electronic file format that we have the ability to accept for 
processing, reviewing, and archiving. PDF is commonly used, easily 
obtainable, and affordable. Software to convert electronic files to PDF 
is commercially available at a cost of approximately $100 to $300. The 
technology necessary to create PDF documents is also publicly 
available. Because PDF is the only acceptable file type, references to 
specific media (microfiche, microform, optical disc, and magnetic tape) 
under Sec. Sec.  314.50(l)(1) and 314.94.(d)(1) will be deleted.
    To be responsive to technological advances, we may recommend in the 
future that new file formats and software applications be used to 
submit labeling electronically. As mentioned in the preamble to the 
proposed rule, we will provide advance notice, in accordance with FDA's 
good guidance practice regulations under Sec.  10.115 (21 CFR 10.115), 
so that affected parties will have adequate time to convert to any new 
format or software. In addition, we expect that such format or software 
will be widely available before we switch to a new technology. Changes 
in format and/or software will be identified in public docket number 
92S-0251. During any such transition, we will accept submissions using 
either file format or software.
    Finally, these new regulations also make minor changes to reformat 
and modernize certain regulatory provisions. This final rule is 
amending Sec.  314.50(l) by adding headings to paragraphs (l)(1) 
through (l)(4) and by removing the word ``shall'' and adding in its 
place the word ``must.''

[[Page 69011]]

III. Comments on the Proposed Rule

    FDA received 13 sets of written comments on the proposed rule from 
manufacturers, trade associations, advocacy groups, consulting firms, 
and individuals. The majority of the comments supported FDA's proposal 
to require that the content of certain labeling be submitted 
electronically in a form that FDA can process, review, and archive. A 
few comments requested clarification on various aspects of the rule and 
one comment opposed the exemptions from specific controls under part 
11. A summary of the comments received and the agency's responses 
follows:

A. General Comments

    (Comment 1) One comment identified as a typographical error the 
citation of Sec.  314.50(l). The comment suggested that Sec.  
314.50(l)(1)(i) was being referenced as (1)(1)(i).
    (Response) This is not a typographical error; we are citing to 
Sec.  314.50(l)(1)(i) in the proposed rule, but the lower case letter L 
(``l'') looks similar to the number 1.
    (Comment 2) One comment recommended adding changes to Sec.  314.70 
and Sec.  601.12 to address labeling supplements.
    (Response) FDA believes that Sec.  314.70 and Sec.  601.12 do not 
need any changes because the recommended requirements already exist.
    Under Sec.  314.71, all procedures that apply to an application 
under Sec.  314.50 also apply to supplement submissions. Thus, by 
amending the provisions in Sec.  314.50, the final rule also covers the 
requirements for labeling supplements. Similarly, Sec.  601.14 requires 
applicants for biological products subject to the requirements of Sec.  
201.100(d)(3) to submit the content of labeling in BLAs, supplements, 
and annual reports electronically in a form that FDA can process, 
review, and archive.
    (Comment 3) One comment stated that it supported the adoption of 
regulations to require bar coding for all pharmaceuticals.
    (Response) The agency is pursuing bar coding initiatives separately 
from this rulemaking. A proposed rule to require bar codes on certain 
human drug product labels and biological product labels was published 
in the Federal Register of March 14, 2003 (68 FR 12500). This final 
rule deals solely with the content of labeling for human prescription 
drugs and biologics submitted to FDA in electronic format that FDA can 
process, review, and archive.
    (Comment 4) Although supportive of the proposed rule, one comment 
was concerned about industry initiatives to use this rule to advocate 
for electronic versions as a substitute for printed patient inserts 
(PPIs).\6\  The comment expressed concern that this rule could serve as 
a basis for the elimination of printed PPIs.
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    \6\ The comment refers to patient package inserts as ``PIs.'' 
FDA, though, refers to such inserts as ``PPIs.''.
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    (Response) FDA understands the comment's concern, but the agency's 
regulation of PPIs is unrelated to the requirement to submit the 
content of labeling electronically. This rule requires that the content 
of labeling (i.e., the content of the package insert or professional 
labeling, including all text, tables, and figures) be submitted 
electronically. It does not alter the current regulatory treatment of 
PPIs. The PPIs can be submitted in paper or electronic format under 
part 11. If the PPI is submitted electronically, it must appear in the 
electronic format as it would in printed form.
    (Comment 5) One comment mentioned that this rule will enable the 
agency to move forward with other initiatives to make labeling more 
rapidly available. The comment asks the agency to consider providing 
certain recommendations on a standard database for labeling and 
standard display formats for viewing labels.
    (Response) FDA welcomes the comment, and we are working on several 
initiatives to make labeling more readily available to the public. This 
rule is a necessary step to provide FDA with the information needed to 
improve the readability, organization, and access to labeling 
information, including the possibility of using the information in a 
standard database.

B. Applicability/Scope of the Proposed Rule

    (Comment 6) One comment requested that FDA clarify whether the 
Circular of Information for the Use of Human Blood Components (the 
Circular) is exempt from this rule. The comment stated that the 
Circular is prepared on a biannual basis by a committee representing 
all blood organizations and a single submission is made to FDA. The 
same version of the Circular is used by the majority of licensed blood 
establishments.
    (Response) It is true that FDA reviews a version of the Circular 
that a consortium of blood establishments submits periodically. 
Although individual blood establishments may use different versions of 
the Circular and must submit those versions in supplemental 
applications to FDA, the amount of variation from the FDA-recognized 
Circular is so minimal that electronic submission is not necessary at 
this time. Therefore, the final rule does not require the submission of 
the Circular to the agency in electronic format.
    (Comment 7) Several comments asked for clarification of the 
following statement in the proposed rule: ``This proposed requirement 
would be in addition to existing requirements, described in section I.A 
of this document, that copies of the label and labeling and specimens 
of enclosures be submitted.'' The comments requested that the agency 
explicitly state that no paper copies of labeling are to be submitted.
    (Response) The content of labeling is a new labeling type not 
previously required in the regulations to be submitted. The content of 
labeling, defined as the contents of the package insert or professional 
labeling, including all text, tables, and figures for prescription 
products approved under an ANDA, BLA, or NDA, does not replace any 
previously required labeling type, including the package insert. In 
other words, the regulations require the package insert to be submitted 
in addition to the content of labeling. However, no paper copies of any 
labeling are required. As discussed in our response to comment 4, the 
applicant has the option of providing the package insert in paper or 
electronic format under part 11. The package insert, if submitted 
electronically, must appear as it would in printed form. Submission in 
this form allows us to evaluate the format of the package insert, such 
as font size and positioning of the text.
    (Comment 8) A few comments asked for clarification of whether the 
rule requires the submission in electronic format of all types of 
labeling, such as carton and container labels, labels submitted with 
advertising material, and labeling that might be submitted with 
periodic adverse drug experience reports.
    (Response) The agency did not intend that the final rule require 
the electronic submission of the previously mentioned types of 
labeling. The rule requires only that the content of labeling (i.e. the 
content of the package insert or professional labeling, including all 
text, tables, and figures) be submitted in electronic format.
    (Comment 9) Some comments requested clarification of whether the 
rule restricts the submission of labeling in electronic format to the 
content of labeling.

[[Page 69012]]

    (Response) The agency did not intend to restrict the voluntary 
submission of labeling in electronic format. Under part 11, an 
applicant may submit labeling in electronic format as long as the 
controls in part 11 are met and the labeling is listed in public docket 
number 92S-0251.\7\  Because the agency has listed labeling in 
conjunction with NDAs, BLAs, and ANDAs in public docket number 92S-
0251, applicants may submit all labeling for an NDA, BLA, or ANDA in 
electronic format.
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    \7\ A recent draft guidance issued by the agency provides for 
the exercise of enforcement discretion with respect to the following 
part 11 requirements: Validation (Sec.  11.10(a) (21 CFR 11.10(a))); 
copies of records Sec.  11.10(b)); record retention (Sec.  
11.10(c)); audit trails (Sec.  11.10(e) and (k)(2)); and any 
corresponding requirements in Sec.  11.30. See FDA guidance for 
industry entitled ``Part 11, Electronic Records; Electronic 
Signatures--Scope and Application,'' available at www.fda.gov/cder/guidance.
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    (Comment 10) Two comments suggested that the electronic submission 
of labeling submitted with annual reports under Sec.  314.81 should be 
optional if the product's labeling has not been revised beyond 
editorial changes. The comments noted that the labeling revisions to 
older products are infrequent and often insubstantial in nature; 
therefore, the submission of annual report labeling is not justified by 
the objectives of this rule.
    (Response) FDA disagrees that the electronic submission of labeling 
in the annual report is not justified by the objectives of the final 
rule. The labeling submitted with the annual report, aside from 
editorial corrections, can also include other changes related to the 
manufacturing of the product. As with other labeling changes, these 
changes must be reviewed and require the same degree of comparison with 
previous versions of labeling. In addition, the labeling changes 
described in the annual report must be included in FDA's database. 
Finally, it is important to note that in our economic analysis, we 
found that the one-time costs to convert the labeling in annual reports 
to electronic format would not be overly burdensome (see section VIII 
of this document). Accordingly, the electronic submission of labeling 
submitted with annual reports under Sec.  314.81 is not optional.

C. Reviewer Support and Training

    (Comment 11) Some comments expressed concern that reviewers will 
accept ``special requests'' to receive the labeling in paper format or 
other formats to bypass existing agency guidance on electronic 
submissions. These same comments emphasized the importance of training 
and support of reviewers and staff in the use of electronic review and 
version comparison utilities.
    (Response) FDA agrees that reviewers should not ``bypass'' our 
guidance documents. We train reviewers and managers on the details and 
provisions of guidance documents. When there are differences in opinion 
concerning the meaning of such provisions, it is best for the applicant 
and agency personnel to discuss those differences to ensure that 
everyone understands the relevant issues and the parties' respective 
positions. In addition, we will update our specific policy and 
procedure documents for reviewers to help enforce the common practice 
of reviewing documents electronically. The reviewers and staff will 
have sufficient training and support to fulfill their duties in 
reviewing the electronic version of the content of labeling.
    (Comment 12) One comment pointed out that the Office of Generic 
Drugs (OGD) has limited experience with electronic labeling because it 
has only recently published guidance on providing an ANDA in electronic 
format.\8\  The comment recommended that OGD pilot a program with 
industry to accept and process electronic labeling before the effective 
date of this rule.
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    \8\ See ``Providing Regulatory Submission in Electronic Format--
ANDAs'' guidance (67 FR 43331, June 27, 2002).
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    (Response) FDA does not believe a pilot program is necessary to 
prepare OGD reviewers for the implementation of this rule. OGD 
reviewers used the electronic label review technology for many years 
before the issuance of the guidance on electronic submissions of 
ANDAs\9\  and; therefore, have adequate experience in this area.
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    \9\ Id.
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D. Requiring Electronic Submission

    (Comment 13) The comments were overwhelmingly supportive of 
requiring the electronic submission of the content of labeling. The 
comments commend FDA's goal of using electronic labeling to facilitate 
labeling reviews. However, a few comments suggested that the agency use 
appropriate metrics for tracking the gains associated with the 
electronic submission of labeling.
    (Response) The agency agrees with the comment, and notes that, as 
explained in section II.A of the proposed rule, there will be numerous 
benefits from the regulation, particularly through enhancing the 
accuracy and speed of the labeling review process. Nevertheless, it may 
be difficult to quantify precisely the improvements derived solely from 
receiving labeling in electronic format because we also plan to improve 
our current business practice for processing and reviewing such 
labeling changes. To the extent possible, we plan to evaluate the 
success of all these changes and hope to make the results of our 
evaluations available to the public.
    (Comment 14) A few comments suggested that the implementation of 
the rule would improve the availability of labeling to the public.
    (Response) We believe that a number of changes are needed to 
improve the public's access to medication information. This rule is an 
important and necessary step toward that goal, because it will greatly 
enhance the accuracy and speed of labeling reviews. We are actively 
working with the pharmaceutical industry, other government agencies, 
and health care information suppliers to achieve success in this area. 
For example, we are currently working with several agencies, including 
the National Library of Medicine, on an initiative to promote patient 
safety through accessible medication information (DailyMed Initiative). 
The electronic submission of the content of labeling will allow the 
agency to provide the DailyMed system with labeling in a comprehensive, 
reliable, and structured format. The DailyMed can then use this 
information to make information on medications available to the public. 
Consumers, health professionals, and others may use this information in 
several ways, including to identify drug interactions, 
contraindications, and possible adverse reactions.
    (Comment 15) Some comments suggested that the use of electronic 
labeling may lead to improvement in the communication between the 
agency and industry when the review division requests modifications for 
proposed labeling changes. Specifically, the comments referred to word 
processing software available for tracking changes and editing 
documents. In addition, the comments suggested that the use of a secure 
electronic mail exchange system between applicants and the agency 
during labeling negotiations could be beneficial.
    (Response) We appreciate the suggestion and our guidance document 
entitled ``Providing Regulatory Submissions in Electronic Format--
NDAs,'' currently describes submission of the content of labeling in a 
word processing format in addition to PDF to support editing changes. 
As mentioned in the proposed rule, PDF is the only type of electronic 
file format that we have the ability to process, review, and archive 
because it is currently the most cost effective and best meets our 
needs

[[Page 69013]]

for word-for-word comparisons of files. As for any direct communication 
between applicants and FDA requiring the editing of specific content of 
labeling, the guidance notes the utility of also submitting labeling in 
word processing format to facilitate this editing process. In addition, 
we are looking into new technologies to improve the methods for 
exchanging and reviewing labeling changes.

E. Providing Labeling to FDA in Electronic Format

    (Comment 16) Two comments requested clarification on how to provide 
labeling with annual reports. They state that some of the confusion 
with the annual report labeling is because of the lack of a published 
guidance document on the submission of annual reports in electronic 
format. The comments also asked if the hard copy information submitted 
with annual reports containing electronic labeling (distribution, 
chemistry, manufacturing and controls, preclinical/clinical) should be 
submitted to the respective reviewing divisions, the central document 
room, or both.
    (Response) As explained previously, the agency has issued guidance 
for the electronic submission of NDAs, ANDAs, and BLAs. Although there 
is no published guidance specifically on providing labeling with annual 
reports, submission of that labeling is covered by these other agency 
guidance documents on electronic submissions. Therefore, the content of 
labeling submitted with annual reports would be prepared and submitted 
electronically as described in the following FDA guidance documents: 
(1) ``Providing Regulatory Submissions in Electronic Format--General 
Considerations,'' (2) ``Providing Regulatory Submissions in Electronic 
Format--NDAs,'' and (3) ``Providing Regulatory Submission in Electronic 
Format--ANDAs'' (see section I for a description of these guidance 
documents).
    It should be noted that this final rule only applies to the 
electronic submission of the content of labeling. It does not address 
the electronic submission of annual reports generally or any other part 
of an application. To the extent that the commentors asked for more 
detailed information about annual report submissions, applicants should 
continue following the regulations and guidance documents pertaining to 
those submissions.
    (Comment 17) One comment requested harmonization of all elements of 
annual reports for NDAs, ANDAs, and BLAs.
    (Response) As noted previously, the content of the annual report, 
other than labeling, is not affected by this regulation. However, the 
labeling submitted with an annual report will be prepared and submitted 
electronically in the same fashion as described for other electronic 
labeling submissions in an application (i.e., original labeling 
submissions in an NDA, ANDA, or BLA).
    (Comment 18) One comment requested that Form FDA 2567 not be 
required with each labeling component submitted to a BLA because CDER 
does not require that such a form accompany labeling.
    (Response) The agency agrees that Form FDA 2567 is not required 
when submitting BLA labeling electronically using form 356h 
(Application to Market a New Drug, Biologic, or an Antibiotic Drug for 
Human Use). The form should only be used for human blood and blood 
components (The human blood and blood components circular is not 
covered by this rule. See comment 6 in section III of this document.)
    (Comment 19) Generally, the comments supported our flexible 
approach regarding the acceptable content of labeling file format. The 
comments recognized that a flexible approach would enable the industry 
and FDA to take advantage of future improvements in computer technology 
and software design. They also agreed with the proposal to describe the 
method for submitting the content of labeling in guidance, but 
requested that FDA guidance accompany the final rule. Some comments, 
however, made suggestions for the use of specific technologies. In 
addition, we were requested to limit changes to the file format or 
software specifications.
    (Response) Currently, guidance on the submission of labeling is 
included in the guidance for industry series ``Providing Regulatory 
Submissions in Electronic Format'' (see section I of this document). We 
understand that changes to the file format or software can lead to 
costly changes in the information technology systems used by industry. 
For this reason, we plan to limit future changes to those that can lead 
to increased benefits for both the agency and industry. As mentioned in 
section II of this final rule, the agency will not switch to new format 
or software until it is widely available.
    (Comment 20) One comment asked that we identify the software used 
for working on an applicant's labeling (e.g., to compare texts) and 
whether the software is commercially available or proprietary.
    (Response) Currently, the reviewers use Adobe Acrobat and Microsoft 
Word for reviewing labeling. Both are commercially available. As new 
technology is developed and we change the software used in reviews, we 
will make this information available to the public.

F. Part 11 Requirements for Electronic Submissions

    (Comment 21) We received a number of comments related to the 
proposed exemption of the submission of electronic labeling from 
specific controls under Sec. Sec.  11.10 and 11.30. Most of the 
comments were positive and supported the rationale for the exemptions. 
One comment, however, raised concerns about the effect of the proposed 
exemptions from part 11 requirements on the integrity of part 11 
generally.
    (Response) We have recently articulated our current thinking on 
part 11 in the draft guidance document entitled ``Part 11, Electronic 
Records; Electronic Signatures--Scope and Application'' (part 11 draft 
guidance) issued in the Federal Register of February 25, 2003 (68 FR 
8775). Among other things, this part 11 draft guidance announces the 
agency's intent to exercise enforcement discretion in the manner 
specified in the draft guidance with respect to the specific part 11 
requirements of validation (Sec.  11.10 (a)), copies of records (Sec.  
11.10(b)), record retention, audit trails (Sec.  11.10(e) and (k)(2)), 
and any corresponding requirements in Sec.  11.30. This final rule 
exempts the electronic submission of labeling content from the 
requirements of Sec.  11.10(a), (c) through (h), and (k), and the 
corresponding requirements of Sec.  11.30.
    We recognize that there are some differences with respect to the 
exemptions from part 11 requirements provided in this final rule (i.e., 
Sec.  11.10(a), (c) through (h), and (k), and the corresponding 
requirements of Sec.  11.30), and the part 11 requirements set forth in 
the part 11 draft guidance for which the agency intends to exercise 
enforcement discretion (i.e., Sec.  11.10(a) through (c), (e), and 
(k)(2), and any other corresponding requirements in 11.30)). Although 
the final rule does not provide an exemption from Sec.  11.10(b), the 
part 11 draft guidance announces that we intend to exercise enforcement 
discretion with respect to that section in the manner described in the 
draft guidance.
    The exemptions in the final rule and the part 11 requirements for 
which we intend to exercise enforcement discretion, as described in the 
part 11

[[Page 69014]]

draft guidance, differ because the final rule is specific to the 
electronic submission of labeling content for human prescription drugs 
and certain biologics, and the part 11 draft guidance applies to the 
maintenance of all electronic records and to all electronic submissions 
subject to part 11.
    We exempted the submission of electronic labeling content from 
certain part 11 requirements because we believe these part 11 
requirements are not critical to ensure the quality of the content of 
labeling submitted under this rule and we want to ensure that industry 
resources are not being spent on unnecessary controls. For example, 
validation for the system used to generate the labeling record is not 
necessary because the applicant's verification that the information in 
the labeling record is accurate serves the same objective. Our review 
of the content of labeling is based on the version of the labeling 
record submitted to us. Earlier versions of the record, as well as 
changes made to the earlier versions, are not relevant to our analysis. 
Thus, other controls related to the creation, modification, and 
maintenance of the labeling records are also not needed.

IV. Legal Authority

    Our legal authority to amend our regulations governing the format 
of labeling for human prescription drugs and biologics derives from 
sections 201, 301, 501, 502, 503, 505, 506, 506A, 506B, 506C, 510, 513-
516, 518-520, 701, 704, 721, and 801 of the act (21 U.S.C. 321, 331, 
351, 352, 353, 355, 356, 356a, 356b, 356c, 360, 360c-360f, 360h-360j, 
371, 374, 379e, and 381); 15 U.S.C. 1451-1561; the Public Health 
Service Act (42 U.S.C. 216, 241, 262, 263, 264); and section 122, 
Public Law 105-115, 111 Stat. 2322 (21 U.S.C. 355 note).

V. Paperwork Reduction Act of 1995

    This final rule contains information collection provisions 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). A 
description of these provisions is given 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 Labeling for Human 
Prescription Drugs and Biologics in Electronic Format.
    Description: FDA is amending its regulations governing the format 
in which certain labeling is required to be submitted for review with 
NDAs, certain BLAs, ANDAs, supplements, and annual reports. The final 
rule requires that the content of labeling for prescription drug and 
biological products required under Sec.  201.100(d)(3) be submitted to 
FDA electronically in a form that we can process, review, and archive. 
Copies of product labeling are currently required to be submitted to 
FDA for review in NDAs, certain BLAs, ANDAs, certain supplements, and 
annual reports under Sec. Sec.  314.50, 314.70, 314.81, 314.94, 314.97, 
314.98, Sec. Sec.  601.2, and 601.12. Copies of labeling may be 
submitted electronically or on paper. The agency is adding the new 
requirements because submitting the content of labeling in electronic 
format will simplify the drug labeling review process and speed up the 
approval of labeling changes.
    As required under section 3506(c)(2)(B) of the Paperwork Reduction 
Act, FDA provided an opportunity for public comments on May 3, 2002 (67 
FR 22367), on the information collection provisions of the proposed 
rule. FDA received two comments stating that the agency underestimated 
the time and costs to prepare the content of labeling in electronic 
format for submission to FDA. Specifically, the comments stated that 
the 15 minutes to convert the labeling into PDF was underestimated 
because it did not take into account the time needed to proofread the 
content of labeling document.
    FDA believes that proofreading is not an additional cost for 
submitting labeling in electronic format for new submissions of NDAs, 
BLAs, and ANDAs. Labeling is proofread prior to submission regardless 
of the format. If the labeling is in a word processing file, it is 
irrelevant whether the document is printed or converted to a PDF file. 
This is because the finished product, the labeling, is proofread for 
quality assurance in either case. We also note that someone may need 
even less time to proofread an electronic file than a printed document 
because the computer could assist in finding errors. As such, we are 
not changing the burden estimate for these applications in the final 
rule.
    However, we agree that we should allow for proofreading of labeling 
under certain circumstances. Applicants that have previously submitted 
labeling in paper format in annual reports or supplements, but also 
maintained the labeling document in electronic format, should be 
provided time for proofreading the converted file. This category of 
labeling would not require any changes to the labeling since it was 
last submitted to the agency. It only requires additional time for 
proofreading to ensure that the electronic document being submitted is 
the same as the labeling previously submitted in paper format. We 
estimate that the hours per response (i.e., the time it will take an 
applicant to submit the labeling content electronically for these 
annual reports and supplements) will be approximately 5 hours. We 
discuss this new category of reporting in more detail in this section V 
when we calculate the burdens associated with submission of electronic 
labeling in supplements and annual reports. We also add sections to the 
estimated annual reporting burden chart to report the burdens.
    As we noted in the proposed rule, we recognize that some older 
annual reports may require additional steps, such as accessing the 
labeling in the archives, putting the content of labeling into an 
electronic format, and converting it to a PDF file. In response to the 
proofreading comments mentioned previously, we are allowing an 
additional 2 hours for proofreading this type of labeling (the proposed 
rule allowed for 8 hours and the final rule is allowing for 10 hours).
    The reporting burdens for submitting labeling as currently required 
under Sec. Sec.  314.50, 314.70, 314.81, 314.94, 314.97, and 314.98 
have previously been estimated by FDA, and this collection of 
information was approved by OMB until March 31, 2005, under OMB control 
number 0910-0001. The reporting burdens associated with current 
Sec. Sec.  601.2 and 601.12 have also previously been estimated and 
this collection of information was approved by OMB until August 31, 
2005, under OMB control number 0910-0338 (this includes the collection 
of information previously approved by OMB under control number 0910-
0315). We are not reestimating these approved burdens in this 
rulemaking. Only the additional reporting burdens associated with the 
electronic submission of the content of labeling are estimated.
    New NDAs (Sec.  314.50), ANDAs (Sec.  314.94), and BLAs (Sec.  
601.2): Based on data in the approved collections of information for 
Sec. Sec.  314.50, 314.94, and Sec.  601.2, we estimate that 
approximately 83 NDA applicants, 117 ANDA applicants, and 17 BLA 
applicants (respondents) submit applications to us annually. We 
estimate that these applicants (respondents) will submit approximately 
85 NDAs, 323 ANDAs, and 17 BLAs each year that will be

[[Page 69015]]

subject to this rule.\10\  Based on our experience with voluntary 
electronic submissions and our knowledge of the drug and biologic 
industries, we assume that applicants for new NDAs, ANDAs, and BLAs 
will already have the necessary labeling in an electronic format that 
can be easily accessed and converted to a PDF file. Thus, we have 
estimated that the hours per response, i.e., the additional time 
necessary for submission of the content of labeling in electronic 
format for these applications, will be less than 15 minutes. Therefore, 
we estimate that respondents will spend approximately 106 hours per 
year submitting the content of labeling to us in accordance with the 
final rule.
---------------------------------------------------------------------------

    \10\ The numbers in this final rule have changed from the 
proposed rule because we have updated the numbers to be more 
current.
---------------------------------------------------------------------------

    Supplements to NDAs (Sec.  314.70) and ANDAs (Sec.  314.97) and 
BLAs (Sec.  601.12(f)(1) and (f)(2)): Based on data in the approved 
collections of information for Sec. Sec.  314.70, 314.97, and Sec.  
601.12(f)(1) and (f)(2), we estimate that approximately 418 NDA 
applicants, 152 ANDA applicants, and 20 BLA applicants (respondents) 
submit supplements to approved applications to us annually. We estimate 
that these applicants (respondents) will submit approximately 630 NDA 
supplements, 1,000 ANDA supplements, and 20 BLA supplements each year 
that will be subject to this rule.
    Based on our experience with voluntary electronic submissions and 
our knowledge of the drug and biologic industries, we assume that 
approximately 254 NDA supplements, 396 ANDA supplements, and 10 BLA 
supplements will be submitted by applicants who already have the 
necessary labeling in an electronic format that can be easily accessed 
and converted to a PDF file. Thus, we have estimated that the hours per 
response, i.e., the additional time necessary for submission of the 
content of labeling in electronic format for these supplements, will be 
less than 15 minutes. Therefore, we estimate that respondents would 
spend approximately 165 hours per year submitting the content of 
labeling to us in these supplements under the final rule.
    As mentioned previously, we are adding a new category to the 
paperwork section to allow for proofreading the converted file of 
labeling that was previously submitted in supplements in paper form 
(and not requiring any changes since it was last submitted), but is 
also maintained by the applicant in an electronic format. We estimate 
that approximately 376 NDA supplements, 604 ANDA supplements, and 10 
BLA supplements will be submitted by applicants who previously 
submitted labeling in paper, but have such labeling available in 
electronic format. We estimate that the hours per response, i.e., the 
time it will take an applicant to submit the labeling content 
electronically for these supplements, will be approximately 5 hours. 
Therefore, we estimate that in the first year, respondents will spend 
approximately 4,950 hours submitting the content of labeling that was 
previously submitted in supplements in paper form. For all supplements 
combined, we estimate that in the first year, respondents will spend 
approximately 5,115 hours submitting the content of labeling to us in 
supplements under the final rule. This expenditure of time will only be 
necessary the first time that a supplement is submitted with the 
content of labeling in electronic format. Once the content of labeling 
has been converted to an electronic format, the time necessary to 
submit the content of labeling in subsequent supplements will be the 
same as that for the other types of submissions or less than 15 
minutes. Therefore, we estimate that, in subsequent years, respondents 
will spend approximately 413 hours per year submitting the content of 
labeling in supplements.
    Annual Reports for NDAs (Sec.  314.81), ANDAs (Sec.  314.98), and 
BLAs (Sec.  601.12(f)(3)): Based on data in the approved collections of 
information for Sec. Sec.  314.81, 314.98, and Sec.  601.12(f)(3), we 
estimate that approximately 275 NDA applicants, 275 ANDA applicants, 
and 75 BLA applicants (respondents) submit annual reports to us 
annually. We also estimate that each NDA applicant submits to us 
approximately 9.45 annual reports, each ANDA applicant submits 
approximately 16.18 annual reports, and each BLA applicant submits 
approximately 1 annual report each year. Further, we estimate that the 
total annual responses, i.e., the total number of annual reports 
submitted to us per year, will remain approximately 2,600 NDA annual 
reports, 4,450 ANDA annual reports, and 75 BLA annual reports.
    Based on our experience with voluntary electronic submissions and 
our knowledge of the drug and biologic industries, we estimate that 
approximately 24 percent of NDA annual reports (624 NDA annual 
reports), 20 percent of ANDA annual reports (890 ANDA annual reports), 
and 24 percent of BLA annual reports (18 BLA annual reports), will 
already have the necessary labeling in an electronic format that can be 
easily accessed and converted to a PDF file. As discussed above, we 
estimate that each NDA applicant submits to us approximately 9.45 
annual reports, each ANDA applicant submits approximately 16.18 annual 
reports, and each BLA applicant submits approximately 1 annual report 
each year. Therefore, approximately 66 NDA applicants, 55 ANDA 
applicants, and 18 BLA applicants can easily access labeling in 
electronic form and convert it to a PDF file. For the applicants 
submitting these annual reports, we estimate that the hours per 
response, i.e., the additional time necessary for submission of the 
content of labeling in electronic format in the annual report, will be 
less than 15 minutes. Therefore, we estimate that respondents would 
spend approximately 383 hours per year submitting the content of 
labeling to us in these annual reports under the final rule.
    As mentioned previously, we are adding a new category to the 
paperwork section to allow for proofreading the converted file of 
labeling that was previously submitted in annual reports in paper form 
(and not requiring any changes since it was last submitted), but is 
also maintained by the applicant in an electronic format. For 
applicants to include labeling content in their annual reports in 
electronic format, we estimate that approximately 36 percent of NDA 
annual reports (936 NDA annual reports), 30 percent of ANDA annual 
reports (1,335 ANDA annual reports), and 36 percent of BLA annual 
reports (27 BLA annual reports) will be submitted by applicants who 
previously submitted labeling in paper, but have such labeling 
available in electronic format. As discussed above, we estimate that 
each NDA applicant submits to us approximately 9.45 annual reports, 
each ANDA applicant submits approximately 16.18 annual reports, and 
each BLA applicant submits approximately 1 annual report each year. 
Therefore, under the final rule, approximately 99 NDA applicants, 83 
ANDA applicants, and 27 BLA applicants would need additional time to 
proofread these annual reports. We estimate that the hours per 
response, i.e., the time it will take an applicant to submit the 
labeling content electronically for these annual reports, will be 
approximately 5 hours. Therefore, we estimate that respondents would 
spend approximately 11,490 hours per year submitting the content of 
labeling to us in these annual reports under the final rule.
    We recognize that annual reports for some drug and biological 
products, particularly older products for which labeling changes have 
not been made in

[[Page 69016]]

several years, may require additional steps. For applicants to include 
labeling content in their annual reports in electronic format, we 
estimate that approximately 40 percent of NDA annual reports (1,040 NDA 
annual reports), 50 percent of ANDA annual reports (2,225 ANDA annual 
reports), and 40 percent of BLA annual reports (30 BLA annual reports) 
will be submitted by applicants who may need to access the labeling in 
their archives, put the content of labeling into an electronic format, 
and convert it to a PDF file. As discussed previously, we estimate that 
each NDA applicant submits to us approximately 9.45 annual reports, 
each ANDA applicant submits approximately 16.18 annual reports, and 
each BLA applicant submits approximately 1 annual report each year. 
Therefore, under the final rule, approximately 110 NDA applicants, 137 
ANDA applicants, and 30 BLA applicants would need to put labeling 
content in an electronic format and convert it to a PDF file. We 
estimate that the hours per response, i.e., the time it will take an 
applicant to submit the labeling content electronically for these 
annual reports, will be approximately 10 hours.\11\  Therefore, we 
estimate that respondents would spend approximately 32,950 hours per 
year submitting the content of labeling to us in these annual reports 
under the final rule.
    We estimate that in the first year, respondents will spend 
approximately 44,823 hours submitting the content of labeling to us in 
annual reports under the final rule. This expenditure of time will only 
be necessary the first time that an annual report is submitted with the 
content of labeling in electronic format. Once the content of labeling 
has been converted to an electronic format, the time necessary to 
submit the content of labeling in subsequent annual reports will be the 
same as that for the other types of submissions or less than 15 
minutes. Therefore, we estimate that, in subsequent years, respondents 
will spend approximately 1,781 hours per year submitting the content of 
labeling in annual reports.
---------------------------------------------------------------------------

    \11\ The number increased from 8 hours to 10 hours to allow for 
additional time to proofread.
---------------------------------------------------------------------------

    Description of Respondents: An applicant submitting an NDA, ANDA, 
BLA, supplement, or annual report to us for a drug or biological 
product.

                                                     Table 1.--Estimated Annual Reporting Burden\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                No. of Responses
                      21 CFR Section                        No. of Respondents   per Respondent    Total Responses  Hours per Response     Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
Applications: 314.50                                                83                   1.02             85                  .25               21
--------------------------------------------------------------------------------------------------------------------------------------------------------
314.94                                                             117                   2.76            323                  .25               81
--------------------------------------------------------------------------------------------------------------------------------------------------------
601.14 (Applications submitted under Sec.   601.2)                  17                   1                17                  .25                4
--------------------------------------------------------------------------------------------------------------------------------------------------------
Subtotal, applications                                      ..................  ................  ................  ..................         106
--------------------------------------------------------------------------------------------------------------------------------------------------------
Supplements: 314.70 (Products not requiring additional             167                   1.52            254                  .25               63
 steps for electronic submission)
--------------------------------------------------------------------------------------------------------------------------------------------------------
314.70 (Products requiring additional proofreading)                251                   1.50            376                 5               1,880
--------------------------------------------------------------------------------------------------------------------------------------------------------
314.97 (Products not requiring additional steps for                 61                   6.50            396                  .25               99
 electronic submission)
--------------------------------------------------------------------------------------------------------------------------------------------------------
314.97(Products requiring additional proofreading)                  91                   6.50            604                 5               3,020
--------------------------------------------------------------------------------------------------------------------------------------------------------
601.14 (Supplements submitted under Sec.   601.12(f)(1)              8                   1.25             10                  .25                3
 and (f)(2))(Products not requiring additional steps for
 electronic submission)
--------------------------------------------------------------------------------------------------------------------------------------------------------
601.14 (Supplements submitted under Sec.   601.12(f)(1)             12                    .83             10                 5                  50
 and (f)(2)) (Products requiring additional proofreading)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Subtotal, supplements, year one                                                                                                              5,115
---------------------------------------------------------------------------------------------------------------------------------------
Subtotal, supplements, subsequent years\2\                                                                                                     413
---------------------------------------------------------------------------------------------------------------------------------------
Annual Reports: 314.81 (Products not requiring additional           66                   9.45            624                  .25              156
 steps for electronic submission)
--------------------------------------------------------------------------------------------------------------------------------------------------------
314.81 (Products requiring additional proofreading)                 99                   9.45            936                 5               4,680
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 69017]]

 
314.81 (Products requiring additional steps for electronic         110                   9.45          1,040                10              10,400
 submission)
--------------------------------------------------------------------------------------------------------------------------------------------------------
314.98 (Products not requiring additional steps for                 55                  16.18            890                  .25              222
 electronic submission)
--------------------------------------------------------------------------------------------------------------------------------------------------------
314.98 (Products requiring additional proofreading)                 83                  16.18          1,335                 5               6,675
--------------------------------------------------------------------------------------------------------------------------------------------------------
314.98 (Products requiring additional steps for electronic         137                  16.18          2,225                10              22,250
 submission)
--------------------------------------------------------------------------------------------------------------------------------------------------------
601.14 (Annual reports submitted under Sec.   601.12(f)(3)          18                   1                18                  .25                5
 not requiring additional steps for electronic submission)
--------------------------------------------------------------------------------------------------------------------------------------------------------
601.14 Annual reports submitted under Sec.   601.12(f)(3)           27                   1                27                 5                 135
 (Products requiring additional proofreading)
--------------------------------------------------------------------------------------------------------------------------------------------------------
601.14 (Annual reports submitted under Sec.   601.12(f)(3)          30                   1                30                10                 300
 requiring additional steps for electronic submission)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Subtotal, annual reports, year one                                                                                                          44,823
---------------------------------------------------------------------------------------------------------------------------------------
Subtotal, annual reports, subsequent years\3\                                                                                                1,781
---------------------------------------------------------------------------------------------------------------------------------------
  Total, year one                                                                                                                           50,044
---------------------------------------------------------------------------------------------------------------------------------------
  Total, subsequent years\3\                                                                                                                 2,300
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are one-time capital costs to: (1) Acquire computer software; (2) train employees to use the software; and (3) convert certain labeling to an
  electronic format. These costs are estimated to be about $2.3 million (see section VIII of this document). There are no operating or maintenance costs
  associated with this collection of information.
\2\ We estimate that for certain annual reports, respondents will spend 5 hours per response in the first year. We estimate that in subsequent years
  respondents will spend less than 15 minutes per response for all supplements.
\3\ We estimate that for certain annual reports, respondents will spend either 5 or 10 hours per response in the first year. We estimate that in
  subsequent years respondents will spend less than 15 minutes per response for all annual reports.

    In compliance with section 3507(d) of the Paperwork Reduction Act 
of 1995 (44 U.S.C. 3507(d)), the agency has submitted a copy of this 
rule to OMB for its review and approval of these information 
collections.
    The information collection provisions in this final rule have been 
approved under OMB control number 0910-0530. This approval expires on 
November 30, 2006. An agency may not conduct or sponsor, and a person 
is not required to respond to, a collection of information unless the 
information collection displays a currently valid OMB control number.

VI. 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.

VII. 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.

VIII. Analysis of Economic Impacts

    We have examined the impacts of this 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). Under the Regulatory 
Flexibility Act, if a rule may have a significant economic impact on a 
substantial number of small entities, an agency must consider 
alternatives that would minimize the economic impact of the rule on 
small entities. Section 202(a) of the Unfunded

[[Page 69018]]

Mandates Reform Act of 1995 requires that agencies prepare a written 
assessment of anticipated costs and benefits before proposing any rule 
that may result in an expenditure by State, local, and tribal 
governments, in the aggregate, or by the private sector, of $100 
million in any one year (adjusted annually for inflation).
    We believe that this final rule is consistent with the regulatory 
philosophy and principles identified in Executive Order 12866 and in 
these two statutes. The final rule is a significant regulatory action 
as defined in section 3 paragraph (f)(4) of the Executive order. 
However, as shown in this section VIII, the final rule will not be an 
economically significant regulatory action as defined by the Executive 
order and will not require further analysis under the Regulatory 
Flexibility Act.
    The Unfunded Mandates Reform Act of 1995 does not require FDA to 
prepare a statement of costs and benefits for the final rule because 
the final rule would not result in an expenditure of $100 million in 
any one year, adjusted for inflation. The current inflation-adjusted 
statutory threshold is approximately $110 million.
    The purpose of this final rule is to require applicants to submit 
in electronic format the content of labeling required under Sec.  
201.100(d)(3) in NDAs, ANDAs, BLAs, annual reports, and applicable 
supplements. Submissions in electronic format will help simplify and 
speed up our review of these documents. Currently, applicants may 
voluntarily submit such data in electronic form, but they are not 
required to do so. The rule will require all applicants of approved and 
new NDAs, BLAs, and ANDAs to convert the content of labeling to an 
electronic format for submission. At this time, PDF is the type of 
electronic file format that we have the ability to accept for 
processing, reviewing, and archiving. Applicants that do not already 
have the capabilities to create PDF files will have to acquire the 
software and expertise to do so or make contractual arrangements to 
have documents converted.
    The economic burden on industry will include a one-time cost to 
acquire the appropriate computer software and train employees on its 
use. Applicants may also incur additional one-time costs to revise 
applications that have not had any labeling changes within the last few 
years to a format that can be converted to a PDF file. We do not know 
the number of applicants that currently have the capability to submit 
electronic files, nor do we have firsthand information on how labeling 
files are currently maintained or on how much time will be required to 
train employees on the software and new procedures.
    Three comments were received regarding the economic impact 
analysis. Two of these comments suggested that the cost to convert the 
content of labeling to a PDF format was underestimated because it did 
not include the cost to proofread the labeling after it is converted to 
a PDF file. The time required for proofreading ranged from 4 to 6 hours 
depending on the complexity/length of the labeling. One of these 
comments also suggested that the cost for converting older labeling 
that is only available on paper was underestimated, suggesting that the 
costs should include costs for equipment, training, and time to scan 
paper documents.
    The agency agrees that we should allow for proofreading of labeling 
under certain circumstances. Applicants that have previously submitted 
annual reports or supplements in paper form, but also maintained the 
documents in electronic format, should be provided time for 
proofreading the converted file. This category of labeling would not 
require any changes to the labeling since it was last submitted to the 
agency. It only requires additional time for proofreading to ensure 
that it is the same as the labeling submitted in paper format. Five 
hours was used in this analysis to reflect the cost under these 
circumstances.
    However, we do not agree that proofreading is an incremental cost 
for labeling that has been changed and is in a word processing file. 
Proofreading of the finished product for submission (in this case, the 
PDF file) is done now as part of current industry quality assurance 
practice. We also do not agree with the comment that costs for scanning 
labeling should be included in the impact analysis. While scanning 
paper labeling and using optical character recognition software is an 
option some firms may choose, it is not required. The labeling can be 
transcribed into a word processing format and then converted. However, 
we did increase the time estimate for such conversions by an additional 
2 hours and we also increased our estimate of the percent of labeling 
that is included in this category because we now believe that number 
was underestimated.
    Annually, we receive approximately 425 applications, 7,125 annual 
reports, and 1,650 supplements that contain labeling from approximately 
625 applicants. Based on our experience working with voluntary 
electronic submissions, we estimate that overall approximately 70 
percent of the applicants (440) already have the necessary software and 
trained personnel to comply with this rule. The remaining 30 percent of 
applicants (190) would need to purchase software, which costs about 
$250. Based on agency review, approximately 78 percent of these 190 
applicants 148 would be considered small (fewer than 750 employees for 
drug product manufacturers and fewer than 500 employees for biological 
product manufacturers). We estimate that each small applicant would 
need to purchase only one copy of the software, for a total of 148 
copies. The remaining 22 percent of applicants (42) that would need to 
purchase software are large entities. The agency estimates that each of 
these firms would need to purchase about 3 copies of the software or 
126 copies (42 x 3). Thus, the total one-time cost for software is 
$68,500 ((148 + 126) x $250). Training costs include the cost of the 
software training course (estimated at $150 for a 6-hour course) and 
the wages of the employees attending the course (assuming an average 
weighted wage rate of $40 per hour). We estimate that applicants would 
train two employees per software purchase (548 employees), for a total 
one-time cost of $213,720 (($150 + (6 hours x $40)) x 548). The total 
one-time cost for software and training combined is estimated to be 
$282,220 ($68,500 + $213,720).
    The cost to convert the applicable labeling to an electronic format 
is a one-time cost. The cost of conversions for new NDAs, BLAs, and 
ANDAs will be nominal because the file would be in a format easily 
convertible to PDF. The PDF file, being the finished product, would be 
proofread for quality assurance. Annually, we receive approximately 
1,650 supplements that would be subject to the final rule. Because the 
majority of products for which supplements are submitted would have had 
labeling changes within the last few years, most labeling files would 
be easily accessible. Currently, the labeling in about 40 percent (660) 
of the supplements received is submitted in a PDF format and would 
require an estimated additional 15 minutes to comply with this final 
rule. The labeling in the remaining 60 percent (990) will require an 
estimated 5 hours to process and proofread. Thus, the total number of 
hours needed to convert applicable labeling in supplements to a PDF 
file format is 5,115 ((0.25 x 660) + (5 x 990)).
    Labeling in most of the annual reports will also need to be 
converted. The conversion of this labeling to a PDF file for about 40 
percent of NDA annual reports (975), 50 percent of ANDA annual reports 
(2,295), and 40 percent of

[[Page 69019]]

BLA annual reports (40), would require additional time to complete 
because they are not in a format easily convertible to PDF. We estimate 
that these annual reports would require 10 hours to complete, for a 
total of 33,100 hours ((975 + 2,295 + 40) x 10). For the content of 
labeling in the remaining annual reports (3,815), an estimated 40 
percent (1,526) would require 15 minutes to process because they are 
currently in PDF format, and the remaining 2,289 annual reports will 
require approximately 5 hours to process and proofread, for a total of 
11,827 hours ((1,526 x 0.25) + (2,289 x 5)). Thus, the total number of 
hours needed to convert all applicable labeling to a PDF file format in 
supplements and annual reports is 50,042 (5,115 + 33,100 + 11,827). 
Using the weighted average wage rate ($40 per hour), the total one-time 
costs to convert applicable labeling in supplements and annual reports 
would be about $2.0 million (50,042 x $40). The cost for the entire 
rule is estimated to be about $2.3 million ($0.3 million (software and 
training + $2.0 million labeling)).
    Approximately 300 domestic entities would be affected by this final 
rule, about 240 of which meet the Small Business Administration's 
definition of a small entity (fewer than 750 employees for drug product 
manufacturers and fewer than 500 employees for biological product 
manufacturers). The economic impact of this final rule would vary by 
firm depending on the number of applications they hold and whether or 
not the company has PDF capabilities. The number of applications per 
firm ranges from 1 to 124, with a median of 4 applications per small 
entity. The average small entity has about 7 applications, and, 
assuming a worst case scenario--the firm did not have the content of 
labeling in an electronic format and needed to purchase software and 
train employees--this rule would cost the average small firm about 
$4,000 ($1,030 software and training + (7 x 10 hours x $40)), which is 
about $550 per application. Because these costs would almost certainly 
be less than 1 percent of product revenues, the agency certifies that 
this final rule will not have a significant economic impact on a 
substantial number of small entities.

List of Subjects

21 CFR Part 314

    Administrative practice and procedure, Confidential business 
information, Drugs, Reporting and recordkeeping requirements.

21 CFR Part 601

    Administrative practice and procedure, Biologics, Confidential 
business information.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act, the Public 
Health Service Act, and under authority delegated to the Commissioner 
of Food and Drugs, 21 CFR parts 314 and 601 are amended as follows:

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG

0
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, 355a, 356, 
356a, 356b, 356c, 371, 374, 379e.

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2. Section 314.50 is amended by revising paragraph (l)(1); by adding 
headings for paragraphs (l)(2), (l)(3), and (l)(4); by removing from 
paragraphs (l)(2) and (l)(3) the word ``shall'' and adding in its place 
the word ``must''; and by adding paragraph (l)(5) to read as follows:


Sec.  314.50  Content and format of an application.

* * * * *
    (l) Format of an original application. (1) Archival copy. The 
applicant must submit a complete archival copy of the application that 
contains the information required under paragraphs (a) through (f) of 
this section. FDA will maintain the archival copy during the review of 
the application to permit individual reviewers to refer to information 
that is not contained in their particular technical sections of the 
application, to give other agency personnel access to the application 
for official business, and to maintain in one place a complete copy of 
the application. Except as required by paragraph (l)(1)(i) of this 
section, applicants may submit the archival copy on paper or in 
electronic format provided that electronic submissions are made in 
accordance with part 11 of this chapter.
    (i) Labeling. The content of labeling required under Sec.  
201.100(d)(3) of this chapter (commonly referred to as the package 
insert or professional labeling), including all text, tables, and 
figures, must be submitted to the agency in electronic format as 
described in paragraph (l)(5) of this section. This requirement is in 
addition to the requirements of paragraph (e)(2)(ii) of this section 
that copies of the formatted label and all labeling be submitted. 
Submissions under this paragraph must be made in accordance with part 
11 of this chapter, except for the requirements of Sec.  11.10(a), (c) 
through (h), and (k), and the corresponding requirements of Sec.  
11.30.
    (ii) [Reserved]
    (2) Review copy. * * *
    (3) Field copy. * * *
    (4) Binding folders. * * *
    (5) Electronic format submissions. Electronic format submissions 
must be in a form that FDA can process, review, and archive. FDA will 
periodically issue guidance on how to provide the electronic submission 
(e.g., method of transmission, media, file formats, preparation and 
organization of files).

0
3. Section 314.81 is amended by revising paragraph (b)(2)(iii) to read 
as follows:


Sec.  314.81  Other postmarketing reports.

* * * * *
    (b) * * *
    (2) * * *
    (iii) Labeling. (a) Currently used professional labeling, patient 
brochures or package inserts (if any), and a representative sample of 
the package labels.
    (b) The content of labeling required under Sec.  201.100(d)(3) of 
this chapter (i.e., the package insert or professional labeling), 
including all text, tables, and figures, must be submitted in 
electronic format. Electronic format submissions must be in a form that 
FDA can process, review, and archive. FDA will periodically issue 
guidance on how to provide the electronic submission (e.g., method of 
transmission, media, file formats, preparation and organization of 
files). Submissions under this paragraph must be made in accordance 
with part 11 of this chapter, except for the requirements of Sec.  
11.10(a), (c) through (h), and (k), and the corresponding requirements 
of Sec.  11.30.
    (c) A summary of any changes in labeling that have been made since 
the last report listed by date in the order in which they were 
implemented, or if no changes, a statement of that fact.
* * * * *

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4. Section 314.94 is amended by revising paragraph (d)(1) to read as 
follows:


Sec.  314.94  Content and format of an abbreviated application.

* * * * *
    (d) * * * (1) The applicant must submit a complete archival copy of 
the abbreviated application as required under paragraphs (a) and (c) of 
this section. FDA will maintain the archival copy during the review of 
the application to permit individual reviewers to refer to information 
that is not contained in their particular technical sections of the 
application, to give other agency personnel access to

[[Page 69020]]

the application for official business, and to maintain in one place a 
complete copy of the application.
    (i) Format of submission. An applicant may submit portions of the 
archival copy of the abbreviated application in any form that the 
applicant and FDA agree is acceptable, except as provided in paragraph 
(d)(1)(ii) of this section.
    (ii) Labeling. The content of labeling required under Sec.  
201.100(d)(3) of this chapter (commonly referred to as the package 
insert or professional labeling), including all text, tables, and 
figures, must be submitted to the agency in electronic format as 
described in paragraph (d)(1)(iii) of this section. This requirement 
applies to the content of labeling for the proposed drug product only 
and is in addition to the requirements of paragraph (a)(8)(ii) of this 
section that copies of the formatted label and all proposed labeling be 
submitted. Submissions under this paragraph must be made in accordance 
with part 11 of this chapter, except for the requirements of Sec.  
11.10(a), (c) through (h), and (k), and the corresponding requirements 
of Sec.  11.30.
    (iii) Electronic format submissions. Electronic format submissions 
must be in a form that FDA can process, review, and archive. FDA will 
periodically issue guidance on how to provide the electronic submission 
(e.g., method of transmission, media, file formats, preparation and 
organization of files).
* * * * *

PART 601--LICENSING

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5. The authority citation for 21 CFR part 601 continues to read as 
follows:

    Authority: 15 U.S.C. 1451-1561; 21 U.S.C. 321, 351, 352, 353, 
355, 356b, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C. 
216, 241, 262, 263, 264; sec. 122, Pub. L. 105-115, 111 Stat. 2322 
(21 U.S.C. 355 note).

0
6. Add 601.14 to subpart C to read as follows:


Sec.  601.14  Regulatory submissions in electronic format.

    (a) General. Electronic format submissions must be in a form that 
FDA can process, review, and archive. FDA will periodically issue 
guidance on how to provide the electronic submission (e.g., method of 
transmission, media, file formats, preparation and organization of 
files.)
    (b) Labeling. The content of labeling required under Sec.  
201.100(d)(3) of this chapter (commonly referred to as the package 
insert or professional labeling), including all text, tables, and 
figures, must be submitted to the agency in electronic format as 
described in paragraph (a) of this section. This requirement is in 
addition to the provisions of Sec. Sec.  601.2(a) and 601.12(f) that 
require applicants to submit specimens of the labels, enclosures, and 
containers, or to submit other final printed labeling. Submissions 
under this paragraph must be made in accordance with part 11 of this 
chapter except for the requirements of Sec.  11.10(a), (c) through (h), 
and (k), and the corresponding requirements of Sec.  11.30.

    Dated: July 31, 2003.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 03-30641 Filed 12-9-03; 8:45 am]
BILLING CODE 4160-01-S