FR Doc 03-30641

[Federal Register: December 11, 2003 (Volume 68, Number 238)]
[Rules and Regulations]
[Page 69009-69020]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr11de03-4]

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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 http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://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.

0
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.
* * * * *

0
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

0
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