“Paperless Labeling Rule” Proposed Rule First Look January 2015

Comment Period Full Title: Electronic Distribution of Prescribing Information for Human Prescription Drugs, Including Biological Products Issued 18-Dec-2014 Comment Period ends 18-Mar-2015 Comments to or to Division of Dockets Managementhttp://

Locator Information Action: Proposed rule. Document Citation:79 FR Page: (22 pages) CFR:21 CFR 201; 21 CFR 606; 21 CFR CFR CFR CFR 610 Agency/Docket Number: Docket No. FDA-2007-N-0363 RIN:0910-AG AG18 Document Number: Shorter URL PDF: 18/pdf/ pdfhttp:// 18/pdf/ pdf

FDA has Authority to Require that the prescribing information be distributed electronically, rather than by the shipment of a paper copy of the prescribing information with each container of a prescription drug. [section 501(f)(1) of the FD&C Act] That the prescribing information no longer physically accompany the product in paper form, except as provided in the exempting provisions That the label will bear a statement that includes – the FDA labeling repository Web site address – toll-free telephone number for alternate access to prescribing information

History (What? SPL?) December 11, 2003: Amended regulations governing the format in which certain labeling is required to be submitted for review with NDAs, ANDAs, certain BLAs, supplements, and annual reports (68 FR 69009). The final rule required the electronic submission of certain prescribing information in a form that FDA can process, review, and archive. This action was taken to simplify the labeling review process and to provide more timely approval of labeling changes.68 FR Guidance to support this requirement (April 2005) entitled “Providing Regulatory Submissions in Electronic Format—Content of Labeling” ( pdf). This guidance describes the Structured Product Labeling (SPL) standard, which is based on extensible markup language (XML), as the most up-to-date electronic format that FDA can use to process, review, and archive prescribing information, and other labeling changes that are submitted electronically as part of a regulatory submission pdf In 2007, Congress enacted the Food and Drug Administration Amendments Act of 2007 (Pub. L ) (FDAAA). Section 224 of FDAAA, which amends section 510(p) of the FD&C Act (21 U.S.C. 360(p)), expressly requires owners and operators of establishments engaged in the manufacture of drugs (manufacturers [3] ) to submit drug establishment registration and drug listing information electronicallyPub. L U.S.C. 360 [3] FDA guidance (May 28, 2009), entitled “Providing Regulatory Submissions in Electronic Format— Drug Establishment Registration and Drug Listing” ( pdf). recommendations to manufacturers on how to create and submit separate electronic SPL files containing drug establishment registration and drug listing information, including a copy of the required components of labeling, for each marketed prescription human drug, including biological products covered by part pdf The FD&C Act currently requires manufacturers to update the drug listing information (which includes the product labeling) at least twice a year, in June and December, if there have been changes to the listing elements in the prior 6 months (21 U.S.C. 360(j)(2)).21 U.S.C. 360

Major Provisions Distribute prescribing information electronically, instead of in paper form. – Submit prescribing information every time there is a change to the labeling. – Review labeling posted at FDA’s web site to verify that the correct version appears – Notify FDA if correct version is not posted Product’s Immediate Container Label and Outside package to bear a statement directing HCPs to FDA’s labeling repository [21 CFR (b)(8), 21 CFR (t)] – Partial label rule still available Possibility of exemption – requested by manufacturer or directed by FDA

Associated Initiatives Electronic prescribing provisions of Medicare Prescription Drug Improvement and Modernization Act (Pub. L ) Requirement for bar codes on certain drug labels Requirement for Submission of Electronic Labeling in Product Approval Applications Electronic Registration of Drug Establishments and Listing of Drug Projects “DailyMed” initiative with NLM

Patient Labeling Not in Scope – for Now FDA-approved information intended for patient use, patient package inserts, Medication Guides Covered by different initiative by FDA Will continue to be provided in paper form Electronic submission to FDA with prescribing information

New Blood & Blood Components intended for transfusion (21 CFR part 607) Compliance date not detailed in Proposed Rule

Paper may still be needed? Public Health Emergency, Natural Disaster or Other Situation involving Field Response – Emergency Use Authorization (21 USC 360 bbb-3) Resource Constraints or Geographic Location – Some rural areas have limited Internet access Export for Humanitarian Use in Other Countries

Implementation Timeline (if/when Final Rule is issued) Effective date of 6 months after publication of final rule in Federal Register Compliance date of 2 years after publication of final rule

Start-up Actions FDA populates labeling repository (labels.fda.gov) with labeling that has already been electronically submitted to FDA to comply with current requirement. Manufacturers must review current prescribing information in the repository

Proposed Label Statements Immediate Container Label and Outside package to bear a statement directing HCPs to FDA’s labeling repository [21 CFR (b)(8), 21 CFR (t)] Biological product containers capable of bearing a full label [21 CFR (a)(8)] – Partial label rule not changed [21 CFR (c), (d)] Blood and blood components container label statement [21 CFR (c)] Current, fully-functional toll-free # to obtain current prescribing information [CFR (c)(5)] Distribution of prescribing information electronically [21 CFR (c)(3)]

Exemptions [ (g)] Manufacturer’s request to FDA must – Describe reasons that compliance with the electronic distribution of prescribing information requirements could adversely affect the safety, effectiveness, purity or potency of the drug; Is not technologically feasible; or Is otherwise inappropriate; AND – Explain the concerns underlying the request could not reasonably be addressed by other measures FDA – on its own initiative -- can also exempt a drug from the requirement

Submission of Labeling [ (c)(4)] ‘in a format that FDA can process, review, and archive for distribution via the FDA’s labeling repository Website’ – i.e., SPL to be posted on labels.fda.gov Newly approved drugs: NDA, BLA, ANDA applicants submit prescribing information in time for the prescribing information to be posted in the labeling repository before the drug enters interstate commerce.

Proposed Submission Requirements Already approved drugs: most current labeling to FDA each time the prescribing information is changed, including those changes submitted as supplements or in an Annual Report [ and ]

Submission Requirements - More Prior Approval Supplement: w/in 2 business days following FDA approval of the supplement CBE Supplement: same business day as supplement submission Manufacturers that are not Applicants (e.g., Repackers): w/in 2 business days of the posting of the applicant’s updated labeling Unapproved drugs: w/in 2 business days of a change to the labeling. ANDAs: Should a conforming amendment cross- referencing be added to [Submission of changes to an abbreviated application]

Submission Requirements - More Drug Listings: IF a supplemental change is submitted under proposed (c)(4) before the required submission for updating registration/listing (207) AND There is no additional change to the label between the time of the submission and the time of the drug listing/registration, THEN Labeling information would not need to be submitted again with drug listing/registration

Post-Submission FDA: Prescribing information will be posted on next business day following the date of submission. Manufacturer responsible for verification that – Labeling is posted to fda.labels.gov w/in 2 business days of submission – Labeling on repository is the correct labeling

Issues & Reporting IssueTimingAction Correct prescribing information is not posted on public repository w/in 2 business days of submission w/in 4 business days of submission to FDA labeling repository Contact SPL OR *Include information such as NDC code, drug name, description of problem with the labeling Incorrect prescribing information is posted on public repository w/in 2 business days of submission to FDA labeling repository Outdated labeling posted on the labeling repository renders a product misbranded; Applicant or manufacturer may be subject to enforcement action by the Agency

Promotional Labeling [ (d)(4)] Continue to disseminate with a copy of FDA- approved product labeling in paper form.

Benefits of electronic distribution 1.The provision of adequate directions for use to persons prescribing, dispensing, and administering the drug; 2.The provision of adequate warnings to prescribers against use in patients where a drug’s use may be dangerous to health; & 3.The prevention of unsafe prescribing of prescription drugs

Proposed Changes to 21 CFR Part 201 (Drugs; Labeling; Reporting and recordkeeping requirements) – (b), (c)(1), (c)(3), (c)(4), (c)(5), (d), (d)(2), (d)(4)-new (g) – – CFR Part 606 (Blood; Labeling; Laboratories; Reporting and recordkeeping requirements) – – CFR Part 610 (Biologics; Labeling; Reporting and recordkeeping requirements) – – (k) and (n)

What’s Next?

Estimates of Reporting Burden