Guidance for Industry
SPL Standard for Content of Labeling
Technical Qs & As
(PDF
version of this document)
U.S. Department of
Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
December 2005
Electronic
Submissions
Guidance for Industry
SPL Standard for Content of Labeling
Technical Qs & As
Additional copies
are available from:
Office of Training and Communication
Division of Drug Information, HFD-240
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
(Tel) 301-827-4573
http://www.fda.gov/cder/guidance/index.htm
U.S. Department of
Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
December 2005
Electronic Submissions
Guidance for
Industry1
SPL Standard for Content of Labeling
Technical Qs & As
This guidance represents the Food
and Drug Administration's (FDA's) current thinking on this
topic. It does not create or confer any rights for or on any
person and does not operate to bind FDA or the public. You can
use an alternative approach if the approach satisfies the
requirements of the applicable statutes and regulations. If
you want to discuss an alternative approach, contact the FDA
staff responsible for implementing this guidance. If you
cannot identify the appropriate FDA staff, call the
appropriate number listed on the title page of this guidance.
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I. INTRODUCTION
This guidance is intended to assist
sponsors who submit the content of their product labeling to the
Center for Drug Evaluation and Research (CDER) using the structured
product labeling standard (SPL) in extensible markup language (XML).
The guidance also provides information to CDER staff who review and
manage that product information using the Electronic Labeling
Information Processing System (ELIPS). We anticipate that additional
guidance will be provided as new questions arise about the use of
SPL and/or ELIPS.
FDA's guidance documents, including
this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the Agency's current
thinking on a topic and should be viewed only as recommendations,
unless specific regulatory or statutory requirements are cited. The
use of the word should in Agency guidances means that
something is suggested or recommended, but not required.
II. BACKGROUND
In the Federal Register of
December 11, 2003 (68 FR 69009), FDA published final regulations
requiring that the content of labeling be submitted to FDA
electronically for new drug applications (NDAs), abbreviated new
drug applications (ANDAs), certain biologics license applications (BLAs),
and annual reports (see 21 CFR 314.50(l), 314.94(d), 601.14(b), and
314.81(b), respectively). The regulations state that the content of
labeling must be submitted electronically "in a form" that FDA can
process, review, and archive. Initially, CDER accepted content of
labeling in portable document format (PDF). Then, in anticipation of
a change to the SPL format, in September 2004, CDER announced it
would accept content of labeling in PDF and in SPL until the fall of
2005 when PDF would be eliminated. On October 21, 2005, CDER
announced in public docket number 92S-0251 the following new
procedures for electronic submission of content of labeling,
effective October 31, 2005:
- PDF is no longer a format FDA can
use to accept the content of labeling submitted electronically.
- Sponsors should use the SPL
standard when submitting all labels, labeling supplements, and
amendments to FDA in XML.
The Agency also announced the
development of a new automated system, ELIPS, to process, review,
and archive the content of labeling using the SPL standard. This
system was also implemented on October 31, 2005.
One of the advantages of using the
SPL standard in product labeling submissions is that SPL will make
the labeling computer readable. Under a collaboration with the
National Library of Medicine (NLM), FDA-approved product information
will be sent to the NLM for inclusion in the NLM's DailyMed, an
online repository that will make the most current medical product
information available to the public on the Internet free of charge.
As a result of initial experience
using the SPL format, FDA is providing guidance on a number of
technical questions. The Agency plans to provide additional guidance
as new questions arise. Please also see the glossary for definitions
of useful terms related to the SPL-ELIPS efforts.
- If you have additional questions
regarding SPL submissions, you can contact Lonnie Smith at
smithlo@cder.fda.gov
For questions on the guidance for
industry Providing Regulatory Submissions in Electronic Format -
Content of Labeling,2
contact the appropriate electronic submission coordinator at
esub@cder.fda.gov
Specific questions pertaining to content of labeling should be
directed to the appropriate review division or office.
III. TECHNICAL QUESTIONS AND
ANSWERS
Beginning October 31, 2005, you
should submit the content of labeling to CDER in SPL. This date
corresponds with the implementation date for ELIPS. Because ELIPS is
compatible with SPL, FDA will use ELIPS to process, review, and
archive the electronic content of all labeling for drugs
submitted to CDER under an ANDA, NDA, or BLA.
SPL is the format for submitting the
electronic content of labeling. Electronic content of labeling must
be submitted with an original application, with certain amendments
and supplements (those that contain changes to the content of
labeling), and with annual reports.3
No. Only the electronic content of
labeling is submitted using the SPL standard (including the XML
document and all associated image files referenced in the XML
document, such as chemical structures or graphs included in a
clinical studies section). Other labeling documents (e.g., the
annotated labeling, container labels, carton labels, and final
printed labeling) should not be submitted using the SPL standard.
Yes. As was previously the case, the
annotated labeling should still be submitted. Now, instead of
submitting the content of labeling in PDF, as was the previous
practice, sponsors should submit it using the SPL standard.
5. Will the sponsor still have
to submit the final printed labeling (FPL) (the graphic version of
the label)?
Yes. The submission of FPL is still
required in A7 314.50(e)(2)(ii) of the regulations. The SPL version
will only replace the PDF version of the content of labeling.
6. How do I send my SPL to the
FDA when I am submitting an electronic submission (i.e., eANDA,
eNDA, eBLA, or hybrid submission)?
When submitting the content of
labeling using SPL as part of an eANDA, eNDA, eBLA or hybrid
submission, the SPL version should be included in a folder marked
spl within the labeling folder (for more information, see the
guidance for industry Providing Regulatory Submissions in
Electronic Format - Content of Labeling).
When accompanying a paper
submission, the SPL version should be sent on electronic media
(e.g., a CD or floppy disk). The SPL should be included in a folder
marked spl (see the guidance for industry Providing
Regulatory Submissions in Electronic Format - Content of Labeling).
For products regulated by CDER, see
http://www.fda.gov/cder/regulatory/ersr/default.htm for
the address where to send SPL.
CDER has been accepting SPL, as well
as PDF, for the content of labeling since September 2004. At that
time, we announced that we would begin to accept only SPL beginning
in the fall of 2005. On October 31, 2005, CDER began accepting only
SPL for the content of labeling.
10. Will sponsors of generic
drugs be granted a grace period (a period of time after the
content of labeling for the reference listed drug (RLD) becomes
available in SPL), or should they submit SPL beginning October 31,
2005?
We recommend that sponsors contact
the Office of Generic Drugs for questions about timing of
submissions of generic drug SPL.
11. For generic drug SPL
submissions, should we include the content of the labeling for the
RLD electronically?
The content of labeling for the RLD
may be provided in paper or electronic format.
12. Can the electronic labeling
be submitted under separate cover and cross-referenced to a paper
submission for all types of submissions, including new ANDAs,
supplements, and annual reports, or should the entire submission
be done electronically?
A combination of paper submission
and electronic labeling can be submitted.
13. Does the SPL content of
labeling replace the 12 copies of paper labeling normally
submitted, or is it in addition to the 12 paper copies?
The content of labeling (which was
in PDF, but is now in SPL format) is in addition to the 12 copies of
paper labeling (see 314.50(L)(1)(i)).
No. SPL should be submitted to the
Agency's Electronic Document Room with documentation appropriate for
the type of electronic submission.
You should no longer submit the
content of labeling in PDF. However, sponsors can submit PDF
versions of other labeling (e.g., cartons, container labels, paper
inserts).
If labeling discussions are
occurring in MS Word (expected initially), at this time, FDA
requests that sponsors provide the MS Word file to support review of
the labeling.
16. If we do not have the
technology to submit the labeling in eCTD format, can we submit it
in electronic NDA format?
Yes. You can submit in eNDA format.
Both components should be sent to
the central document room (as was done before implementation of SPL).
As before, the staff will upload the electronic component.
Yes. SPL should be included with the
initial submission. Before an approval action, FDA may ask a sponsor
to submit SPL updated to include the changes that occurred as a
result of labeling discussions with the Agency.
19. Should companies resubmit
labels submitted before October 31, 2005, in SPL that are
currently under review?
No, but sponsors should work with
the individual review division or divisions to ensure that SPL is
available for new products within a reasonable time frame.
20. Is it possible that the FDA
will refuse to file my submission if I do not provide SPL
beginning October 31, 2005?
That is a possibility, but we will
work with you to help you submit the SPL.
An SPL document can be created using
a variety of possible tools, ranging from a general-purpose word
processor or XML editor to an SPL-specific editing tool. The type of
tool suitable for a specific organization will vary depending upon a
wide variety of business and technical factors. Whatever tool is
used, the final SPL document will be independent of the tool used
for creation; all tools should be valid against the SPL schema and
should conform to FDA guidance documents.
XML is a standard language for
exchanging structured information or documents. The details are
frequently provided in what is called a schema. SPL is a standard
for exchanging the information in product labeling using XML. The
details for the SPL XML submission is in a schema.
The SPL schema currently being used
is on the FDA Web site at
http://www.fda.gov/oc/datacouncil/spl.html This version is a
subset of the full HL7 SPL Release 2 schema.
24. What happens when a new
version of the schema is released? Should sponsors resubmit
current labels according to the new schema?
When the SPL schema is revised, FDA
will inform sponsors regarding the time frame for implementation. We
anticipate that resubmissions will not be necessary if a new schema
is adopted. However, this policy depends on the specific schema
changes adopted.
25. Should I submit patient
package inserts (PPIs), medication guides (MedGuides), and patient
information leaflets (PILs) in SPL?
If your package insert has a PPI,
MedGuide, or PIL at the end, that information should be included in
SPL. There is a specific LOINC code for Supplemental Patient
Information (i.e., patient information following the How
Supplied section of labeling) and for the PPI and the
MedGuide subsections of the Supplemental Patient Information
section. Each of the approved patient labeling documents should have
a separate LOINC code.
Patient information that is not part
of the approved labeling, such as patient information produced by
third parties, should not be included in SPL. Questions regarding
the inclusion of approved labeling for patients in SPL should be
directed to ONDEIO@cder.fda.gov
or to the appropriate review division.
26. Should SPL contain the
entire content of labeling or just the portion of the content that
has changed since the last submission?
All submissions should include the
entire content of labeling in SPL. FDA cannot support partial
submissions at this time.
27. The SPL schema provides
tags to identify insertions and deletions of content in an SPL
document. Should we submit a redlined or annotated version of the
labeling, indicating version to version changes?
No. You should not use the tags
provided in the schema to mark up the insertion and deletion of
content. Using SPL instead of PDF will not affect the labeling
discussions with FDA (including the submission of redlined and
annotated documents).
28. Should
manufacturer-specific graphics (e.g., registered trademark
symbols, controlled substance symbols, corporate or product logos)
be used in SPL?
No. Corporate or product logos, or
similar graphics, are not considered part of the content of labeling
and therefore should not be included in SPL. Trademark symbols can
be included using standard text and unicode characters.
Controlled substance symbols can be provided as text (e.g., CII)
No. The document LOINC code for SPL
will identify SPL as human prescription drug labeling.
30. Can a sponsor retain
within-document hypertext links if they were present in a Word or
PDF file of content of labeling (e.g., clickable
cross-references)?
Yes. Hypertext links can be retained
within the SPL document. However, these links should be restricted
to semantic links that are strictly identified within the
content of labeling (e.g., 93see CLINICAL PHARMACOLOGY,94 or
93see references/footnotes94). Because links to documents
outside of the SPL document may change without a change in the
content of labeling, they should not be used.
31. Can there be more than one
title in a header (e.g., Example Tablets, 10 mg, and
Example Suspension, 1 mg/mL)?
No. There should only be one <title>
element in SPL. However, the schema permits <br/> tags within the
<title> element for multiline titles.
32. Will the FDA distribute SPL
documents to the NLM with minor changes to the sections without
changing the section identifiers from those submitted?
No. FDA will change the section
identifiers from those submitted when it transmits the SPL to the
National Library of Medicine (NLM), consistent with the principle
that new identifiers should be changed when a section (or an
enclosed section) changes.
Yes. The scope of a section
identifier is all of the child elements of that section.
34. If a section or subsection
is relocated without change to its content, should its section
identifier be changed?
No. The identifier of a section that
is relocated without content change remains unchanged, but the
identifiers of any enclosing sections before and/or after the
relocation should be changed, as should the document identifier.
Yes. A section can contain only
subsections and no text. For example,
Precautions
General: The use of this drug may
promote . . .
Skeletal Muscle: In Phase 3 complicated skin and skin structure
infections . . .
36. Are the active and inactive
ingredients included in the data elements?
Yes. All the active ingredients and
inactive ingredients in the content of labeling are included as data
elements.
FDA electronically transmits SPL to
NLM.
38. How will the sponsor know
that the correct (i.e., agreed upon) labeling is transmitted to
NLM?
The sponsor will receive a rendering
of the content of labeling transmitted to NLM with the action
letter.
39. If the sponsor notes an
inconsistency in the label, what is the process to make the
necessary changes?
As was previously the case, if a
sponsor notes an inconsistency, the sponsor should contact the
review division.
No. SPL is processed using ELIPS
with defined procedures for allowing sponsors to know when to expect
the posting of labeling changes. There is no specific notification
to the sponsor that a label has been posted to NLM.
41. Should I submit SPL
with an annual report? And should two paper copies of an NDA
annual report still be submitted to the appropriate review
division?
Submit SPL with your annual report
if this is your first SPL submission since October 31, 2005, or if
there have been changes to the content of labeling since your last
SPL submission. If there have been no changes since your last
submission of SPL, then it is not necessary to submit any SPL with
an annual report. Two paper copies of formatted labeling with each
annual report are still required under 21 CFR parts 314 and 601.
42. What is the process for the
review of SPL content of labeling submitted with an annual report?
When is the SPL transmitted to NLM? How will the sponsor be
notified?
For annual reports that contain the
first submission of SPL for a specific application, FDA will forward
the SPL to NLM after review of the content of labeling. Because
annual reports contain the version of labeling in current use, the
sponsor will not be notified unless the FDA reviewer finds a problem
that should be corrected.
43. If the first SPL submission
is a supplement (i.e., not an annual report), should both the
current and proposed labeling be submitted in SPL, or is it
sufficient to submit only the proposed label in SPL?
For supplements, only the proposed
content of labeling should be submitted in SPL.
See FDA Data Standards Council
Structured Product Labeling Resources on the Internet at
http://www.fda.gov/oc/datacouncil/spl.html and
http://www.hl7.org
Currently, foreign language
directions do not need to be submitted in SPL.
1 This guidance has been prepared by
the Structured Product Labeling (SPL) Project Development Staff in
the
Office of Business Process Support
in the Center for Drug Evaluation and Research (CDER) at the
Food and Drug Administration.
2 We update guidances periodically.
To make sure you have the most recent version of a guidance, check
the CDER guidance page at
http://www.fda.gov/cder/guidance/index.htm
3 See 21 CFR 314.50(l) for NDAs,
314.94(d) for ANDAs, 601.14(b) for BLAs, and 314.81(b) for annual
reports.
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Date created: December 8, 2005 |