PLR


[ref: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/LawsActsandRules/ucm084159.htm

Which products are affected under the Physician Labeling Requirement?

Physician Labeling Rule affects the following products:

  • New NDAs, BLAs, and efficacy supplements (e.g., new indication, new dosage regimen, new route of administration).
  • Applications and efficacy supplements approved up to 5 years prior to final rule

Older products are on an implementation schedule as follows:
NDA, BLA, or efficacy supplement
Labeling must conform
Submitted on or after 06/30/06
At time of submission
Pending on 06/30/06 Approved on 06/30/05 – 06/30/06
06/30/09 (3 years)
Approved 06/30/04 – 06/29/05
06/30/10 (4 years)
Approved 06/30/03 – 06/29/04
06/30/11 (5 years)
Approved 06/30/02 – 06/29/03
06/30/12 (6 years)
Approved 06/30/01 – 06/29/02
06/30/13 (7 years)
Approved Pre-06/30/01
Voluntary at any time
(encouraged to conform)





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 are specific LOINC codes for the PPI and the MedGuide subsections of the Patient Counseling 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.

References
:
SPL Standard for Content of Labeling Technical Qs & As



What are the foreign language requirements?

Currently, foreign language directions do not need to be submitted in SPL.
References
:
SPL Standard for Content of Labeling Technical Qs & As



When do I need to Cross-reference?


When information about the same topic is contained in more than one section, the section with the greatest clinical relevance (i.e., containing the most important information relevant to prescribing) will typically include a succinct description and will cross-reference the related sections that contain additional detail. If the detailed information is appropriately divided into more than one section, those sections should cross-reference each other. In some cases, cross references are required (e.g., §201.57(c)(1), (c)(6)(iv) and (c)(15)(ii)).


References:
Labeling for Human Prescription Drug and Biological Products --- Implementing New Content and Format Requirements (draft) Jan 2006 Labeling See http://www.fda.gov/cder/regulatory/physLabel/default.htm for any updates to the guidance.
See http://www.fda.gov/OHRMS/DOCKETS/98fr/06-545.pdf for the Final Rule: Requirements on the Content and Format of Labeling for Human Prescription Drug and Biological Products, January 24, 2006. Effective June 30, 2006



What format should cross-references be in? / What is the preferred presentation of cross-references?

In highlights…..

The preferred presentation of cross-references is the numerical identifier in parentheses following the summarized labeling information (e.g., (1.1)).

In Full Prescribing Information (FPI)…..
The preferred presentation of cross-references is the section heading followed by the numerical identifier (e.g., see Indications and Usage (1.1)). Because cross-references are embedded in the text in the FPI, the use of italics to achieve emphasis is encouraged.

References:
Labeling for Human Prescription Drug and Biological Products --- Implementing New Content and Format Requirements (draft) Jan 2006 Labeling
See http://www.fda.gov/cder/regulatory/physLabel/default.htm for any updates to the guidance.
See http://www.fda.gov/OHRMS/DOCKETS/98fr/06-545.pdf for the Final Rule: Requirements on the Content and Format of Labeling for Human Prescription Drug and Biological Products, January 24, 2006. Effective June 30, 2006



Can I retain within-document hypertext links if they were present in a Word or PDF file of content 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.

References
:
SPL Standard for Content of Labeling Technical Qs & As




What if I have multiple ‘Initial U.S. Approval’ (§201.57(a)(3)) dates?

Multiple dates should not be listed for products with multiple formulations approved or licenses in different years. For these products, list the initial approval date of the new molecular entity, new biologic product, or new combination of active ingredients.


References:
Labeling for Human Prescription Drug and Biological Products --- Implementing New Content and Format Requirements (draft) Jan 2006 Labeling
See http://www.fda.gov/cder/regulatory/physLabel/default.htm for any updates to the guidance.
See http://www.fda.gov/OHRMS/DOCKETS/98fr/06-545.pdf for the Final Rule: Requirements on the Content and Format of Labeling for Human Prescription Drug and Biological Products, January 24, 2006. Effective June 30, 2006




What format should the information within a boxed warning be in?

FDA recommends the information in the BOXED WARNING be presented in a bulleted format with each bullet communicating a discrete warning or contraindication. In rare instances, the BOXED WARNING in the FPI may be sufficiently concise to warrant repeating the statement verbatim in the Boxed Warning in Highlights.


References:
Labeling for Human Prescription Drug and Biological Products --- Implementing New Content and Format Requirements (draft) Jan 2006 Labeling
See http://www.fda.gov/cder/regulatory/physLabel/default.htm for any updates to the guidance.
See http://www.fda.gov/OHRMS/DOCKETS/98fr/06-545.pdf for the Final Rule: Requirements on the Content and Format of Labeling for Human Prescription Drug and Biological Products, January 24, 2006. Effective June 30, 2006




Can there be than one title in the header? (e.g., Example Tablets, 10mg, and Example, Suspension, 1mg/mL)?
No. There should only be one <title> element in SPL. However, the schema permits <br/> tags within the <title> element for multi-line titles.
References
:
SPL Standard for Content of Labeling Technical Qs & As




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.

References
:
SPL Standard for Content of Labeling Technical Qs & As



Can SPL have a section that contains other sections but does not contain any other text?

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 . . .


References:
SPL Standard for Content of Labeling Technical Qs & As





Do I always have to associate Table Titles, Notes and Table information to the Table?

Table titles, notes and information must be associated with the table at all times. This associated information is expected by the FDA, failure to do so may result in non-compliance of your submission.


References:
SPL Implementation Guide Release 4/July 2008
See http://www.fda.gov/oc/datacouncil/spl.html for any updates to the Implementation Guide


What format should my images be in?

The 'FDA SPL Implementation Guide for FDA Content of Labeling Submissions' recommends that all images be in the *.jpg format or *.gif format. In A4L, Images are automatically converted into *.jpg when exported.


References:
SPL Implementation Guide Release 4/July 2008
See http://www.fda.gov/oc/datacouncil/spl.html for any updates to the Implementation Guide.



What size and resolution should my images be in?

The SPL schema does not allow for resizing graphics or changing the resolution of graphic files.
Thus, all images are rendered in the browser as-is, with all characteristics of the actual graphic file itself. To ensure that a graphic will appear as desired, the graphic file should be edited to a dimension appropriate for its presentation within the browser. The recommended resolution is 300 dpi. Images greater than 300 dpi should not be submitted to keep the file size manageable.


References:
SPL Implementation Guide Release 4/July 2008
See http://www.fda.gov/oc/datacouncil/spl.html for any updates to the Implementation Guide.



My tables don’t look proper. Can I format my table (i.e., cell spacing etc) to reflect the way I want it to look?

Attributes for table elements are currently not supported by the standard stylesheet and thus only minimal formatting will be seen by the FDA when they view your label. It is stated that “
SPL is used to communicate labeling content rather than the exact representation of drug information present in a typeset document. The table presentation in SPL is unlikely to exactly duplicate the presentation in word processed or typeset versions of the package insert”.

References:
SPL Implementation Guide Release 4/July 2008
See http://www.fda.gov/oc/datacouncil/spl.html for any updates to the Implementation Guide.



Can I rename Section Headings (ie. ‘Indications and Usage’) to something else?


The default SPL template complies with the section headers specified in §201.56 (d)(1) and §201.56(e)(1). Renaming these section headers may result in non-compliance of your submission.

References:
Final Rule: Requirements on the Content and Format of Labeling for Human Prescription Drug and Biological Products, January 24, 2006. Effective June 30, 2006

http://www.fda.gov/OHRMS/DOCKETS/98fr/06-545.pdf
Code of Federal Regulations http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm




Can I Rearrange Document Sections?

The default SPL template complies with the section headers specified in §201.56 (d)(1) and §201.56(e)(1).
Rearranging these sections may result in your document no longer complying. However, especially in the case of legacy labels, these may be accepted by the FDA.

References
:
Final Rule: Requirements on the Content and Format of Labeling for Human Prescription Drug and Biological Products, January 24, 2006. Effective June 30, 2006
http://www.fda.gov/OHRMS/DOCKETS/98fr/06-545.pdf
Code of Federal Regulations http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm




Can I delete sections, subsections?

Any required section, subsection, or specific information that is clearly inapplicable must be omitted from Highlights and the FPI. For example, if a drug is indicated for use only in males, and there are no preclinical data or clinical data relevant to women of childbearing potential, the ‘Pregnancy, Labor and Delivery and Nursing Mothers’ subsections would be omitted because they are not applicable.


When a section or subsection is omitted from the FPI, the section must also be omitted from the Contents (§201.56(d)(4)). The heading
‘Full Prescribing Information:Contents´ must be followed by an asterisk and the following statement must appear at the end of the Contents: “*Sections or subsections omitted from the Full Prescribing Information are not listed” (§201.56(d)(4).

In the example of a drug indicated for use only in males, the Contents heading appears as follows:

FULL PRESCRIBING INFORMATION: CONTENTS*
The numbering in the Contents and FPI appears as follows:
8 USE IN SPECIFIC POPULATIONS
8.4 Pediatric Use
8.5 Geriatric Use

9 DRUG ABUSE AND DEPENDENCE

At the end of the Contents, the following statement appears:
*Sections or subsections omitted from the Full Prescribing Information are not listed.


References:
Labeling for Human Prescription Drug and Biological Products --- Implementing New Content and Format Requirements (draft) Jan 2006 Labeling
See http://www.fda.gov/cder/regulatory/physLabel/default.htmfor any updates to the guidance.




Can my document contain formatted (ie. bold, underline and italicized) text?

A major reason behind the implementation of SPL documents is to separate formatting from content. However, minimal formatting such as bold, italics and underline can be used and is accepted. In addition, the following combinations of these attributes are also allowed:

· bold-italics
· italics-underline
· bold-underline
· bold-italics-underline.

References:
SPL Implementation Guide Release 4/July 2008
See http://www.fda.gov/oc/datacouncil/spl.html for any updates to the Implementation Guide.




Can I add symbols or special characters? / What kind of symbols or special characters can I add?

Certain symbols and special characters can be included in the text content or the header of the document. The following symbols and special characters are accepted by the FDA:



  • mg/m2 (superscript)
  • C12H12O6 (subscript)
  • ©
  • ◦ (degree)
  • ≤, <, ±
  • - (m-dash)
  • Β (e.g., β-isomer)
  • ® (e.g., Registered 1996)
  • ™ (Trademark)
  • &
  • †, ‡
  • §
  • ‘ (apostrophe)

References:
SPL Implementation Guide Release 4/July 2008
See http://www.fda.gov/oc/datacouncil/spl.html for any updates to the Implementation Guide.



Can I use specific graphics (eg. Registered trademark symbols, controlled substance symbols, corporate or product logos)?

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 (eg. CII).


References: SPL Standard for Content of Labeling Technical Qs & As



Can I use a graphic for the Rx symbol?
No. The document LOINC code for SPL will identify SPL as human prescription drug labeling.

References: SPL Standard for Content of Labeling Technical Qs & As




What is the numbering format for footnotes?


  • Footnotes are rendered using Arabic numbers (i.e., 1,2,3,4 etc.) within the text body of the document.
  • Within tables, footnotes are rendered using footnote marks in the series * # † ‡ § ¶ ♠ ♥ ♦ ♣
    Footnotes within tables are rendered at the bottom of the table.
References:
SPL Implementation Guide Release 4/July 2008
See http://www.fda.gov/oc/datacouncil/spl.html for any updates to the Implementation Guide.



Is there a specific numbering style or bullet type for lists?
The 'FDA SPL Implementation Guide for FDA Content of Labeling Submissions' specifies a standard set of specialized markers for numbered and bulleted lists.

Ordered lists can be listed in any of the following ways:

  • Arabic (1, 2, 3 …)
  • Little Roman (i, ii. iii …)
  • Big Roman (I, II, III…)
  • Little Alpha (a,b,c…)
  • BigAlpha (A,B,C….)

Unordered lists can be listed in any of the following ways:

·Disc (List bullets are simple solid discs: ●)
·Circle (List bullets are hollow discs: )
·Square (List bullets are solid squares: )

References:
SPL Implementation Guide Release 4/July 2008
See http://www.fda.gov/oc/datacouncil/spl.html for any updates to the Implementation Guide.




Can the proprietary and established (or proper) names be presented on the same line in Highlights?

To conserve space in Highlights, the proprietary and established names should be presented on the same line, unless they are too long. In that case, the established name should be presented on the line underneath the proprietary name.


References:
Labeling for Human Prescription Drug and Biological Products --- Implementing New Content and Format Requirements (draft) Jan 2006 Labeling
See http://www.fda.gov/cder/regulatory/physLabel/default.htm for any updates to the guidance.





Is there a preferred format for the revision date?/What format should the revision date be in?

The date of the most recent revision must be presented at the end of Highlights in accordance with §201.57(a)(15). The preferred format is “Revised: Month (yyyy) or Revised: 0m/yyyy” (i.e., Revised: June 2003 or Revised: 06/2003)

References:
Labeling for Human Prescription Drug and Biological Products --- Implementing New Content and Format Requirements (draft) Jan 2006 Labeling http://www.fda.gov/cder/guidance/6005dft.pdf
See http://www.fda.gov/cder/regulatory/physLabel/default.htm for any updates to the guidance.



Should Latin abbreviations be used in the ‘Dosage and Adminsitration’ section (e.g., qd versus once daily?)

FDA recommends that Latin abbreviations be avoided because of the greater potential for medication errors should an abbreviation be misread.


References:
Labeling for Human Prescription Drug and Biological Products --- Implementing New Content and Format Requirements (draft) Jan 2006 Labeling
See
http://www.fda.gov/cder/regulatory/physLabel/default.htm for any updates to the guidance.




How should the ‘Contraindications’ section be formatted?

FDA recommends that each contraindication be identified by its own subheading.


References:
Labeling for Human Prescription Drug and Biological Products --- Implementing New Content and Format Requirements (draft) Jan 2006 Labeling
See
http://www.fda.gov/cder/regulatory/physLabel/default.htm for any updates to the guidance.

Recent Major Changes


Links

Physicians Labeling Rule: http://www.fda.gov/cder/regulatory/physLabel/default.htm