[Federal Register Volume 79, Number 243 (Thursday, December 18, 2014)]
[Proposed Rules]
[Pages 75506-75527]
[FR Doc No: 2014-29522]

=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 201, 606, and 610

[Docket No. FDA-2007-N-0363]
RIN 0910-AG18

Electronic Distribution of Prescribing Information for Human
Prescription Drugs, Including Biological Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA or the Agency) is
proposing to amend its prescription drug and biological product
labeling regulations to require electronic distribution of the
prescribing information intended for health care professionals, which
is currently distributed in paper form on or within the package from
which a prescription drug or biological product is dispensed. FDA is
also proposing that prescribing information intended for health care
professionals will no longer be permitted to be distributed in paper
form with the package from which a prescription drug or biological
product is dispensed, except as provided by this regulation. We are
proposing these actions to help ensure that the most current
prescribing information is publicly accessible for the safe and
effective use of human prescription drugs.

DATES: Submit either electronic or written comments on the proposed
rule by March 18, 2015. Submit comments on information collection
issues under the Paperwork Reduction Act of 1995 by January 20, 2015
(see the ``Paperwork Reduction Act of 1995'' section of this document).
See section XI for the proposed effective date of a final rule based on
this proposed rule.

ADDRESSES: You may submit comments, by any of the following methods,
except that written comments on information collection issues under the
Paperwork Reduction Act of 1995 must be faxed to the Office of
Information and Regulatory Affairs, Office of Management and Budget
(OMB), Attn: FDA Desk Officer, FAX:<PHONE_NUMBER>, or emailed to
<EMAIL_ADDRESS>(see the ``Paperwork Reduction Act of
1995'' section of this document).

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments.

Written Submissions

    Submit written submissions in the following ways:
     Mail/Hand delivery/Courier (for paper submissions):
Division of Dockets Management (HFA-305), Food and Drug Administration,
5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
    Instructions: All submissions received must include the Docket No.
FDA-2007-N-0363 for this rulemaking. All comments received may be
posted without change to http://www.regulations.gov, including any
personal information provided. For additional information on submitting
comments, see the ``Comments'' heading of the SUPPLEMENTARY INFORMATION
section of this document.
    Docket: For access to the docket to read background documents or
comments received, go to http://www.regulations.gov and insert the
docket number, found in brackets in the heading of this document, into
the ``Search'' box and follow the prompts and/or go to the Division of
Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Emily Gebbia, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 6217, Silver Spring, MD 20993, 240-402-
0980.

SUPPLEMENTARY INFORMATION:

Table of Contents

Executive Summary
Purpose of the Regulatory Action
Summary of the Major Provisions of the Regulatory Action
Costs and Benefits
I. Background
    A. How do ``Prescription Drug Labeling'', ``Prescribing
Information'', and ``Patient Labeling'' for human prescription drugs
differ?
    B. Who receives paper prescribing information and who uses it?
    C. Discussion of Special Consideration of Types of Human
Prescription Drug Labeling
    D. What is the history of electronic regulatory submissions?
    E. Discussion of Other Labeling Initiatives
II. Discussion
    A. What are we proposing?
    B. Why is electronic distribution of prescribing information
better?
    C. Need for Up-To-Date Prescribing Information
    D. How are the application processes for changes to labeling
affected?
III. Public Hearing on the Electronic Distribution of Prescribing
Information
    A. Summary of Comments
    B. FDA's View on the Comments and Testimony
IV. Description of the Proposed Rule
    A. Labeling Accompanying the Product
    B. Label Statement
    C. Paper Versus Electronic
    D. Exemptions
    E. Submission of Most Current Version of Prescribing Information
to FDA
    F. Conforming Amendments
V. Legal Authority
VI. Environmental Impact
VII. Paperwork Reduction Act of 1995
    A. Summary of Provisions in Proposed Rule That Contain
Collections of Information
    B. Estimates of Reporting Burden
    C. Other Annualized Cost Burdens to Respondents: Operating and
Maintenance Costs of the Toll-Free Telephone Number and Responding
to Requests
    D. Capital Costs
VIII. Federalism
IX. Analysis of Impacts
X. Comments
XI. Proposed Effective Date
XII. Proposed Compliance Date
XIII. References

Executive Summary

Purpose of the Regulatory Action

    The Food and Drug Administration (FDA) is proposing to amend its
labeling regulations at 21 CFR 201.100, 201.306, 201.310, 606.121,
606.122, 610.60, and 610.61 for human prescription drugs and biological
products, and blood and blood components intended for transfusion, to
require that the prescribing information intended for health care
professionals be distributed electronically and, with few exceptions,
not in paper form. Prescribing information provides health care
professionals the information necessary for the safe and effective use
of the product. It is updated periodically to include the most current
information, such as newly acquired safety information. Currently, the
prescribing information is distributed in paper form on or within the
package from which a prescription drug is dispensed. The paper form of
the prescribing information may not contain the most current
information because it may have been printed and distributed prior to
more recent labeling changes, while the electronic form of prescribing
information can be updated in real-time. FDA is taking this action to
ensure that the most current prescribing information for prescription
drugs will be available and readily accessible to health care
professionals at the time of clinical decisionmaking and dispensing.
    The electronic distribution requirements of this proposed rule
would not apply to patient labeling

(including patient package inserts and Medication Guides), or to
prescribing information accompanying promotional labeling, which would
continue to be provided in paper form.
    FDA is authorized under various sections of the Federal Food, Drug,
and Cosmetic Act (the FD&C Act) to require that prescribing information
be distributed electronically and to require that paper copies of the
prescribing information no longer be distributed, except as provided in
this regulation, to ensure that human prescription drugs have adequate
directions for use and to ensure the efficient enforcement of the FD&C
Act. These sections include sections 201(n), 502, 503, 505, and 701(a)
of the FD&C Act (21 U.S.C. 321(n), 352, 353, 355, and 371(a)), and
section 351 of the Public Health Service Act (the PHS Act) (42 U.S.C.
262). The electronic distribution of prescribing information for human
prescription drugs would permit the efficient enforcement of the
misbranding provisions in sections 502(a) and (f) of the FD&C Act, as
well as the safety and effectiveness provisions of section 505 of the
FD&C Act.

Summary of the Major Provisions of the Regulatory Action

    The proposed rule would amend the labeling regulations to require
manufacturers to distribute the prescribing information electronically,
instead of in paper form. Manufacturers would be required to submit the
prescribing information to FDA for posting on FDA's publicly available
labeling repository Web site (labels.fda.gov) every time there is a
change in the labeling. Manufacturers would also be required to review
the labeling posted at FDA's Web site to verify that the correct
version of the labeling appears in the repository, and to promptly
notify FDA if the correct version is not posted. This would ensure that
the most up-to-date version of the prescribing information is available
to health care professionals and the public.
    The proposed rule would require a product's immediate container
label and outside package to bear a statement directing health care
professionals to FDA's labeling repository to view the electronic
version of prescribing information. The statement would also provide a
toll-free telephone number, maintained by the manufacturer, to receive
requests for the manufacturer to send an emailed, faxed or mailed paper
copy of the prescribing information. The manufacturer would be required
to ensure the toll-free number service was available 24 hours a day, 7
days a week. This would ensure that the prescribing information is
accessible in most situations when Internet access is not available to
the health care professional.
    In addition, the proposed rule would provide that FDA may grant an
exemption from the electronic distribution of labeling requirements
when compliance could adversely affect the safety, effectiveness,
purity, or potency of the drug, is not technologically feasible, or is
otherwise inappropriate. Manufacturers of exempted products would
distribute prescribing information in paper form on or within the
package from which the product is dispensed. Examples of circumstances
where it may be appropriate to exempt a product include a product
intended for use in an emergency room or a product that may be
stockpiled for an emergency.

Costs and Benefits

    The proposed rule impacts the drug and biological products
industries that supply prescribing information, as well as the
prescribers, pharmacists and other health care professionals who are
the intended users of the information. After initial set-up costs,
industry will experience net savings by providing the prescription
information electronically. Pharmacies will incur net costs due to
initial capital costs to access the information, increased search time
when accessing the information and the printing cost when a request is
received for the prescribing information in printed form. We estimate
no cost increases to most health care professionals to access the
information.
    At a 7 percent discount rate over a 10-year period, the annualized
cost savings range from $52 million to $164 million and are
predominantly savings to industry; the annualized costs range from $47
million to $89 million and are mainly incurred by pharmacies; and the
annualized net savings range from $5 million to $74 million. The public
health benefits of users having access to the most up-to-date version
of the prescribing information have not been quantified.

                        Summary of Annualized Costs and Cost Savings of the Proposed Rule
                                                  [$ millions]
----------------------------------------------------------------------------------------------------------------
                                                    7% discount rate, 10 years      3% discount rate, 10 years
                                                 ---------------------------------------------------------------
                                                        Low            High             Low            High
----------------------------------------------------------------------------------------------------------------
Cost Savings....................................           $51.8          $163.7           $56.6          $170.8
Costs...........................................            46.8            89.2            46.6            88.6
                                                 ---------------------------------------------------------------
    Net savings.................................             5.0            73.5            10.0            82.2
----------------------------------------------------------------------------------------------------------------

I. Background

    We are proposing to amend the labeling regulations to require
electronic distribution of prescribing information for human
prescription drugs.\1\ This is intended to facilitate the distribution
of updated prescribing information as new information becomes available
and as changes in prescribing information are made. FDA is taking this
action so that the most current prescribing information for distributed
prescription drugs will be available and readily accessible to health
care professionals at the time of clinical decisionmaking and
dispensing.
---------------------------------------------------------------------------

    \1\ When used in this proposed rule, the term ``drug'' includes
biological products e.g. allergenic products, vaccines, blood and
blood components intended for transfusion, plasma derivatives, gene
therapies, and human cells, tissues, and cellular- and tissue-based
products licensed under section 351 of the PHS Act.
---------------------------------------------------------------------------

    This proposed rule complements other FDA and Department of Health
and Human Services initiatives that are intended to provide accessible
electronic drug product information to health care professionals,
consumers, and/or the public. These initiatives include the electronic
prescribing provisions of the Medicare Prescription Drug Improvement
and Modernization Act (Pub. L. 108-173), the requirement for bar codes
on certain drug product labels, the requirement for submission of
electronic labeling in product approval applications, and electronic
registration of drug establishments and

listing of drug products. Additionally, the Agency has been involved in
an initiative known as ``DailyMed''. ``DailyMed'' is a publicly-
available, computerized repository of a broad array of drug
information, which is maintained by the National Library of Medicine.

A. How do ``Prescription Drug Labeling'', ``Prescribing Information'',
and ``Patient Labeling'' for human prescription drugs differ?

    ``Prescription drug labeling,'' as relevant to this proposed rule,
includes prescribing information; patient labeling; the product's
immediate container label; outer container; the outside package; and
other written, printed, or graphic information that accompanies the
product. Prescription drug labeling meets the definition of
``labeling'' in section 201(m) of the Federal Food, Drug, and Cosmetic
Act (the FD&C Act) (21 U.S.C. 321(m)) and must comply with all
applicable provisions of section 502 of the FD&C Act (21 U.S.C. 352).
In addition, in order to be exempt from the statutory requirement of
section 502(f)(1) of the FD&C Act, prescription drug labeling must also
satisfy the requirement of Sec.  201.100(d) (21 CFR 201.100(d)) which
states that any labeling, as defined in section 201(m) of the FD&C Act,
whether or not it is on or within a package from which the drug is to
be dispensed, distributed on or behalf of the manufacturer, packer, or
distributor of the drug, that furnishes or purports to furnish
information for use or which prescribes, recommends, or suggests a
dosage for the use of the drug contains adequate information for such
use, as further described in that provision. In this document, the
terms ``prescription drug labeling'', ``product labeling'', and
``labeling'' will be used interchangeably as broader terms to encompass
prescribing information and other information considered to be
components of labeling. All components of labeling are submitted to FDA
as part of an applicant's new drug application (NDA), abbreviated new
drug application (ANDA), biologics license application (BLA),
supplement, annual report, or in other submissions, such as
establishment registration and drug listing.
    ``Prescribing information'', commonly referred to as ``professional
labeling'', ``content of labeling'', ``package insert'', ``physician
labeling'', ``direction circular'', ``circular of information'', or
``package circular'', is a component of prescription drug labeling and
is periodically updated to include the most current information about
the product. For products approved by FDA, approval of the prescribing
information is based on the Agency's thorough analysis of the marketing
application, including the proposed label, submitted by the applicant.
Prescribing information contains the information necessary for safe and
effective use of the product, and is intended for use by the health
care professional. Prescribing information is subject to the format and
content requirements of Sec. Sec.  201.56, 201.57, 201.80, 606.122, or
610.61 (21 CFR 201.56, 201.57, 201.80, 606.122, or 610.61). Prescribing
information is currently distributed in paper form with the product to
meet the condition stating that labeling on or within the package from
which a prescription drug is to be dispensed bears adequate information
for its use (Sec.  201.100(c)(1)). This proposed rule applies to
prescribing information that is currently distributed in paper form on
or within the package from which the prescription drug is to be
dispensed. In addition, prescribing information must also accompany
``promotional'' labeling, as described in Sec.  202.1(l)(2) (21 CFR
202.1(l)(2)).\2\ This proposed rule will not apply to prescribing
information that accompanies promotional labeling, which will continue
to be distributed in paper form. Therefore, we propose new Sec.
201.100(d)(4) to make clear that prescribing information accompanying
promotional labeling must be distributed in paper form.
---------------------------------------------------------------------------

    \2\ Such labeling is described in Sec.  202.1(l)(2) and
includes, for example, printed, audio, or visual matter containing
drug information supplied by and disseminated by or on behalf of the
manufacturer, packer, or distributer. Examples include but are not
limited to: Brochures, booklets, mailing pieces, calendars, price
lists, catalogs, letters, motion picture films, sound recordings,
exhibits, or literature. Such promotional material is labeling as
defined in section 201(m) of the FD&C Act, and therefore, must
comply with Sec.  201.100(d) which states that any labeling, as
defined in section 201(m) of the FD&C Act, whether or not it is on
or within a package from which the drug is to be dispensed,
distributed by or on behalf of the manufacturer, packer, or
distributor, that furnishes or purports to furnish information for
use or which prescribes, recommends, or suggests a dosage for the
use of the drug contains adequate information for such use.
---------------------------------------------------------------------------

    ``Patient labeling'', another component of labeling for some
prescription drugs, is FDA-approved information that is intended for
patient use and includes patient package inserts and Medication Guides.
Patient labeling must be reprinted in the prescribing information or
must accompany the prescribing information (Sec. Sec.  201.57(c)(18)
and 201.80(f)(2)). Because FDA is examining methods to improve the
content and distribution of patient labeling in a different initiative,
patient labeling is not affected by this proposed rule and will
continue to be provided in paper form, as required by applicable
regulations, and to be electronically submitted to FDA with the
prescribing information. Therefore, for those products including
patient labeling, patients will continue to receive warnings, risk
information, and special instructions for use in paper form as patient
labeling.
    Prescription drug labeling also includes the product's immediate
container label and the outside package. It is noted that labeling
regulations of biological products distinguish between a ``container
label'' and ``package label'' (Sec. Sec.  610.60 and 610.61 (21 CFR
610.60 and 610.61)). For purposes of this document, any reference to
the ``outside package'' applies to the ``package label'' for biological
products or the outer carton, outer container, or outer package of the
prescription drug. Based on the FD&C Act definitions of the terms
``label'' and ``labeling'', any outer container, carton, or package is
``labeling''.

B. Who receives paper prescribing information and who uses it?

    The prescribing information that is the subject of this proposed
rule is the paper version that is on or within the package from which
the drug is to be dispensed (e.g., physically attached to the bottle
containing the drug, inside the carton or box containing the drug, with
the bulk pharmacy package). Usually, it is printed on thin paper in
small size font, and is folded multiple times so that it can be
contained within the drug carton or can be otherwise attached to drug
packaging. Drug products, with the paper prescribing information on or
within their packaging, are distributed to pharmacies for dispensing.
    This paper prescribing information is intended for use by all
health care professionals. However, health care professionals have come
to rely on electronic or other paper versions (e.g., compendia such as
the Physicians' Desk Reference (PDR)) compiled by third parties instead
of this paper version. Prescribing physicians and many health care
professionals (e.g., nurses) typically do not receive this paper
version because they do not dispense drugs. Pharmacists do receive it
along with the drug product from the manufacturer or distributer, but
it is often difficult to read due to the small font size, thin paper,
and multiple folds, and we have heard anecdotally that it is often
discarded. In addition, pharmacies usually have some form of compendia
purchased from a third party, and many

hospitals and chain pharmacies rely on electronic compendia. Patients
ordinarily do not receive the paper prescribing information because the
pharmacist dispenses the drug to a patient in a different container
than the packaging from the manufacturer, but they do receive other
information intended for patients from the pharmacy (see section I.A).

C. Discussion of Special Consideration of Types of Human Prescription
Drug Labeling

1. Instructions for Use for the Pharmacist
    Instructions for use for the pharmacist are considered part of
human prescription drug labeling, specifically part of the prescribing
information. For the purposes of this proposed rule, instructions for
use for the pharmacist include any instructions for administering,
assembling, reconstituting, mixing, diluting, or other preparation that
is done prior to dispensing the drug product to the patient. These
preparation steps for the pharmacist are contained in the ``Dosage and
Administration'' section of the prescribing information (Sec. Sec.
201.57(c)(3) and 201.80(j)), which currently accompanies the product in
paper form. If the information is adequately concise, it may also be
printed on the product's immediate container label or on the outside
package. To the extent that this information is available on the
immediate container label or outside package, it does not fall within
the scope of this proposed rule. However, usually the product's
immediate container label is too small to contain the preparation
instructions, so the immediate container label or the outside package
typically bears a statement referring to the prescribing information
for the detailed instructions. Therefore, where the container label
refers to the prescribing information for preparation instructions,
this proposed rule would require that these instructions for use for
the pharmacist be available electronically, rather than in paper form.
This proposed rule provides a mechanism, if needed, to request the
prescribing information in paper form. FDA welcomes comments on
whether, in circumstances where the instructions for use for the
pharmacist are not sufficiently concise to be printed on the immediate
container label or outside package, the electronic version of the
prescribing information is adequate.
2. Prescribing Information (Circular of Information) for Blood and
Blood Components Intended for Transfusion
    In addition to Sec.  201.100, blood and blood components intended
for transfusion are also subject to labeling requirements under
Sec. Sec.  606.121 and 606.122, including the requirement that the
circular of information be available for distribution, and to
registration and listing requirements under 21 CFR part 607. This rule,
if finalized, would require that the prescribing information (i.e., the
circular of information) for blood and blood components intended for
transfusion be provided electronically, rather than in paper form. This
rule would also provide the mechanism for a request to be made for
prescribing information in paper form. In contrast to biological
products that register and list under part 207 (21 CFR part 207),
however, labeling and registration and listing information for blood
and blood components are currently not electronically submitted to the
Agency. FDA is in the process of developing standards for the
electronic submission of labeling for these products, and these
standards will eventually accommodate blood and blood components. The
Agency will consider progress in developing such standards when setting
a compliance date for blood and blood components and/or on our own
initiative granting an exemption for blood and blood components for a
period of time until electronic submission of the labeling for blood
and blood components is supported. Thus, the final regulation may
include staggered compliance dates, with a later compliance date for
blood and blood components and an earlier compliance date for all other
drug products. We also invite public comment on whether blood and blood
components intended for transfusion should be subject to the electronic
distribution of prescribing information requirements in this proposed
rule once the electronic submission standards accommodate these
products.
3. Access to Prescribing Information When Internet Access Is
Unavailable
    FDA recognizes that there may be situations that present challenges
for accessing electronic prescribing information of prescription drugs.
Some of these situations were identified in the July 2013 Government
Accountability Office Report ``Electronic Drug Labeling: No Consensus
on the Advantages and Disadvantages of Its Exclusive Use'' (GAO Report)
(Ref. 1).
    During a public health emergency, natural disaster, or other
situation involving field response, there may be power outages or
technology service interruptions that render electronic prescribing
information unavailable to health care professionals. Responders
generally enter an emergency situation with all the medical supplies
and materials necessary to address the emergency situation. Therefore,
we do not anticipate that they would rely on the Internet being
available to be able to provide medical care. For example, deployment
units often have electronic medical resources that can be used with
wireless mobile devices. If wireless service is not available, units
are also equipped with back-up sources of drug information (e.g.,
compendia downloaded onto laptops or tablets, paper compendia, and
other targeted information to address the public health emergency).
Responders also train extensively for emergency situations and are very
familiar with the specific drugs they are dispensing, reducing the
risks associated with not having access to the electronic prescribing
information. Thus, reference to the full content of labeling would
rarely be necessary in such an emergency. When it comes to natural
disasters that affect pharmacies, they often have contingency plans in
place for how services will be provided (e.g., during events such as
power disruptions). For example, some pharmacies may rely on back-up
generators or refer patients to another nearby pharmacy (Ref. 1). We
invite comment from public health authorities and the medical care
community on how product labeling is currently handled and whether
current practices are sufficient when Internet access is not available
due to disasters or public health emergencies. We also invite comment
on what impact, if any, this proposed rule will have during a public
health emergency, natural disaster, or other situation involving field
response when Internet or wireless access is not available or reliable.
    We also recognize that, during the course of a declared emergency,
FDA may issue an emergency use authorization for an unapproved use of
an FDA-approved drug (21 U.S.C. 360bbb-3). In such a situation, it may
be appropriate to direct health care providers to materials about the
Emergency Use Authorization as the primary source of information about
product use for and during the emergency, in addition to FDA-approved
labeling available in the labeling repository or in paper form, as
appropriate. We invite comment on whether the proposed exemptions
provision provides emergency planners

with sufficient flexibility regarding the labeling of their stockpiled
products.
    We also are concerned that there may be health care providers that
are routinely unable to access electronic prescribing information due
to a lack of Internet access, either because of resource constraints or
geographic location, e.g., in rural areas with limited Internet access.
As described in detail in section IV.B, we are proposing that such
health care providers would be able to access current prescribing
information through mail, fax, or email, by calling a toll-free number
that would be required to be included on the immediate container label
and outer container of human prescription drugs. In section IV.B, we
invite comment on whether requesting the prescribing information over
the telephone is a sufficient method for obtaining it when it cannot be
accessed using the Internet. We also invite comment on alternative or
additional methods for ensuring that health care professionals without
regular Internet access have the most current prescribing information,
including comment on other systems described in section II.C.
    Finally, we note that drugs may be exported from the United States
for humanitarian use in other countries. We expect that labeling for
such products will often be in the language of the country to which it
is being exported and include units of measurement used in or
designated by the country to which the drug would be exported. Further,
in some instances, the country to which a drug is being exported may
have different or additional labeling requirements or conditions for
use (compared to those on the FDA-approved labeling), and the foreign
country may require the drug to be labeled in accordance with those
requirements or uses. For these reasons, we expect that drugs intended
for export generally will be labeled in accordance with the foreign
requirements and conditions for use, as long as the conditions in the
relevant provisions of the FD&C Act, or if applicable, section 351(h)
of the PHS Act, are met. Nevertheless, we request comment on any impact
that our current proposal to require the electronic distribution of
labeling may have on drugs exported for humanitarian use and whether
any modifications to the proposal should be made to address such
products.

D. What is the history of electronic regulatory submissions?

    On December 11, 2003, we amended the 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. To support
this requirement, we issued guidance in April 2005 entitled ``Providing
Regulatory Submissions in Electronic Format--Content of Labeling''
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072331.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.
    In 2007, Congress enacted the Food and Drug Administration
Amendments Act of 2007 (Pub. L. 110-85) (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 electronically
unless an exemption is granted. As part of the drug listing
information, each manufacturer must submit a copy of all components of
each drug's current labeling to the Agency with the exception of
promotional labeling (Sec.  207.25(b)). To assist manufacturers with
electronic submissions of drug establishment registration and drug
listing information, FDA issued a guidance on May 28, 2009, entitled
``Providing Regulatory Submissions in Electronic Format--Drug
Establishment Registration and Drug Listing'' (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072339.pdf). This guidance provides 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
207. 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)).
---------------------------------------------------------------------------

    \3\ For the purposes of this proposed rule, the term
``manufacturer'' will be used to refer to manufacturers, repackers,
relabelers, and private label distributors, unless otherwise stated.
(See Sec.  207.3(a)(8)).
---------------------------------------------------------------------------

    This proposed rule will complement FDA's other electronic
initiatives and is intended to improve access to up-to-date prescribing
information for health care professionals, thereby enhancing the safe
and effective use of prescription drugs.

E. Discussion of Other Labeling Initiatives

    The final rule entitled ``Requirements on Content and Format of
Labeling for Human Prescription Drug and Biological Products'' (71 FR
3922; January 24, 2006) became effective on June 30, 2006 (the 2006
rule) (21 CFR parts 201, 314, and 601). The purposes of this final rule
were to improve the management of the risks of medical product use and
reduce medical errors by health care professionals, as well as enable
health care professionals to better communicate risk information to
their patients. The new content and format requirements make it easier
for health care professionals to access, read, and use prescribing
information, thereby increasing the extent to which they rely on it to
obtain information on prescribing, dispensing, and administering
prescription drugs. In announcing the final rule, FDA explained that
these new requirements should enhance the safe and effective use of
prescription human drugs and in turn reduce the number of adverse
reactions resulting from medication errors due to misunderstood or
incorrectly applied drug information.
    The 2006 rule only applies to applications or efficacy supplements
approved since June 30, 2001; those pending on June 30, 2006; and to
new applications and efficacy supplements submitted after June 30,
2006. There are older drug products that are not subject to the new
labeling content and format requirements and that have a different
format of labeling and may have different headings in the labeling. As
proposed, this rule does not require the electronic versions of the
labeling of these older drug products to comply with the content and
format requirements of the 2006 rule. FDA invites comment on whether
the existence of the two different formats of electronic labeling would
present barriers to their value when used in the health care setting.

II. Discussion

A. What are we proposing?

    This proposed rule would require electronic distribution of
prescribing information for human prescription drugs and biological
products that meet the definition of a drug (see footnote 1) instead of
the paper form. Electronic distribution would ensure that the most
current prescribing information is available so that health care
professionals can readily access the information and be better informed
at the time of clinical decisionmaking and dispensing. This proposed
rule would apply to manufacturers, applicants, and persons who market
prescription drugs that they regard as not subject to section 505 of
the FD&C Act (21 U.S.C. 355). Again, for ease of reference, in the
preamble of this regulation, we will use the phrase ``manufacturer or
applicant'' to refer to manufacturers, applicants (including holders of
NDAs, ANDAs, and BLAs), and persons who market unapproved drugs. The
proposed rule would require manufacturers and applicants to distribute
electronically prescribing information by submitting the labeling in an
electronic format that FDA can process, review, and archive (currently
SPL format) to FDA each time the labeling content is changed. The
submitted labeling would be distributed via FDA's labeling repository
Web site (labels.fda.gov), which is a publicly available Web site. By
proposing to make the most current prescribing information available at
a single, comprehensive Web site, the rule would address a concern
raised by stakeholders and identified in the GAO Report regarding the
limitations of the multiple Web sites that currently provide electronic
labeling and the importance of having a single data source that is
reliable, authoritative, and comprehensive (Ref. 1). The proposed rule
also would require the immediate container label and outer container of
human prescription drugs to bear a statement explaining that the most
current prescribing information is available at FDA's labeling
repository Web site (labels.fda.gov) and to provide a toll-free
telephone number that health care professionals may use to request that
the manufacturer or applicant send current prescribing information
through alternative means, such as FAX, email, or mail (e.g., U.S.
Postal Service or other delivery service). In cases where the immediate
container label does not have adequate space for the statement, the
statement would be required to be affixed to the immediate container by
other means such as a peel-back label. As described in further detail
in section IV.B, the only products that would not be required to bear
the statement on both the immediate container and the outside package
are biological products that are capable of bearing only a partial
label or are incapable of bearing a container label.
    Given the time necessary for industry to make preparations needed
to comply with this regulation, FDA is proposing an effective date of 6
months after the publication date of the final rule in the Federal
Register and a compliance date of 2 years after the date of publication
of the final rule (see sections XI and XII for the compliance dates and
implementation plans for this rule). FDA is requesting comments on the
proposed effective and compliance dates, and whether they allow
sufficient time for industry to implement this rule and, if not, how
much additional time would be needed for implementation.

B. Why is electronic distribution of prescribing information better?

    FDA has determined that requiring electronic distribution of
prescribing information and eliminating the paper form that is
contained on or within the package from which the drug is to be
dispensed is important to ensure health care professionals have access
to the most up-to-date information about the safe and effective use of
the drug. To meet the requirement that states that labeling on or
within the package from which the drug is to be dispensed bears
adequate information for its use (Sec.  201.100(c)(1)), currently,
prescribing information that accompanies human prescription drugs is
provided in paper form. The paper form of the prescribing information
is either attached to the immediate container or it may accompany the
product if the product has an outer container or package. It is
possible that the paper form of the prescribing information
accompanying a product in interstate commerce or in the possession of a
pharmacist or other health care professional may not contain the most
current information because, as described in II.B.1, the paper form
accompanying the product may have been printed and distributed prior to
more recent labeling changes.
1. Time for Updated Paper Form of Prescribing Information To Reach
Marketplace
    Paper prescribing information may be outdated by the time the drug
product reaches pharmacy shelves. The manufacturer or applicant of a
prescription drug may take months to incorporate a labeling change for
the product and print new paper forms of the updated prescribing
information. This process includes printing, folding, storing until
used, and attaching the prescribing information to the immediate
container or placing the prescribing information within the outer
package that may house the product. Each of these steps typically
requires equipment made specifically for these functions. For some
products, manufacturers or applicants may only produce updated printed
prescribing information once a year. In cases such as this, the
information in the paper form of the prescribing information may be
outdated if the product is not manufactured frequently and there have
been new labeling changes since manufacturing. Because of these
factors, products with prior versions of the prescribing information in
paper form may remain in use. FDA contracted with the consulting firm
Eastern Research Group, Inc. (ERG) to investigate, among other things,
how industry currently implements safety labeling changes and the
associated timelines for making changes. ERG issued a report entitled
``Analysis of the Feasibility of Safety Labeling Changes Implementation
Timelines'' that describes that it may be months, if not years, before
updated prescribing information is available with finished drug
product. It was estimated that, for printed prescribing information
attached to a drug product, a change will generally reach the market
anywhere from as little as 3 months to more than 39 months after the
change is made (Ref. 2).
    Such delays in updating the paper prescribing information raise
concerns about health care professionals using outdated information for
clinical decisionmaking. While not all changes may be related to
significant safety or effectiveness concerns, some changes to the
prescribing information are critically important for the safe use of
the drug (e.g., a new contraindication or warning). Because drugs that
are already in distribution are not generally recalled to update the
prescribing information, this new risk information would not appear in
the paper prescribing information, while it could be promptly
incorporated in an electronic version.
2. Time for Updated Electronic Prescribing Information To Reach the
Marketplace
    Unlike the paper form, electronic prescribing information can be
updated in real-time with newly acquired safety or effectiveness
information, and would be available for use by prescribers and other
health care professionals within days of an update. Currently,
electronic forms of the prescribing information for many, but not all,
human prescription

drugs, are available through various sources to health care
professionals and consumers in a variety of formats. This information,
though, may not be the most up-to-date version of the prescribing
information. The proposed rule would require that applicants and
manufacturers distribute the drug's most current labeling
electronically by submitting the prescribing information to FDA in a
format that FDA can process, review, and archive each time the content
is changed. These submissions will populate FDA's publicly available
labeling repository so that the updated prescribing information is
distributed in a timely fashion to prescribers, pharmacists, and health
care providers. This proposed rule would require the manufacturer or
applicant to verify that its prescribing information appears on FDA's
labeling repository Web site and is accurate, complete, and up-to-date,
and to notify FDA if the labeling is not promptly posted or if the
labeling on FDA's labeling repository Web site is not accurate,
complete, and up-to-date. Since FDA's labeling repository Web site will
link prescribing information to specific National Drug Code (NDC)
numbers, the prescribing information will be product-specific and will
correspond to the NDC that may appear on a product's label. The Agency
expects that the repository will also be searchable by, among other
things, active ingredient and proprietary name. In this way, FDA will
be able to provide the public with a complete source for the most
current prescribing information for products approved under NDAs,
ANDAs, and BLAs, and those marketed and not approved.

C. Need for Up-To-Date Prescribing Information

    Based on the availability of a complete source for up-to-date
electronic prescribing information upon implementation of this
regulation, coupled with much higher use of electronic systems in
health care, FDA concludes that the time is right to transition to
electronic distribution of prescribing information from the static,
potentially outdated paper version on pharmacy shelves. A recent survey
of 436 pharmacists was conducted to assess pharmacists' readiness to
adopt ``paperless labeling'' (i.e., electronic prescribing information)
(Ref. 3). Among this sample of pharmacists from chain pharmacies,
independent retail pharmacies, hospitals, and other rural or urban
dispensing sites, approximately 79 percent of respondents believed that
paperless labeling would improve the adequacy of drug information
available in their worksite and most pharmacists believed that patient
safety would improve as a result because updated information about a
drug would be readily accessible. Most pharmacists also reported that
communication with patients would improve as a result of a paperless
system as 81 percent of pharmacists reported using prescribing
information when educating or counseling patients and verifying dose
information. Pharmacists participating in the survey, in all settings
except chain pharmacies, reported relying on manufacturer Web sites for
online prescribing information. Pharmacists of chain pharmacies
reported using corporately curated prescribing information. Of all
pharmacists surveyed, only 6 percent reported using exclusively paper
resources to retrieve prescribing information and only 4 percent did
not have Internet access.
    In addition, as described in this document, at present there are
delays between when the labeling change occurs and when a product with
the updated paper copy of the prescribing information actually reaches
the pharmacy or point of care. During our public meeting in 2007 (see
72 FR 15701; April 2, 2007), described in section III, we heard that
this is a concern of many health care professionals and consumers.
Health care professionals and representative organizations believed
that having the most up-to-date prescribing information would allow
them to make better informed clinical decisions for their patients and
would benefit the public health overall.
    FDA tracks safety labeling changes and classifies them by type,
depending on the risk described and the section of the prescribing
information that is changed. Based on 11 years of data (2003 to 2013),
we determined that there are approximately 500 safety labeling changes
made each year (Ref. 4). Postapproval, safety-related labeling changes
to the prescribing information that may impact public health include
adding or strengthening a contraindication, warning, precaution, or
adverse reaction, or the addition of, or changes to, a boxed warning
for the product. In general, when important new safety information has
been acquired, a new boxed warning may be added to the prescribing
information to alert prescribers about the new serious risk. Our
regulations also require that the boxed warning information be
explained in more detail in the ``Contraindications'' or ``Warnings and
Precautions'' sections of the labeling (Sec.  201.57(c)(1)). Therefore,
addition of a new boxed warning or changes to the boxed warning
generally will also affect more than one section of the prescribing
information.
    We conducted an internal review of labeling changes for new
molecular entities, a small subset of all marketed prescription drugs,
for the calendar years of 2005 to 2007, and found 36 new boxed warnings
were added to the prescribing information during this 3 year period
(Ref. 5). It should be noted that approximately two-thirds of these
boxed warnings were the result of class-related safety labeling changes
that added new boxed warnings to several different products in specific
drug classes, including antidepressants, nonsteroidal anti-inflammatory
drugs, and atypical antipsychotics.
    In addition to boxed warnings, there are many other safety-related
changes to other sections of the labeling that will add new information
that is important for patient care. For example, changes to the
``Contraindications'' section can affect prescribing decisions and the
patient population eligible for the drug, while changes to the
``Warnings and Precautions'' section and ``Adverse Reactions'' section
can affect patient monitoring or management. We conducted an internal
review of changes made to the boxed warning and ``Contraindications''
sections between the years 2003 to 2013 and found that there are about
50 additions or changes to boxed warnings each year and about 60
changes to the ``Contraindications'' section (Ref. 4). For example, in
2013, the prescribing information for codeine products (including all
generic products containing codeine) was revised to include a new boxed
warning and an addition to the ``Contraindications'' section to inform
prescribers of the risk of respiratory depression and death in children
who underwent tonsillectomy and/or adenoidectomy related to ultra-rapid
metabolism of codeine to morphine. That same year, FDA issued a safety
announcement regarding the use of valproate drug products for pregnant
women taking the drug for migraine prevention and the prescribing
information was updated to add new information to the boxed warning to
inform prescribers that use of the drug while pregnant can cause major
congenital malformations, particularly neural tube defects such as
spina bifida, and decreased IQ scores in children. The serious nature
of these warnings highlight the need for health care professionals to
have access to, and utilize, the most current prescribing information
from a reliable and consistent source.
    FDA has tentatively concluded that health care professionals should
have

access to, and rely on the most updated prescribing information when
making prescribing or other clinical decisions about the safe and
effective use of a drug. For this reason, FDA considered a mandatory
dual system for distribution of prescribing information (i.e., one in
which both paper and electronic versions would be distributed
simultaneously). Under such a system, the paper version of the
prescribing information could include a statement that would notify the
health care professional that the paper version may not contain the
most up-to-date information and would direct the health care
professional to the electronic version. FDA is concerned that, even
with this statement, the potentially outdated paper version may be used
to make a decision impacting patient care. If the paper prescribing
information remains available, a busy health care professional may not
look to the labeling repository to ensure he or she is reading the
current paper version of the prescribing information or to ascertain
what section of the prescribing information has been updated since the
paper version was printed. A health care provider who does not have
Internet access may continue to rely on an outdated paper version of
the prescribing information, rather than contacting the manufacturer
for the most updated version.
    FDA also considered a dual system that requires the electronic
version of the prescribing information and permits voluntary
distribution of the paper version. In addition, to the concerns we
describe previously with a mandatory dual system, FDA is concerned that
a voluntary dual labeling system could cause confusion and workflow
disruptions for health care professionals where it would be left to
each manufacturer's discretion to decide whether its products will be
distributed with the paper version of the prescribing information.
    One additional system that FDA is soliciting comment on is a system
that requires manufacturers to distribute the prescribing information
electronically, as described in this proposed rule. Where paper
prescribing information is needed, dispensers (e.g., pharmacies) would
have the option of ordering single or multiple copies of the paper
prescribing information when ordering a shipment of drug from the
distributor. The distributor, or other entity that delivers the drug to
a dispenser, would be required to provide the paper prescribing
information in the quantity ordered along with the shipment of the drug
to the dispenser. The manufacturer would be required to provide
sufficient numbers, or a means to produce sufficient numbers, of the
paper prescribing information to the distributor. With this option, for
the reasons described previously, FDA does not anticipate that
dispensers would routinely order paper prescribing information because
they would rely on the electronic version of the prescribing
information and because pharmacies usually have some other form of
compendia purchased from a third party. Nevertheless, this option would
permit dispensers to receive paper prescribing information with drug
shipments, as needed.
    We seek comment on the dual systems described previously.
Specifically, we request comment on whether and how dual systems could
achieve the goal of ensuring that health care providers have the most
current prescribing information. We also request comment on the
structure of a dual system (e.g., if such a system should require both
a paper and electronic version be distributed, or require the
electronic version while allowing the paper version to be distributed
voluntarily or ordered by dispensers), what kind of statement the paper
prescribing information should contain to advise health care providers
about the electronic version, and if there are concerns or benefits not
identified by FDA with such an approach. With respect to the system
that would provide the dispenser the option of ordering paper
prescribing information, we request comment on any challenges,
including administrative challenges, to manufacturers, distributors, or
dispensers related to an ordering and fulfillment process for paper
prescribing information. Finally, we note that a system in which paper
copies could be ordered from the distributor could address concerns
discussed in section I.C.3 about health care providers that do not have
reliable regular Internet access and we invite comment on this aspect
of a system.
    The GAO Report noted that a potential disadvantage of the exclusive
use of electronic prescribing information is that it could disrupt
pharmacists' workflow by requiring different steps for pharmacists to
use to consult prescribing information and also preventing them from
retrieving the prescribing information from the box when the pharmacist
felt it was necessary to show it to the patient during a consultation
(Ref. 1). The GAO Report said that these workflow disruptions could
reduce the time available for patient consultations and noted that
interruptions to pharmacists' workflow have been shown to increase the
risk of errors made when dispensing a drug. We are aware that
transitioning from a paper to electronic delivery system for
prescribing information may be a change in practice that may require
adjustments. In addition, if a pharmacist determines that accessing
electronic prescribing information would be too disruptive, the
pharmacist might instead rely on memory or outdated prescribing
information available to the pharmacist in paper format, e.g., in a
paper-based compendia. We note, however, that in the recent survey of
pharmacists discussed previously, most reported that a paperless system
would improve patient safety and communication with patients (Ref. 3).
Further, some of the workflow disruptions that a paperless system might
cause could be offset by the advantages of having electronic
prescribing information. For example, as noted in the GAO Report, in
comments, and in public testimony received by FDA, electronic
prescribing information is more user-friendly than the current paper
package inserts: Pharmacists can quickly identify the information they
are seeking by using hyperlinks and can adjust the font size to make it
easy it read. We request comment on the potential workflow disruptions
associated with a switch to an online-only system, and any related
risks to the public health. We also request comment on whether the
effective and compliance dates described in sections XI and XII of this
proposed rule should be modified to allow for more time to adapt to
workflow changes and to mitigate any potential risks caused by changes
in workflow resulting from the proposed rule.

D. How are the application processes for changes to labeling affected?

    This proposed rule would not affect the applicant's
responsibilities regarding the content of labeling or the process for
submitting labeling changes to FDA for approval. The prescribing
information component of labeling would contain the most current
changes approved by FDA, changes being effected pending FDA approval,
and editorial changes that may be submitted in the annual report. Any
postapproval labeling changes to an application (NDA, ANDA, or BLA)
must comply with Sec. Sec.  314.70, 314.97, or 601.12, as applicable,
and under those requirements FDA would continue to be notified about
supplements and other changes to approved applications (Sec. Sec.
314.70(a) and 601.12(a)). Depending on the type of change, the changes
would continue to be submitted as a supplement for prior approval
(``prior approval supplements'') before

distribution, as a Changes Being Effected (CBE) supplement, or by
inclusion of the information in the annual report (Sec. Sec.
314.70(b), (c), and (d); 314.81(b)(2); 601.12(b), (c), and (d)). (See,
also section IV.E. ``Submission of Most Current Version of Prescribing
Information to FDA'' for more information.)
    This proposed rule would require manufacturers and applicants to
distribute labeling electronically via posting on FDA's labeling
repository. We propose to require submission of the prescribing
information, in a format that FDA can process, review, and archive for
distribution via the FDA's labeling repository Web site. Generally, it
is expected that labeling can be posted as early as the next business
day following its submission to FDA. In the case of a labeling change
submitted in a prior approval supplement, the proposed regulation would
require applicants to submit the labeling within 2 business days
following FDA approval of the supplement.
    For changes contained in a CBE supplement, the labeling should be
submitted to FDA on the same day that a CBE supplement is submitted to
the Agency. Minor changes to the prescribing information that would
normally be documented in the applicant's annual report to FDA would
still be reported and described in the annual report, but the
prescribing information reflecting the labeling update would be sent to
FDA at the time of the change for posting on FDA's labeling repository
Web site. This will help to ensure that the most current labeling is
considered by FDA and available to the public.

III. Public Hearing on the Electronic Distribution of Prescribing
Information

A. Summary of Comments

    In the Federal Register of April 2, 2007 (72 FR 15701), we
announced a public hearing to solicit views and information from
interested parties concerning the concept of electronic distribution of
FDA-approved prescribing information currently contained in the package
insert for human prescription drug and biological products. We also
sought information on the feasibility of establishing a modern and
efficient process for industry to electronically distribute prescribing
information to dispensers and asked specific questions to evaluate the
possible benefits of electronic prescribing information and the
logistics of such an electronic system (72 FR 15701 at 15702). At the
public hearing, we explained that FDA is committed to facilitating the
transition to use of electronic information and capitalizing on the
efficiencies that an electronic environment could offer. The public
hearing and comments submitted to FDA in connection with the public
hearing suggested that:
     The majority believe that electronic distribution of
prescribing information would give health care professionals access to
the most current information in the labeling, and this would result in
better care for patients and improved public health.
     Electronic distribution of prescribing information would
be better for the environment (because most prescribing information
provided in paper form is discarded) and could be more user-friendly if
individuals are able to manipulate font sizes to make the print larger
and easier to read.
     Use of electronic distribution of prescribing information
should not impose undue hardship on pharmacists and pharmacies in
regard to workflow, process, and costs related to implementing a new
system (which may include training, maintenance, and printing).
     Education or training should be provided to health care
professionals if FDA converts to electronic distribution of prescribing
information.
     There are varying opinions as to whether FDA should
require electronic distribution of prescribing information for all
prescription drugs, whether there should be a transition period whereby
paper forms would coexist with the electronic format, and whether
certain drugs, due to warnings for the drugs or special instructions
regarding their use, always should be accompanied by prescribing
information in paper form.
     Parties also differed as to whether we should provide for
other sources of prescribing information if emergency situations
resulting in a loss of electricity or Internet access arose. Some
suggested that we should create an annual compendium that health care
professionals could consult as a backup resource.

B. FDA's View on the Comments and Testimony

    We considered these comments in drafting this proposed rule. For
example, FDA agrees that electronic distribution of prescribing
information should give health professionals access to the latest
information for a particular human prescription drug and contribute to
improving patient care. The paper prescribing information that is the
subject of this proposed rule is the version that is on or within the
package from which the drug is to be dispensed (e.g., the bulk pharmacy
package). In general, prescribing physicians do not dispense drugs, so
they usually do not have access to the paper version appended to the
bulk pharmacy package. Instead, they use electronic or paper versions
(e.g., compendia such as the Physicians' Desk Reference (PDR)) and
would have access to FDA's labeling repository. Pharmacists that
currently use the paper prescribing information will need to seek drug
information by accessing FDA's up-to-date electronic labeling
repository or by requesting the paper version of the prescribing
information from the manufacturer or, if needed, consulting another
source (e.g., paper or electronic compendia). Patients generally do not
receive the paper prescribing information, but they would also have
access to up-to-date electronic prescribing information from FDA's
labeling repository Web site. Since patient labeling is not subject to
this rule, warnings, risk information, and special instructions for use
in patient labeling will continue to be provided in paper form to
patients.
    We also agree that electronic distribution of prescribing
information may reduce waste. We have heard anecdotally that the paper
form of prescribing information is not generally used and is frequently
discarded with the drug packaging to conserve shelf space in the
pharmacy. However, we did not evaluate the environmental impacts
resulting from fewer paper forms of labeling and did not cite
environmental benefits as a justification for this proposed rule.
    We also agree that electronic prescribing information is more user-
friendly. Pharmacists have stated that the paper version is very
difficult to read because of small font sizes and hard to keep
organized once it is unfolded. The user of an electronic version would
have ability to make the print larger and easier to read, and to
navigate the prescribing information through the use of hyperlinks.
    This proposal represents a continuation of our efforts to improve
access to prescription drug labeling and to make a transition from
paper to electronic distribution of prescribing information so that
health care providers utilize the most up-to-date version of the
prescribing information. To help understand the impact of this proposed
rule, we invite any additional comments on the use of prescribing
information by prescribers and other health care professionals, as well
as consumers/patients.

IV. Description of the Proposed Rule

A. Labeling Accompanying the Product

    Section 201(m) of the FD&C Act defines ``labeling'' to mean ``all
labels and other written, printed, or graphic matter (1) upon any
article or any of its containers or wrappers, or (2) accompanying such
article.'' For purposes of this rulemaking only, we consider electronic
distribution of prescribing information to be ``accompanying'' the
drug, through the label statement directing interested parties to
access the prescribing information through the Internet or other
electronic means.

B. Label Statement

    Proposed Sec. Sec.  201.100(b)(8) and 610.61(t) would require a
statement to appear on the immediate container label (or be affixed to
the immediate container by other means such as a peel-back label) and
the outer container or package stating that to obtain the current
prescribing information, go to labels.fda.gov or call (insert the toll-
free telephone number) for a faxed, emailed, or mailed copy. In order
to ensure that it is readable, the statement would be required to be no
smaller than 6-point type.
    Proposed Sec.  610.60(a)(8) would require biological product
containers capable of bearing a full label to bear the statement.
However, we do not propose to amend Sec.  610.60(c) or (d) to require
the statement to appear on the container label or to be affixed to the
immediate container by other means for containers that bear only a
partial label or no container label. Consistent with current Sec.
610.60(c) and (d) and proposed Sec.  610.61(t), containers capable of
bearing only a partial label and containers incapable of bearing a
label must be placed in a package that must have a label bearing the
required statement detailed in this proposed rule. FDA recognizes that
the package may be discarded at the time containers are stored and
invites comment on the availability of the package in cases where the
immediate container label does not have adequate space for the required
statement.
    Proposed Sec.  606.121(c) would require the container label of
blood and blood components to bear the statement: See circular of
information for indications, contraindications, cautions, and methods
of infusion. To obtain the current circular of information, go to
labels.fda.gov or call (insert toll-free telephone number) for a faxed,
emailed, or mailed copy. In order to ensure that it is readable, the
statement would be no smaller than 6-point type. If the immediate
container label is too small to accommodate the statement, the
statement must be affixed to the immediate container by other means,
such as a peel-back label.
    We request comment on the feasibility of requiring a statement of
this length on containers such as small volume single dose vials and
syringes of product, some of which already bear one or more peel-off
labels for product identification and inclusion in patient charts. In
addition, we request comments on whether the new required statement
will diminish the ability to include peel offs for inclusion in patient
charts.
    In order to ensure that the prescribing information is accessible
in situations when Internet access is not available to the health care
professional seeking the current prescribing information, the
manufacturer or applicant would be required to print a toll-free
telephone number in the statement appearing on the immediate container
label and outer container or package that the health care professional
could call to have the manufacturer or applicant send the most current
prescribing information by FAX, email, or mail. This is intended
primarily for use by health care professionals without regular access
to the Internet, but could also be used in the case of a public health
emergency or natural disaster to the extent that the emergency
responders retain some means of communication, e.g., telephone and fax.
As discussed in section I.C.3, we expect that in most emergency
situations, first responders and other deployed units would be prepared
with the key information from prescribing information necessary to
appropriately dispense medications in an emergency, even if Internet
and other methods of communication are unavailable.
    Under proposed Sec.  201.100(c)(5), the manufacturer or applicant
would be required to ensure that the toll-free telephone number is
current, fully functioning, and maintained so that there is always an
alternate method to obtain the current prescribing information if the
requestor cannot access the FDA's labeling repository Web site. The
toll-free telephone number service would be required to be available 24
hours a day, 7 days a week. If a request is received for a FAX, email,
or mailing of the current prescribing information, the manufacturer or
applicant would be required to take adequate steps to ensure that it
provides the requested prescribing information promptly. As previously
noted, the requirements of this regulation, including the requirement
to provide the toll-free number and to provide the requested
prescribing information applies to all manufacturers, including
repackagers and relabelers. Thus, each manufacturer would be required
to provide a toll-free number on the label and outer container and to
respond to requests for faxed, emailed, or mailed copies of the
labeling. FDA invites comment on whether these alternatives available
on request through the telephone are sufficient methods for obtaining
the current prescribing information if it cannot be accessed using the
Internet. FDA also invites comment on what would be considered a
reasonable amount of time to respond to a request for current
prescribing information. The proposed requirement is to ``promptly''
respond.

C. Paper Versus Electronic

    Under proposed Sec.  201.100(c)(3), the covered prescribing
information would be distributed electronically and would not be
distributed in paper form, except where a paper copy is requested or
where an exemption is granted. By contrast, FDA-approved patient
package inserts, including patient instructions for use, Medication
Guides required under 21 CFR part 208, and any other type of patient
labeling are not within the scope of this rule and would continue to be
provided in paper form.
    The Web site labels.fda.gov presently holds prescribing information
submitted to the Agency under current requirements, such as with
listing information and annual reports. It is searchable by proprietary
name, active ingredient, company name, NDC number, and application
number or regulatory citation. We note that certain classes of
products, such as cord blood products, may not have a proprietary name
or NDC number, and we request comment on other categories by which the
repository should be searchable. FDA also solicits comment regarding
the ease of use of the labels.fda.gov Web site.

D. Exemptions

    Under proposed Sec.  201.100(g) a manufacturer or applicant would
be able to submit a written request to FDA for exemption of a human
prescription drug from the requirements for electronic distribution of
prescribing information. The person requesting the exemption would be
required to describe the 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 why the concerns underlying the

request could not reasonably be addressed by other measures.
Additionally, FDA, on its own initiative, would be able to exempt a
drug from the requirements for electronic distribution of prescribing
information, if FDA determines that compliance with the electronic
distribution of labeling requirements could adversely affect the
safety, effectiveness, purity, or potency of the drug; is not
technologically feasible; or is otherwise inappropriate. Examples of
circumstances where it may be appropriate to exempt a product from the
requirements for electronic distribution of prescribing information
include a product which requires multiple steps for reconstitution, a
product that is intended for use in an emergency room, or a product
that may be stockpiled for use during an emergency. In addition, many
cell therapy products require proper handling, preparation, and
administration of the final licensed product to ensure that the correct
product has been received; that the product remains viable, pure, and
potent; and that the product is administered safely. Because steps for
ensuring the safety and effectiveness of cell therapy products are
important, we request comment on the feasibility of the application of
electronic distribution of prescribing information under this proposed
rule for cellular therapy products regulated under section 351 of the
PHS Act.
    We propose that requests for exemption be directed to the
appropriate review division and submitted to the Center for Drug
Evaluation and Research and the Center for Biologics Evaluation and
Research at the addresses in proposed Sec.  201.100(g)(2). We plan to
issue guidance prior to the effective date of the final regulation to
inform manufacturers of any additional means of submitting requests for
exemption, such as electronic submission.

E. Submission of Most Current Version of Prescribing Information to FDA

    This proposed rule would require submission of the prescribing
information, in a format that FDA can process, review, and archive, for
distribution via FDA's labeling repository Web site. For newly approved
drugs, proposed Sec.  201.100(c)(4) would require that applicants,
including NDA, BLA, and ANDA applicants, submit prescribing information
in this format in time for the prescribing information to be posted in
the labeling repository before the drug enters interstate commerce. For
drugs already approved, proposed Sec.  201.100(c)(4) would require
applicants or manufacturers to submit the most current labeling to FDA
each time the prescribing information is changed, including those
changes submitted as supplements or in an annual report (Sec. Sec.
314.70 and 601.12). Compliance with this proposed section would not
exempt applicants from compliance with Sec.  314.70 or Sec.  601.12,
related to supplements and other changes to approved applications,
including for labeling. Applicants would be required to submit updated
labeling within 2 business days of FDA approval of a prior approval
supplement. Under the proposed regulation, labeling should be submitted
to FDA for distribution on the same day that a CBE supplement is
submitted to the Agency under Sec.  314.70(c)(6). Manufacturers who are
not applicants, for example, repackers, would be required to submit the
prescribing information within 2 business days of the posting of the
applicant's updated labeling. For unapproved drugs, the person
responsible for the content of labeling must submit the labeling within
2 business days of a change to the labeling. Finally, with regard to
supplements to ANDAs, we request comment on whether a conforming
amendment cross-referencing Sec.  201.100 should be added to Sec.
314.97, which addresses the requirements for submitting supplemental
applications and other changes to an approved abbreviated application.
    A primary reason for migrating to electronic prescribing
information is to ensure that the most up-to-date information about the
drug product is available. Currently, per Sec.  207.30(a), every
manufacturer required to list drugs under Sec.  207.20 must review and
provide updated listing information to the Agency, including labeling,
each subsequent June and December, or at their discretion as the change
occurs. To minimize the number of submissions to the Agency, if a
supplemental change to the prescribing information is submitted to FDA
under proposed Sec.  201.100(c)(4) before the required submission for
updating electronic registration and listing (part 207), and there is
no additional change to the labeling between the time of the Sec.
201.100(c)(4) submission reflecting the supplemental change and the
date on which updated drug listing information would be required to be
submitted under Sec.  207.30, then this labeling information would not
need to be submitted again when electronic registration and listing
information is updated.
    FDA anticipates that prescribing information will be posted on the
next business day following the date of submission. In addition, under
proposed Sec.  201.100(c)(4), it would be the responsibility of the
entity who submits the labeling to verify, within 2 business days of
submission to the FDA labeling repository, that the correct version of
the prescribing information is being distributed at FDA's labeling
repository Web site and available for public access. FDA would not be
responsible for incorrect prescribing information that is submitted and
then posted. If prescribing information is not posted to the labeling
repository within 2 business days of submission, the manufacturer,
applicant, or other person submitting the labeling must notify FDA's
SPL Coordinator by calling 1-888-463-6332 or emailing<EMAIL_ADDRESS>within 4 business days of submission. If the manufacturer, applicant,
or other person submitting the labeling observes that incorrect
prescribing information has been posted on the labeling repository,
that person must contact FDA's SPL Coordinator by calling 1-888-463-
6332 or emailing<EMAIL_ADDRESS>within 2 business days of its posting.
We invite comment on whether this is a sufficient amount of time for a
manufacturer or applicant to check the accuracy and completeness of the
posted prescribing information. The SPL coordinator should be provided
information such as the NDC code, drug name, and a description of the
problem with the labeling. If updates to labeling are not provided as
required, labeling posted on FDA's labeling repository Web site will be
outdated and inaccurate. Outdated labeling posted on the labeling
repository renders a product misbranded and in these cases the
applicant or manufacturer may be subject to enforcement action by the
Agency.

F. Conforming Amendments

    We propose the following conforming amendments. Proposed Sec.
201.100(b)(7), would replace the phrase on or within the package from
which it is to be dispensed with the phrase either on or within the
package from which it is to be dispensed or accompanying the package
from which it is to be dispensed under 21 CFR 201.100(b)(8). Proposed
Sec. Sec.  201.100(c)(1) and (d)(2), 201.306(a)(1)(ii) and (b)(2), and
201.310(a) would replace the phrase on or within the package from which
the drug is to be dispensed with the phrase either on or within the
package from which the drug is to be dispensed or accompanying the
package from which the drug is to be dispensed under 21 CFR
201.100(b)(8). The first sentence of Sec.  201.100(d) would be revised
to state

whether or not it is on or within a package from which it is to be
dispensed or accompanying a package from which the drug is to be
dispensed under 21 CFR 201.100(b)(8).
    Proposed Sec.  201.100(d)(4) would require that promotional
labeling continue to be disseminated with a copy of FDA-approved
product labeling in paper form. This requirement would ensure that, for
example, a health care professional that receives promotional labeling
or detailing materials containing promotional claims would also have
the full FDA-approved product labeling readily available in paper form.
    The introductory paragraph of Sec.  606.122 would be revised to
replace the phrase must be available for distribution with the phrase
must be distributed electronically. Finally, paragraph (k) of Sec.
610.61 would be revised to state that the route of administration
recommended, or reference to such directions in an enclosed circular or
the electronic prescribing information and paragraph (n) would be
revised to state that the inactive ingredients when a safety factor, or
reference to an enclosed circular or the electronic prescribing
information.

V. Legal Authority

    FDA is authorized under various sections of the FD&C Act to require
that prescribing information be distributed electronically and to
require that paper copies of the prescribing information no longer be
distributed, except as provided in this regulation, to ensure that
human prescription drugs have adequate directions for use and to ensure
the efficient enforcement of the FD&C Act. These sections include
sections 201(n), 502, 503, 505, and 701(a) of the FD&C Act (21 U.S.C.
321(n), 352, 353, 355, and 371(a)), and section 351 of the PHS Act (42
U.S.C. 262). The electronic distribution of prescribing information for
human prescription drugs would permit the efficient enforcement of the
misbranding provisions in sections 502(a) and (f) of the FD&C Act, as
well as the safety and effectiveness provisions of section 505 of the
FD&C Act.
    First, FDA has the 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. Under section 502(f) of the FD&C Act, a drug or
device is deemed to be misbranded unless its labeling bears adequate
directions for use, adequate warnings against use by patients where its
use may be dangerous to health, and adequate warnings against unsafe
dosage or methods or duration of administration, in such manner and
form as are necessary to protect users. (See 21 U.S.C. 352(f).)
Adequate directions for use means directions under which the layman can
use a drug safely and for the purposes for which it is intended. (See
21 CFR 201.5.) Additionally, section 502(f) of the FD&C Act authorizes
FDA to create a regulatory exemption from this requirement.
    Under this authority, FDA has issued regulations exempting drugs
subject to section 503(b)(1) of the FD&C Act (prescription drugs) from
the requirements of section 502(f)(1) of the FD&C Act if certain
conditions are met. (See e.g., 26 FR 8389 (September 6, 1961) (final
rule amending then Sec.  1.106 (21 CFR 1.106)); see also 17 FR 6818
(July 25, 1952) (final rule amending then Sec.  1.106).) The 1961
amendments to then Sec.  1.106 exempted a drug subject to section
503(b)(1) of the FD&C Act from section 502(f)(1) of the FD&C Act if,
among other things, labeling on or within the package from which the
drug is to be dispensed bears adequate information for its use, under
which professionals licensed by law to administer the drug can use the
drug safely and for the purposes for which it is advertised or
represented. (See Sec.  1.106(b)(3).) The relevant provision of the
exempting regulations is currently codified at Sec.  201.100(c)(1).
Section 201.100(c)(1), like its predecessor Sec.  1.106(b)(3), exempts
a drug subject to section 503(b)(1) of the FD&C Act from section
502(f)(1) of the FD&C Act if labeling on or within the package from
which the drug is to be dispensed bears adequate information for its
use, under which professionals licensed by law to administer the drug
can use the drug safely and for the purposes for which it is advertised
or represented. Subsection (c)(2) provides that, for an article subject
to section 505 of the FD&C Act, the labeling bearing such information
is the labeling authorized by the approved new drug application or
required as a condition for the certification or the exemption from
certification requirements applicable to preparations of insulin or
antibiotic drugs. (See Sec.  201.100(c)(2).)
    The review in this proposed rule of the language of the exempting
regulations shows that, for decades, the mechanism through which the
pharmaceutical industry has met the requirement for exempting a
prescription drug from section 502(f)(1) of the FD&C Act is the
shipment of a paper copy of the prescribing information with each
container of a prescription drug. The statutory language authorizing
FDA to create a regulatory exemption from the requirements of section
502(f)(1) of the FD&C Act is broad. We have concluded that nothing in
the statutory language mandates that the regulatory exemption can be
met only through shipment of a paper copy of the labeling accompanying
each container of the drug. Advances in technology now allow for the
electronic distribution of labeling, an option that was not feasible at
the time FDA initially issued the predecessor to this proposed
regulation.
    The electronic distribution of prescribing information is expected
to advance: (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; and (3) the prevention of unsafe
prescribing of prescription drugs. Currently, the prescriber, health
care provider, or pharmacist may review a paper copy of the labeling
that has been shipped and stored with a drug for a number of months and
that may not contain the most recent information with regard to
indications, warnings, or directions for use. In contrast, the
electronic distribution of prescribing information provides access to
the most recent information about the directions for use, warnings, and
contraindications. This information will be available within days of a
change via posting on the FDA labeling repository or by FAX, email, or
mail. Accordingly, FDA has concluded that it has the authority to amend
Sec.  201.100(c)(1) to require that the exemption from section
502(f)(1) of the FD&C Act must be met through electronic means.
    Second, FDA concludes that it has authority to base the regulatory
exemption from the adequate directions for use requirements of section
502(f) of the FD&C Act on the condition that a paper copy of the
prescribing information not be shipped with each container of the drug,
except where FDA has concluded that compliance with electronic
distribution would adversely affect the safely, effectiveness, purity,
or potency of the drug; is not technically feasible; or is otherwise
inappropriate. Although the regulation exempting prescription drugs
from the requirement to provide adequate directions for use has
previously conditioned the exemption on distribution of paper copies of
the prescribing information, at the time those regulations were drafted

the electronic distribution of prescribing information was not
feasible. As described in this document, given the shelf life of many
prescription drug products, changes to the prescribing information may
occur between the time a product is shipped from the manufacturer and
the time the product is received at the pharmacy or health care
facility. Changes to the prescribing information may also occur during
the time that the drug is stored at the pharmacy and prior to the time
it is dispensed. Under such circumstances, a pharmacist or health care
provider who relies upon a paper copy of the labeling, rather than the
electronic version, may not have access to the current version of the
prescribing information, including the latest warnings or
contraindications that may appear in the electronic version of the
prescribing information at the time a drug is prescribed and dispensed.
Thus, where the electronic distribution of labeling is feasible, the
continued distribution of paper labeling is not always sufficient to
ensure that the products have adequate directions for use, adequate
warnings against use by patients where its use may be dangerous to
health, and adequate warnings against unsafe dosage or methods or
duration of administration, in such manner and form as are necessary to
protect users.
    In contrast, the electronic distribution of prescribing information
would make it easier for the person prescribing, dispensing, or
administering the drug to have full access to all of the drug's current
prescribing information, including directions for use, warnings, and
contraindications. Specifically, the electronic distribution of the
prescribing information via its placement in the FDA labeling
repository, accessible through FDA's Web site, would better ensure that
pharmacists and other health professionals have access to the most
recent version of the directions for use and to the most current
warnings and contraindications. With the electronic distribution of
prescribing information, pharmacists and health care professionals
would have timely access to the most current version of the prescribing
information, in contrast to the paper form of the prescribing
information, which may contain outdated information by the time it
reaches the pharmacist or other health care professional. For these
reasons, FDA has concluded that it has legal authority to require the
prescribing information no longer physically accompany the product in
paper form, except as provided in the exempting provisions of this
proposed regulation.
    Third, we conclude that FDA has the legal authority to require the
label to bear a statement including the FDA labeling repository Web
site where the electronic prescribing information will appear and a
toll-free telephone number maintained by the manufacturer or applicant
and that a manufacturer or applicant must maintain a toll-free
telephone number through which individuals may request the prescribing
information to be faxed, emailed, or mailed.
    As explained in this document, section 502(f) of the FD&C Act
provides that a drug is misbranded unless its labeling bears adequate
directions for use, adequate warnings against use by patients for whom
use may be dangerous to health, and adequate warnings against unsafe
dosage or methods or duration of administration in such manner and form
as necessary to protect users. Since this rule would make the
distribution of this information electronic, the requirement that the
Internet address and telephone number appear on the label is necessary
so that a health care professional prescribing, administering, or
dispensing the product would have the information needed to access the
most current prescribing information. This statement will ensure that
health care providers are directed to the FDA labeling repository
(which will contain the most updated version of the prescribing
information), as opposed to other electronic versions of the
prescribing information, which may not be updated as frequently as the
FDA labeling repository. Similarly, the toll-free number and the
requirement that manufacturers and applicants maintain labeling via
FAX, email, or mail will ensure that health care providers and
pharmacists without Internet access can obtain the most current version
of the prescribing information. Thus, this requirement ensures that the
prescribing information bearing adequate directions for use, adequate
warnings against use by patients for whom use may be dangerous to
health, and adequate warnings against unsafe dosage or methods or
duration of administration in such manner and form as necessary to
protect users accompanies the drug.
    In addition, section 502(a) of the FD&C Act prohibits false or
misleading labeling of drugs, including the failure to reveal material
facts relating to potential consequences under customary conditions of
use under section 201(n) of the FD&C Act. The requirement that the
label include the Internet address of the FDA labeling repository and
the manufacturer's or applicant's telephone number ensures that the
drug product will have accompanying labeling, which should include
relevant information such as the drug strength, dosage form, route of
administration, active ingredient, and drug interactions. In addition,
it ensures that the prescribing information is accurate, up-to-date,
and readily available to the health care provider. Because the labeling
that is linked to the drug product via either the Internet address or
the telephone number includes material facts relating to potential
consequences under customary conditions of use under section 201(n) of
the FD&C Act, the requirement that the Internet address and telephone
number be placed on the label is also justified under section 502(a) of
the FD&C Act. Furthermore, section 701(a) of the FD&C Act authorizes
FDA to issue regulations for the efficient enforcement of the FD&C Act.
    For all these reasons, FDA concludes that we have the legal
authority to require that the prescribing information be provided
electronically, rather than by the shipment of a paper copy of the
prescribing information with each container of a prescription drug
(except where exempted by this regulation), and to require that the
label bear a statement including the Internet address where the
electronic labeling may be found and a toll-free telephone number
through which individuals may request the prescribing information by
other means (such as by FAX, email, or mailing of a paper copy).

VI. Environmental Impact

    The Agency has determined under 21 CFR 25.30(i) and (k) 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. Paperwork Reduction Act of 1995

    This proposed rule contains information collection provisions that
are subject to review by OMB under the Paperwork Reduction Act of 1995
(44 U.S.C. 3501-3520). The title, description, and respondent
description of the information collection are given under this section
with an estimate of the annual reporting burden. Included in the
estimate is the time for reviewing instructions, searching existing
data sources, gathering and maintaining the data needed, and completing
and reviewing the collection of information.
    We invite comments on these topics: (1) Whether the proposed
collection of information is necessary for the proper

performance of FDA's functions, including whether the information will
have practical utility; (2) the accuracy of FDA's estimate of the
burden of the proposed collection of information, including the
validity of the methodology and assumptions used; (3) ways to enhance
the quality, utility, and clarity of the information to be collected;
and (4) ways to minimize the burden of the collection of information on
respondents, including through the use of automated collection
techniques, when appropriate, and other forms of information
technology.
    Title: Electronic Distribution of Prescribing Information for Human
Prescription Drugs, Including Biological Products
    Description: The proposed rule would amend certain labeling
regulations to require applicants or manufacturers of human
prescription drugs (including biological products and blood and blood
components intended for transfusion) to distribute the prescribing
information for these drugs electronically. This information is
currently distributed in paper form on or within the package from which
a prescription drug is dispensed. The electronic distribution
requirements of this regulation would not apply to patient labeling
(including patient package inserts and Medication Guides), which would
continue to be provided in paper form, as currently required by
applicable regulations. The proposed regulation would require
manufacturers and applicants to submit labeling containing prescribing
information to FDA for distribution via FDA's labeling repository Web
site every time there is a change in the labeling and to review the
labeling posted at FDA's Web site to ensure that the correct version of
the labeling appears in the repository. The regulation would require a
product's immediate container label or a label affixed to the immediate
container by other means, such as a peel-back label (if the immediate
container label is too small to bear the statement) and outside package
to bear a statement directing health care professionals to FDA's
labeling repository to view the electronic version of prescribing
information and to provide a toll-free telephone number maintained by
the manufacturer to receive requests that the manufacturer send an
emailed, faxed, or mailed paper copy of the prescribing information.
The prescribing information would be distributed in paper form where a
pharmacist or health care provider requests that the manufacturer send
a paper copy of the labeling or where an exemption to the electronic
distribution of labeling requirements has been granted. Manufacturers
and applicants of exempted products would distribute prescribing
information in paper form on or within the package from which the
product is dispensed and would not be required to distribute the
labeling electronically or by FAX, email, or mail. We are taking this
action to help ensure that the most current prescribing information is
publicly accessible for the safe and effective use of the product.
    Description of Respondents: Persons and businesses, including small
businesses and manufacturers responsible for the labeling of
prescription drugs, including applicants, repackagers, relabelers, and
persons responsible for the labeling of unapproved drugs.

A. Summary of Provisions in Proposed Rule That Contain Collections of
Information

1. Labeling Accompanying a Product To Include Electronic Distribution
of Prescribing Information (proposed Sec. Sec.  201.100(c)(1), (c)(3),
(c)(4), (c)(5), (d), and (d)(2); 201.306; 201.310; 606.122; 610.61(k)
and (n))
    This proposed rule would require that prescribing information be
distributed through electronic means, unless FDA exempts a specific
product from the electronic distribution requirement or unless the
manufacturer is requested to send a paper copy of the labeling. The
addition of new Sec.  201.100(c)(3) would require prescribing
information to be distributed electronically and, with the exceptions
noted in this document, not in paper form. The mechanism by which the
labeling will be distributed electronically would be through posting on
the FDA labeling repository at labels.fda.gov. The labeling repository
would be initially populated with labeling that had already been
electronically submitted to FDA to comply with current requirements
(part 207, and Sec. Sec.  314.50(l), 314.94(d), 601.14). On the
effective date of this regulation, manufacturers and applicants would
not need to make a new submission of labeling to FDA under this
regulation if the labeling available in the repository is current.
However, before distributing product with labels directing users to
labels.fda.gov for prescribing information, the manufacturer or
applicant must review the prescribing information in the repository,
and, if the prescribing information in the repository is not current,
must submit the current version of the prescribing information.
    This proposed rule would revise Sec.  201.100, with the addition of
paragraph (c)(4), which would require that, upon initial approval of a
drug, or following any change to approved labeling, the applicant or
other manufacturer must submit the content of labeling in an electronic
format to FDA at the time of the change for distribution via the FDA's
labeling repository Web site. Minor changes to the prescribing
information would continue to be reported in the applicant's annual
report; however, the revised labeling would be required to be submitted
to FDA at the time of the change for distribution via FDA's labeling
repository Web site. Submissions at the time of a change would ensure
that the most up-to-date prescribing information is posted on the FDA's
labeling repository Web site and available to the public, particularly
health care professionals, for use with the drug at the time it is
prescribed, dispensed, or administered.
2. Label Statement for Human Prescription Drugs, Including Biological
Products and Blood and Blood Components Intended for Transfusion, on
the Product's Immediate Container Label and Outside Package (Proposed
Sec. Sec.  201.100(b)(8), 606.121(c), 610.60(a)(8), and 610.61(t))
    Current Sec. Sec.  201.100(b), 606.121, 610.60, and 610.61 set
forth the information that is required to appear on the label of the
prescription drug product or the container label and outside package of
biological products. This proposed rule would require, except where an
exemption is granted, that all immediate container labels and outside
packages bear a statement directing users to the FDA labeling
repository to obtain the current prescribing information or circular of
information and to a toll-free number to request that this information
instead be provided by mail, email, or FAX. In order to ensure that the
statement is readable, this statement would be no smaller than 6-point
type. Where the immediate container label does not have sufficient
space to bear this statement, it would be required to be affixed to the
immediate container by other means, such as a peel-back label.
3. Provision of Prescribing Information via Fax, Email, or Mail
(Proposed Sec.  201.100(c)(5)) and Exemptions (Sec.  201.100(g))
    To ensure that the prescribing information is readily accessible if
Internet access is not available to the health care professional
seeking the current prescribing information, the label statement would
be required to include a toll-free telephone number on

the product's immediate container label and outside package. The health
care professional would call this number to request the most current
prescribing information by FAX, email, or mail. The manufacturer would
be responsible for ensuring that the toll-free telephone number is
current, fully functioning, and maintained so that there is always an
alternate method available (24 hours a day, 7 days a week) to obtain
the current prescribing information if the requestor cannot access the
information electronically. The manufacturer would be responsible for
taking adequate steps to ensure that it promptly provides the
prescribing information to the requestor.
    Proposed Sec.  201.100(g) would permit a manufacturer to request
that a drug or biological product be exempt from the requirements for
electronic distribution of labeling set forth in this section. The
exemption request must document why compliance with the electronic
distribution of labeling requirements could adversely affect the
safety, effectiveness, purity, or potency of the drug; is not
technologically feasible; or is otherwise inappropriate and must
document that the concerns underlying the request could not reasonably
be addressed by other measures. In addition, FDA would be able to
exempt products on its own initiative. Manufacturers and applicants of
exempted products would be required to distribute prescribing
information in paper form on or within the package from which the drug
is to be dispensed.

B. Estimates of Reporting Burden

1. Electronic Submissions of Prescribing Information to the Agency, for
Inclusion in the Electronic Labeling Repository (Proposed Sec.
201.100(c)(4))
    Prescribing information for prescription drugs (i.e., content of
labeling required under Sec.  201.100(d)) already must be submitted to
the Agency in an electronic format that the Agency can process, review,
and archive as part of NDAs, ANDAs, BLAs, and annual reports. (See
Sec. Sec.  314.50(l), 314.94(d), 601.14(b), and 314.81(b).) These
submissions are approved by OMB under the PRA under OMB control numbers
0910-0530 and 0910-0338. In addition, under section 510(p) of the FD&C
Act, enacted in 2007, listing information required to be submitted
under section 510(j) of the FD&C Act and implementing regulations in
part 207 has been required to be submitted electronically since June
2009. Labeling for all drugs is a subset of that information, including
prescribing information both for prescription drugs that are subject to
approved NDAs, ANDAs, and BLAs, and for prescription drugs that are not
subject to approved applications. Information collections associated
with the electronic submission of listing information are approved
under OMB control number 0910-0045. In May 2009, FDA issued a guidance
entitled ``Providing Regulatory Submissions in Electronic Format--Drug
Establishment Registration and Drug Listing,'' (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072339.pdf. In this guidance, FDA explained that labeling updates to
applications under the content of labeling regulations could be
duplicative in content and format of labeling required to be submitted
for listing under part 207. To avoid duplicative submissions, FDA
recommended that applicants simultaneously fulfill the ``content of
labeling'' and listing requirements regarding submission of labeling by
submitting a single SPL file through the listing system and cross-
referencing it in their applications.
    FDA intends to adopt the same electronic format used in these other
submissions (currently SPL) for submitting labeling required under this
proposed regulation. FDA intends to use labeling previously submitted
under these other provisions to initially populate the labeling
repository prior to the effective date of the rule, so that where
labeling is current, no new submissions will be needed to achieve
initial compliance. Further, if this proposed rule becomes final, going
forward, a single submission will in many cases fulfill the
requirements under this regulation, under the content of labeling
requirements in parts 314 and 601, and under certain provisions of part
207. Because this regulation would require submission of labeling in
electronic form prior to the time at which such labeling must be
submitted under those other provisions (and therefore, may result in
some additional submissions not accounted for in those information
collections), in the burden estimates that follow, FDA has included the
estimated burden of all submissions that would be required to meet the
terms of this proposed regulation, without excluding those that would
duplicate submissions already addressed under one of the previously
named provisions. In the future, however, FDA anticipates that if this
rule becomes final and its information collection provisions are
approved, it would be appropriate to reduce the estimated information
collection burdens approved under control numbers 0910-0530, 0910-0338,
and 0910-0045, as FDA does not intend to require duplicative
submissions.
    To estimate the burden hours per submission, we adopted an estimate
of 1.25 hours per submission (which was the time estimate used for
submission of electronic content of labeling under the most recent OMB
extension of approval for that information collection, approved under
OMB control number 0910-0338, which expires on January 31, 2017). The
total estimated number of labeling submissions is the sum of several
items.
    The proposed regulation would require applicants to submit the
labeling upon initial approval of a drug. To estimate the annual number
of submissions for newly approved products, the Agency reviewed the
number of NDA and ANDA approvals and new licenses for biological
products to estimate the average number of approvals on an annual
basis. We have estimated that there will be approximately 106 NDA
applicants who had an average of 150 NDA approvals per year and
approximately 250 ANDA applicants who had 1,200 ANDA approvals. We
further estimate that approximately 25 respondents will have an average
of 45 BLAs licensed on an annual basis. The total burden hour estimate
for these submissions to the Agency is 1,744 hours (1,395 x 1.25 =
1,744).
    To estimate the number of labeling submissions that may occur due
to updates to the labeling of currently marketed drugs for changes that
would require a supplement to an application, we reviewed the number of
supplements to NDAs and BLAs reflecting labeling changes that were
submitted to FDA in fiscal year 2013 for drug and biological product
manufacturers and applicants. An average of 200 applicants submitted an
average of 5.5 supplements reflecting labeling changes per applicant
per year to the Agency (n = 1,100). The burden hour estimate for these
submissions to the Agency is 1,375 hours ([200 x 5.5] x 1.25 = 1,375).
    Because this proposed rule would require that applicants submit
labeling changes to FDA at the time of the change, there may be
submissions to the Agency due to a minor labeling change that
previously would have been submitted to the Agency with annual reports
(Sec. Sec.  314.81 and 601.12). To estimate the number of submissions
for minor label changes, we assumed that the percentage of firms making
label changes via annual reports would be similar to the percentage
making changes via supplements and moderate

changes being effected in 30 days. Thus, we assumed that one change per
applicant, (200 NDA/BLA firms, 225 ANDA firms, and 457 repackagers),
for a total of 882 submissions. The total burden hour estimate for
these submissions to the Agency is 1,103 hours (882 x 1.25 = 1,103).
    Holders of ANDA applications would also submit updated labeling if
the applicant who holds the NDA for the innovator drug makes a change
to its labeling. We estimate that, on an annual basis, 225 ANDA
applicants will make 1,830 submissions of updated labeling. The total
burden hour estimate for these additional submissions to the Agency is
2,288 hours (1,830 x 1.25 = 2,288).
    This regulation also would require repackagers and relabelers (who
are subject to part 207 but not to parts 314 or 612) to submit labeling
for their repackaged or relabeled products. Thus, each time an
applicant submits updated labeling for a particular product for
distribution via the repository, any manufacturers who repack or
relabel that product would also be required to submit updated labeling
for posting in the labeling repository. Based on the number of
repackers and relabelers that would be subject to this proposal, we
estimate that 169 repackers and relabelers would make approximately 566
submissions of updated labeling for NDA products for posting in the
labeling repository. In addition, we estimate that 575 repackers and
relabelers would make a total of 2,196 submissions of labeling due to
an ANDA change. The total burden hour estimate for these submissions to
the Agency is 3,453 hours (2,762 x 1.25 = 3,453).
    To estimate the annual burden on blood establishments of submitting
updated versions of the circular of information and reviewing the
posted circular of information, we have estimated that there are 1,300
blood establishments that will be affected by this regulation. The vast
majority of blood establishments use the same circular of information,
and we estimate that the circular of information will change once
annually. Thus, the annual burden of submitting the circular of
information is estimated to be 1,625 hours (1,300 x 1.25 = 1,625).
    The sums of all of these prior estimates are included in tables 1
and 2 as our estimates of the information collection burden associated
with proposed Sec.  201.100(c)(4). In developing our estimates for NDA,
ANDA, and BLA products, we are not able to fully account for the
possible overlap in respondents submitting labeling under each of the
scenarios described in this document. For example, it is possible that
a firm submitting labeling in conjunction with a new drug approval
might also submit labeling to address a minor labeling change that is
reportable in an annual report. In the number of respondents reported
in the table, we have not attempted to account for this overlap, but
have merely added the number of respondents from each subestimate. The
result may be an overestimate of the number of respondents, and a
consequent underestimate of the average number of responses per
respondent. We invite comment on this and other aspects of our
estimate.
2. Submission and Review of Circular of Information by Blood
Establishments
    Because FDA regulations do not currently require blood
establishments to submit the circular of information electronically,
blood establishments would be required to submit the circular of
information to FDA prior to the effective date of this regulation. To
estimate the burden on blood establishments of submitting updated
versions of the circular of information, we have estimated that there
are 1,300 blood establishments that will be affected by this
regulation. The vast majority of blood establishments use the same
circular of information. Thus, the initial burden of submitting the
circular of information is estimated to be 1,625 hours (1,300 x 1.25 =
1,625) (table 2).
3. Review of Accuracy and Completeness of Posted Prescribing
Information (Proposed Sec.  201.100(c)(4))
    Because the labeling repository will be populated with labeling
received by the Agency under current requirements, we do not expect a
mass submission of prescribing information upon the effective date of
this regulation. We require that manufacturers and applicants will
verify the accuracy and completeness of the labeling already posted in
the repository. This will ensure that labeling available via the FDA
labeling repository is accurate and up-to-date. An estimate of
establishments that would be affected by this rule was made based on
information available in FDA's establishment and product listing
databases for drug and biological products. An average of the estimated
1,500 to 2,000 drug manufacturers and applicants was combined with an
estimate of 1,800 biological establishments (either licensed
establishment or registered blood establishments) for an estimate of
3,550 possible respondents (1,750 + 1,800 = 3,550) for estimating the
burden. Collectively, these respondents are responsible for producing
46,000 to 57,600 prescription drug products. An average of this range
was used for determining the frequency of responses, resulting in
51,800 individual prescription drug products. The frequency of
responses was determined by taking the number of individual
prescription drug products divided by the number of respondents,
resulting in an estimate of 14.60 responses per respondent. (51,800/
3,550 = 14.60).
    To estimate the burden hours associated with each submission, we
adopted an estimate of 5 hours, which is equal to the time estimated
for proofreading the electronic document in the electronic submission
final rule (68 FR 69009). We believed this estimate would be similar to
the estimate of the amount of time needed to review the accuracy and
completeness of the posted prescribing information and compare it with
the electronic file that was submitted to the Agency. Although a
manufacturer may have to review the accuracy of more than one copy of a
single version of the prescribing information that corresponds to
multiple NDC numbers, we believe the 5-hour estimate is reasonable. We
request comment on whether this estimate would be applicable to the
proposed requirement for reviewing the accuracy and completeness of the
prescribing information after it is posted. The total first year burden
hour estimate for review for accuracy and completeness of the posted
prescribing information is 259,150 hours (3,550 x 14.60 x 5 = 259,150)
(table 2). This burden hour estimate includes the time for each
manufacturer to review the accuracy and completeness of the prescribing
information once it is posted, following a change to the labeling, on
the FDA's labeling repository Web site.
    In addition, on an annual basis, upon approval of a new NDA, ANDA,
or BLA, or upon a change made to prescribing information, all
manufacturers and applicants, including repackers of such products will
be required to review for accuracy the newly posted prescribing
information. As explained in this document, on an annual basis we
estimate that there will be 1,395 labeling submissions for newly
approved or licensed products (NDAs, BLAs, ANDAs), 1,100 labeling
submissions for NDA/BLA supplements, 1,830 labeling submissions for
ANDA supplements due to innovators' labeling changes, 882 labeling
submissions for annual reportable changes, and 2,762 labeling
submissions by repackers due to changes in NDA/ANDA holders' labeling.
The total annual burden hour

estimate for review for accuracy and completeness of the posted
prescribing information for these products is 13,480 hours ([1,395 +
1,100 + 1,830 + 882 + 2,762 = 7,969] x 5 = 39,845) (table 1). The
annual burden of checking the circular of information for accuracy is
estimated to be 6,500 (1,300 x 5 = 6,500). The total annual burden for
drugs, biologics, and blood and blood components is 46,345 hours (table
1).
4. Production of New Product Labels for the Immediate Container Label
and Outer Container or Package To Bear Label Statement (Proposed Sec.
201.100(b)(8))
    Under proposed Sec.  201.100(b)(8), a new label statement would be
required on a product's immediate container label (or on a label
affixed to the container by other means, such as a peel-back label, if
the immediate container is too small to bear the statement) and outer
container or package. A portion of this statement, directing users to
access labels.fda.gov to view electronic prescribing information, is
information provided by FDA to manufacturers and applicants for
disclosure to the public, and therefore does not constitute a
collection of information under 5 CFR 1320.3(c)(2). However, the
portion of the statement that provides a toll-free number for
requesting prescribing information by mail, email, or FAX is not
provided by FDA. Accordingly, we have accounted for the burden of
including that statement. The frequency of responses was determined by
taking the average of the estimated number of stock keeping units
(SKUs) (150,000-200,000), divided by the number of respondents,
resulting in an estimate of 49.3 responses per respondent (175,000/
3,550 = 49.3). To estimate the burden hours associated with adding the
statement to existing product labels, we adopted an estimate of 24
hours, which was the estimate used for redesigning labels to
incorporate bar codes (see 69 FR 9119 at 9149; February 26, 2004). The
total burden hour estimate for adding the new label statement to all
presently marketed prescription drugs is 4,200,360 hours (3,550 x 49.3
x 24 = 4,200,360) (table 3).
    In addition, immediate container labels and outside packages for
newly approved products would need to be designed to include the
statement. Because the inclusion of the statement would be one
requirement of multiple requirements considered in preparing drug
product labels, this burden is included as part of the overall burden
to design, test, and produce the label for a drug product's immediate
container and outer container or package. The format and content of
prescription drug and biological product labels must comply with FDA
regulations in 21 CFR part 201 for drugs, including Sec.  201.100(b)
and other sections in subparts A and B, and 21 CFR part 610 subpart G.
For blood and blood components, the label must comply with 21 CFR part
606 subpart G. Based on characteristics of the product, there are some
differences in the label requirements for prescription drugs,
biological products and blood and blood components. However, in
general, prescription drug labels contain the following information
about the drug: (1) Proprietary and established name (or proper name
for biological products); (2) recommended or usual dose; (3) route of
administration; (4) any warnings or cautionary statements; (5) ``Rx
only'' statement; (6) other required statements or information based on
type of product; (7) quantity or proportion of each active ingredient,
or amount of product; (8) names of inactive ingredients (if the drug is
for other than oral use); (9) identifying lot or control number; (10)
manufacturer name and address (and license number for biologics); (11)
expiration date; and (12) barcode. Based on FDA's burden estimates for
other types of drug product labeling and information from the
pharmaceutical industry, FDA estimates that it takes applicants or
manufacturers approximately 160 hours to design, test (i.e., to ensure
that the designed label fits on the drug product container or carton),
and produce each prescription drug product label, including the
statement required under proposed Sec.  201.100(b)(8). Based on an
average of the estimated number of SKUs (175,015) and the estimated
number of respondents (3,550), as discussed previously, the total
burden for the design, testing, and production of prescription drug
product labels for existing products is approximately 28,002,400 hours
(table 3). Going forward for newly approved drug products, we estimate
that the total burden hours for the design, testing and production of
new prescription drug product labels for a drug product's immediate
container and outer container or package would be approximately 223,220
hours (table 4). This is based on the average annual submission of
approximately 150 NDAs from approximately 106 applicants, approximately
1200 ANDAs from approximately 250 applicants, and approximately 45 BLAs
from approximately 25 applicants.
5. Exemptions (Proposed Sec.  201.100(g))
    Under proposed Sec.  201.100(g), the Agency would permit a
manufacturer who markets a product to submit a written request to FDA
for exemption of a human prescription drug, including a biological
product, from the requirements for electronic distribution of
prescribing information. We anticipate very few exemption requests will
be submitted. Therefore, we estimate that approximately 10
manufacturers and applicants would request an exemption annually, and
that each request would take approximately 1 hour to prepare and submit
to FDA. In those instances where we grant an exemption, the covered
prescribing information would be distributed in paper form by the
manufacturer.
    The total estimated annual reporting burden for this collection of
information is as follows:

                                 Table 1--Estimated Annual Reporting Burden 1 2
----------------------------------------------------------------------------------------------------------------
                                                    Number of                         Average
  Type of reporting and 21 CFR      Number of     responses per    Total annual     burden per      Total hours
            section                respondents      respondent       responses       response
----------------------------------------------------------------------------------------------------------------
Submission of updated labeling            3,732              2.5           9,269            1.25          11,586
 and circular of information
 under Sec.   201.100(c)(4)....
Review of accuracy of posted              3,732              2.5           9,269            5             46,345
 labeling and circular of
 information under Sec.
 201.100(c)(4).................
Requests for exemptions under                10              1                10            1                 10
 Sec.   201.100(g).............