
[Federal Register Volume 79, Number 243 (Thursday, December 18, 2014)]
[Proposed Rules]
[Pages 75506-75527]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2014-29522]



[[Page 75506]]

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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.

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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: 202-395-7285, or emailed to 
oira_submission@omb.eop.gov (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

[[Page 75507]]

(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]
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                                                    7% discount rate, 10 years      3% discount rate, 10 years
                                                 ---------------------------------------------------------------
                                                        Low            High             Low            High
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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
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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.
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    \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.
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    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

[[Page 75508]]

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.
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    \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.
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    ``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

[[Page 75509]]

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

[[Page 75510]]

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)).
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    \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)).
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    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.

[[Page 75511]]

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

[[Page 75512]]

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

[[Page 75513]]

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

[[Page 75514]]

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.

[[Page 75515]]

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

[[Page 75516]]

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 spl@fda.hhs.gov 
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 spl@fda.hhs.gov 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

[[Page 75517]]

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

[[Page 75518]]

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

[[Page 75519]]

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

[[Page 75520]]

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

[[Page 75521]]

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

[[Page 75522]]

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).............
Requests to receive prescribing         129,090              1           129,090           *0.25         516,360
 information by fax, email, or
 mail when requested (Sec.
 Sec.   201.100(c)(5) and
 201.100(g))...................
                                --------------------------------------------------------------------------------

[[Page 75523]]

 
    Total......................  ..............  ...............  ..............  ..............         574,301
----------------------------------------------------------------------------------------------------------------
\1\ Totals may not sum because frequency numbers are rounded.
\2\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.
* (15 minutes).


                                 Table 2--Estimated One-Time Reporting Burden 1
----------------------------------------------------------------------------------------------------------------
                                                       Number of     Total one-       Average
   Type of reporting and 21 CFR       Number of      responses per      time        burden per      Total hours
             section                 respondents      respondent      responses      response
----------------------------------------------------------------------------------------------------------------
Review for accuracy and                      3,550           14.60        51,830            5            259,150
 completeness of posted
 prescribing information under
 Sec.   201.100(c)(4)............
Submission of circular of                    1,300               1         1,300            1.25           1,625
 information by blood
 establishments under Sec.
 201.100(c)(4)...................
                                  ------------------------------------------------------------------------------
    Total........................  ...............  ..............  ............  ..............         260,775
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.


                           Table 3--Estimated One-Time Third-Party Disclosure Burden 1
----------------------------------------------------------------------------------------------------------------
   Type of disclosure and 21 CFR        Number of      Frequency per      Total       Hours per
              section                  respondents      disclosure     disclosures   disclosure     Total hours
----------------------------------------------------------------------------------------------------------------
Design, testing, and production of             3,550            49.3       175,015           160      28,002,400
 labels for existing products......
Production of new label statement              3,550            49.3       175,015            24       4,200,360
 on immediate container label or
 outside package (Web site and toll-
 free number) under Sec.  Sec.
 201.100(b)(8), 606.121(c)(8)(ii),
 610.60(a)(8), and 610.61(t).......
                                    ----------------------------------------------------------------------------
    Total..........................  ...............  ..............  ............  ............      32,202,760
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.


                                                 Table 4--Estimated Annual Third-Party Disclosure Burden
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                Number of        Number of                     Average
   Type of disclosure and 21 CFR section     disclosures per   responses per  Total annual   burden per    Total hours    Total capital, operating  and
                                                respondent      respondent     disclosures   disclosure                         maintenance costs
--------------------------------------------------------------------------------------------------------------------------------------------------------
Distribution of prescribing information by               993             130       129,090             1       129,090  $26,500 to $90,750.
 fax, email, or mail when requested (Sec.
 Sec.   201.100(c)(5) and 201.100(g)).
Design, testing and production of labels                 381            3.80         1,395           160       223,200
 for new prescription drug and biological
 products and blood and blood components.
                                            ------------------------------------------------------------------------------------------------------------
    Total..................................  ...............  ..............  ............  ............       352,290
--------------------------------------------------------------------------------------------------------------------------------------------------------

C. Other Annualized Cost Burdens to Respondents: Operating and 
Maintenance Costs of the Toll-Free Telephone Number and Responding to 
Requests

    This proposed rule would require that manufacturers provide and 
maintain a toll-free telephone number that users of prescribing 
information can call if they want the prescribing information to be 
faxed, emailed, or mailed to them. It was assumed that all 
manufacturers would use existing telephone infrastructure, and they 
would need to add options to the system so that someone could request 
the prescribing information in other forms, particularly if Internet 
access is not available. The costs would include labor costs to modify 
the phone system and to respond to requests. We will adopt the estimate 
for the annualized cost to have a functioning system and maintaining it 
from the economic impact analysis. The recurring annual costs to 
operate and maintain the toll-free telephone number and to send paper 
prescribing information upon request would range from $26,500 to 
$90,750 (Ref. 6). An average of this range will be used for this 
estimation, resulting in $58,619 per manufacturer.
    Concerning the distribution of prescribing information by fax, 
email, or mail when requested (Sec. Sec.  201.100(c)(5) and 
201.100(g)), and based on data described in section IX.H of the 
Analysis of Impacts, we estimate that each manufacturer, repacker, 
relabeler, or contract manufacturer will receive approximately 130 
requests annually to distribute prescribing information by fax, email, 
or mail, and that each distribution of prescribing information

[[Page 75524]]

would take approximately 1 hour (table 4). In addition, we estimate 
that each request to receive prescribing information by fax, email, or 
mail will take approximately 15 minutes (table 1).
    In compliance with the Paperwork Reduction Act of 1995 (44 U.S.C. 
3507)(d)), the Agency has submitted the information collection 
provisions of this proposed rule to OMB for review. To ensure that 
comments on the information collection are received by January 20, 
2015, OMB recommends that written comments be faxed to the Office of 
Information and Regulatory Affairs, OMB, Attn: FDA Desk Officer, FAX: 
202-395-7285, or emailed to oira_submission@omb.eop.gov. All comments 
should be identified with the title ``Electronic Distribution of 
Prescribing Information for Human Prescription Drugs, Including 
Biological Products.''

VIII. Federalism

    FDA has analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. We have determined that 
the proposed rule, does not contain policies that have substantial 
direct effects on the States, on the relationship between the National 
Government and the States, or on the distribution of power and 
responsibilities among the various levels of government. Accordingly, 
we have concluded that the proposed rule does not contain policies that 
have federalism implications as defined in the Executive order and, 
consequently, a federalism summary impact statement is not required.

IX. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5 
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 
104-4). Executive Orders 12866 and 13563 direct Agencies to assess all 
costs and benefits of available regulatory alternatives and, when 
regulation is necessary, to select regulatory approaches that maximize 
net benefits (including potential economic, environmental, public 
health and safety, and other advantages; distributive impacts; and 
equity). This proposed rule would be an economically significant 
regulatory action under Executive Order 12866.
    The Regulatory Flexibility Act requires Agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. The proposed rule would have a significant economic 
impact on a substantial number of small entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that Agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $141 million, using the most current (2013) Implicit 
Price Deflator for the Gross Domestic Product. FDA expects this 
proposed rule to result in a 1-year expenditure that would meet or 
exceed this amount.

Summary

    The proposed rule would generate costs to set up a system for the 
electronic distribution of prescribing information for human 
prescription drugs. While this system may support other or all 
components of the product labeling in addition to the prescribing 
information, this proposed rule covers the prescribing information 
portion of product labeling.
    The proposed rule would generate costs for users of prescribing 
information who would need additional hardware, training, Internet 
access, and information access time. In addition, incremental costs 
would be associated with some printing of the prescribing information. 
Table 5 shows a summary of the ranges of annualized costs using 
discount rates of 7 percent and 3 percent over 10 years. The proposed 
rule would generate benefits in the form of production cost savings 
because eliminating the production of most paper forms would reduce the 
costs of providing prescribing information on human prescription drugs. 
Table 5 shows the ranges of savings. The large ranges for both costs 
and savings indicate the uncertainty associated with such a large 
change in practices for such a large number of manufacturers and users. 
If we use a 7 percent discount rate to annualize the costs and savings 
over 10 years, the effects of the proposed rule could range from 
annualized net savings of $5.0 million to annualized net savings of 
$73.5 million. With a 3 percent discount rate to annualize cost 
savings, the effects could range from an annualized net savings of 
$10.0 million to annualized net savings of $82.2 million. These 
quantified effects do not include the public health benefits associated 
with users having access to the most up-to-date versions of the 
prescribing information.
    The full assessment of the economic analysis is available in Docket 
FDA-2007-N-0363 and at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm (Ref. 7).

                              Table 5--Summary of Annualized Costs and Cost Savings
                                                  [In millions]
----------------------------------------------------------------------------------------------------------------
                                                     Low  (7%)      High  (7%)       Low  (3%)      High  (3%)
----------------------------------------------------------------------------------------------------------------
Cost Savings....................................           $51.8          $163.7           $56.6          $170.8
Costs...........................................            46.8            89.2            46.6            88.6
                                                 ---------------------------------------------------------------
    Net Savings (Cost Savings-Costs)............             5.0            73.5            10.0            82.2
----------------------------------------------------------------------------------------------------------------

X. Comments

    Interested persons may submit either electronic comments regarding 
this document to http://www.regulations.gov or written comments to the 
Division of Dockets Management (see ADDRESSES). It is only necessary to 
send one set of comments. Identify comments with the docket number 
found in brackets in the heading of this document. Received comments 
may be seen in the Division of Dockets Management between 9 a.m. and 4 
p.m., Monday through Friday, and will be posted to the docket at http://www.regulations.gov.

XI. Proposed Effective Date

    We propose that any final rule based on this proposal become 
effective 6 months after publication in the Federal Register. 
Implementation of this rule

[[Page 75525]]

would require that manufacturers and applicants have up-to-date 
electronic prescribing information posted on FDA's labeling repository 
Web site, that manufacturers and applicants have verified the content 
of that information, that the immediate container label and outer 
container or package bear the required statement, and that paper 
labeling no longer accompany the drug. The FDA labeling repository Web 
site is currently available at labels.fda.gov and is populated with 
prescribing information submitted to the Agency under current 
regulatory requirements, such as requirements to submit labeling with 
listing information or with annual reports. If the prescribing 
information available in the repository is current, manufacturers and 
applicants would not be required to resubmit labeling before beginning 
the electronic distribution of labeling.
    Any human prescription drug that an applicant or manufacturer 
introduces into interstate commerce after the effective date that does 
not have accurate, complete, and updated electronic prescribing 
information available on FDA's labeling repository Web site, as well as 
the statement on the product's immediate container label and the outer 
container or package explaining how to access the information, or that 
continues to be accompanied by paper prescribing information would not 
meet the criteria to be exempt from the requirement to provide 
``adequate directions for use'' and would be misbranded under section 
502(f)(1) of the FD&C Act. As explained further in section XII, we 
understand that 6 months is not likely to be sufficient time for many 
manufacturers and applicants to implement this rule with regard to some 
or all of their marketed products. As a result, we are proposing to 
exercise enforcement discretion for 2 years from publication of the 
final rule. However, we anticipate that some will be able to comply 
with the rule beginning on the effective date. We want to ensure that 
those that are able to comply as soon as 6 months after publication can 
take advantage of the benefits of electronic distribution of labeling 
at that time and will no longer need to provide paper labeling with 
their products (as long as all other requirements of the rule are met). 
Because, technically, full implementation (elimination of paper 
labeling that accompanies the product) cannot take place until the rule 
is effective, a longer effective date could delay implementation by 
those able to comply as soon as 6 months after the publication date. We 
request comment on whether a 6 month effective date is sufficient given 
the concerns raised in the GAO report about potential workflow 
disruptions in pharmacies as a result of an online-only system for 
prescribing information. Additionally, FDA requests comments on whether 
a dual system, where the regulation would require distribution of both 
paper and electronic versions of labeling until the compliance date, is 
desirable and information about the potential benefits or consequences 
of such a requirement.

XII. Proposed Compliance Date

    Given the time that may be needed for industry to make necessary 
changes to the drugs' immediate container labels and outer containers 
or packages to comply with this rule and to enable firms to exhaust 
existing stock of drugs already packaged with paper prescribing 
information, we propose a compliance date of 2 years after the final 
rule is published. Thus, until the compliance date, we will exercise 
enforcement discretion with regard to products subject to the 
electronic labeling requirements, so long as those products continue to 
be distributed with the current prescribing information in paper form. 
However, a product distributed between the effective date and the 
compliance date that bears the new required statement on the label and 
outer container must have the current electronic prescribing 
information in the labeling repository at labels.fda.gov and should not 
be accompanied by the paper prescribing information.
    We note that registration and listing information for blood and 
blood components is currently not electronically submitted to the 
Agency. FDA is in the process of developing standards for the 
electronic submission of labeling for blood and blood components. The 
Agency will consider progress in developing such standards when setting 
a compliance date in a final rule for blood and blood components and/or 
on our own initiative grant 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.
    FDA is requesting comments on the proposed effective and compliance 
dates, and whether they are appropriate. Specifically, we request 
comment on whether a delayed compliance date would alleviate concerns 
raised in the GAO report about potential workflow disruptions in 
pharmacies as a result of an online-only system for prescribing 
information and, if so, how much additional time would be needed to 
change operations.

XIII. References

    The following references have been placed on display in the 
Division of Dockets Management (see ADDRESSES) and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday, 
and are available electronically at http://www.regulations.gov. (FDA 
has verified the Web site address in this reference section, but FDA is 
not responsible for any subsequent changes to the Web site after this 
document publishes in the Federal Register.)

1. ``Electronic Drug Labeling: No Consensus on the Advantages and 
Disadvantages of Its Exclusive Use,'' GAO-13-592, Report by the 
Government Accountability Office, July 8, 2013.
2. ``Analysis of the Feasibility of Safety Labeling Changes 
Implementation Timeline,'' Final Report by Eastern Research Group, 
Inc., June 22, 2012.
3. Ho, Y., Q. Chen, H. Nian, K.B. Johnson, ``An Assessment of 
Pharmacists' Readiness for Paperless Labeling: A National Survey.'' 
Journal of the American Medical Informatics Association, 1-6, 2013.
4. Internal analysis of safety-related labeling changes approved by 
FDA between 2003 and 2013.
5. Internal review of labeling changes for new molecular entities 
for calendar years 2005 to 2007.
6. ``Electronic Distribution of Labeling Proposed Rule Final Report 
Economic Impact Analysis,'' Report by Eastern Research Group, Inc., 
October 4, 2010.
7. Preliminary Regulatory Impact Analysis, Initial Regulatory 
Flexibility Analysis, and Unfunded Mandates Reform Act Analysis for 
Electronic Distribution of Prescribing Information for Human 
Prescription Drugs, Including Biological Products; Proposed Rule, 
available at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.

List of Subjects

21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.

21 CFR Part 606

    Blood, Labeling, Laboratories, Reporting and recordkeeping 
requirements.

21 CFR Part 610

    Biologics, Labeling, Reporting and recordkeeping requirements.

    Therefore, under the Federal Food, Drug, and Cosmetic Act, the 
Public

[[Page 75526]]

Health Service Act, and under authority delegated to the Commissioner 
of Food and Drugs, it is proposed that 21 CFR parts 201, 606, and 610 
be amended as follows:

PART 201--LABELING

0
1. The authority citation for 21 CFR part 201 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 358, 360, 
360b, 360gg-360ss, 371, 374, 379e; 42 U.S.C. 216, 241, 262, 264.

0
2. Amend Sec.  201.100 as follows:
0
a. In paragraph (b)(7), remove the phrase ``on or within the package 
from which it is to be dispensed'' and add in its place ``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 paragraph (b)(8) of 
this section'';
0
b. Add paragraph (b)(8);
0
c. In paragraph (c)(1) remove the phrase ``on or within the package 
from which the drug is to be dispensed'' and add in its place ``on or 
within or accompanying the package from which the drug is to be 
dispensed under paragraph (b)(8) of this section'';
0
d. Add paragraphs (c)(3) through (5);
0
e. Revise the introductory text of paragraph (d);
0
f. In paragraph (d)(2), remove the phrase ``on or within the package 
from which the drug is to be dispensed'' and add in its place ``on or 
within or accompanying the package from which the drug is to be 
dispensed under paragraph (b)(8) of this section'';
0
g. Add paragraphs (d)(4) and (g).
    The additions and revisions read as follows:


Sec.  201.100  Prescription drugs for human use.

* * * * *
    (b) * * *
    (8) The statement: ``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.'' This statement must be no 
smaller than 6-point type. Provided, however, that in the case of a 
container too small or otherwise unable to accommodate a label with 
sufficient space to bear the statement, the statement shall be affixed 
to the immediate container label by other means, such as a peel-back 
label. Additionally, if the container is packaged within an outer 
container from which it is removed for dispensing or use, the statement 
shall also be included on the outer container or package.
    (c) * * *
    (3) Labeling containing prescribing information accompanying the 
package from which the drug is to be dispensed under paragraphs (b)(8) 
and (c)(4) of this section is distributed electronically and not in 
paper form except for any FDA-approved patient labeling, any labeling 
containing prescribing information that is distributed upon request by 
FAX or mail, any labeling distributed under the exemption provisions of 
paragraph (g) of this section that is on or within the package from 
which the drug is to be dispensed, and any prescribing information 
accompanying promotional labeling.
    (4) Labeling containing prescribing information must be submitted 
to FDA in an electronic format that FDA can process, review, and 
archive. FDA will periodically issue guidance on how to provide the 
electronic submission (e.g., method of transmission, media, file 
formats, preparation and organization of files). Upon initial approval 
of a new drug or biological product, labeling containing prescribing 
information must be submitted and posted before introducing the drug 
into interstate commerce. For drugs already approved under section 505 
of the Federal Food, Drug, and Cosmetic Act or biological products 
licensed under section 351 of the Public Health Service Act, applicants 
must submit labeling containing prescribing information within 2 
business days of a change to the prescribing information. For 
unapproved drugs, the person responsible for the content of labeling 
must submit labeling containing prescribing information within 2 
business days of a change to the prescribing information. Other 
manufacturers, such as repackers or relabelers, must submit labeling 
containing prescribing information within 2 business days of the 
posting or new posting of an applicant's labeling. The entity 
responsible for submitting the labeling for the drug must verify that 
the correct version of the prescribing information appears on FDA's 
labeling repository Web site labels.fda.gov. The entity responsible for 
submitting the labeling must contact FDA's Structured Product Labeling 
Coordinator by calling 1-888-463-6332 or emailing spl@fda.hhs.gov 
within 4 business days of its submission if the labeling is not posted 
on FDA's labeling repository Web site or within 2 business days of its 
posting if the labeling that is posted is incorrect. Products with 
missing, inaccurate, false, misleading, or outdated labeling on the 
FDA's labeling repository Web site are misbranded.
    (5) The applicant, manufacturer, or person responsible for the 
content of labeling must provide a toll-free telephone number in the 
label statement required in paragraph (b)(8) of this section.
    (i) The applicant, manufacturer, or person responsible for the 
content of labeling must ensure that the telephone number is current, 
fully functioning, and maintained for 24 hours a day, 7 days a week.
    (ii) The applicant, manufacturer, or person responsible for the 
content of labeling must have a fully functioning and maintained system 
to respond to requests to obtain an alternate form of the prescribing 
information which the manufacturer receives through the toll-free 
number. The applicant, manufacturer, or person responsible for the 
content of labeling must take adequate steps to provide the requested 
prescribing information promptly to the requestor.
    (d) Any labeling, as defined in section 201(m) of the Federal Food, 
Drug, and Cosmetic Act, whether or not it is on or within a package 
from which the drug is to be dispensed or accompanying a package from 
which the drug is to be dispensed under paragraph (b)(8) of this 
section, distributed by or on 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 (other than dose information required by 
paragraph (b)(2) of this section and Sec.  201.105(b)(2)) contains:
* * * * *
    (4) In the case of prescribing information accompanying promotional 
labeling, the information required, in paper form and in the format 
specified, by Sec. Sec.  201.56, 201.57, and 201.80.
* * * * *
    (g) If FDA has granted an exemption of the drug from the 
requirements for the electronic distribution of labeling, the 
applicant, manufacturer, or person responsible for the content of 
labeling of unapproved drugs, distributes the content of labeling in 
paper form.
    (1) On FDA's initiative, or in response to a written request from 
an applicant, manufacturer, or person responsible for the content of 
labeling of unapproved drugs, the appropriate Center Director may 
exempt a human prescription drug 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;

[[Page 75527]]

and must explain why the concerns underlying the request could not 
reasonably be addressed by other measures. If an exemption is granted, 
the applicant, manufacturer, or person responsible for the content of 
labeling of unapproved drugs must distribute the content of labeling in 
paper form.
    (2) For products regulated by the Center for Drug Evaluation and 
Research, requests for an exemption should be sent to the Office of New 
Drugs, Center for Drug Evaluation and Research, Food and Drug 
Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993, or 
for drug products for which there is no reference listed drug, to the 
Office of Generic Drugs, Center for Drug Evaluation and Research, Food 
and Drug Administration, 7500 Standish Pl., Rockville, MD 20855. For 
products regulated by the Center for Biologics Evaluation and Research, 
requests for an exemption should be submitted to the attention of the 
appropriate Review Division in the relevant Center for Biologics 
Evaluation and Research Product Office using the following address: 
Center for Biologics Evaluation and Research, Food and Drug 
Administration, Document Control Center, 1401 Rockville Pike (HFM-99), 
Rockville, MD 20852.
0
3. In Sec.  201.306, revise paragraph (a)(1)(ii) introductory text and 
paragraph (b)(2) to read as follows:


Sec.  201.306  Potassium salt preparations intended for oral ingestion 
by man.

    (a) * * *
    (1) * * *
    (ii) The labeling 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 Sec.  201.100(b)(8) bears adequate information 
for its use by practitioners in accord with the ``full disclosure'' 
labeling requirements of Sec.  201.100, including the following warning 
statement: * * *
* * * * *
    (b) * * *
    (2) The labeling 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 Sec.  201.100(b)(8) bears adequate information 
for its use by practitioners in accord with the ``full disclosure'' 
labeling requirements of Sec.  201.100, including a recommendation that 
patients be directed to dissolve any such tablets in an appropriate 
amount of liquid and to dilute any such liquid preparations adequately 
to assure against gastrointestinal injury associated with the oral 
ingestion of concentrated potassium salt preparations.
0
4. In Sec.  201.310, revise the third sentence of paragraph (a) to read 
as follows:


Sec.  201.310  Phenindione; labeling of drug preparations intended for 
use by man.

    (a) * * * In view of the potentially serious effects found to be 
associated with preparations of this drug intended for use by man, the 
Commissioner of Food and Drugs will regard such preparations as 
misbranded within the meaning of section 502(f)(1) and (2) of the 
Federal Food, Drug, and Cosmetic Act, unless the label and labeling 
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 Sec.  201.100(b)(8), and any other labeling furnishing or 
purporting to furnish information for use of the drug, bear a 
conspicuous warning statement to the following effect: * * *
* * * * *

PART 606--CURRENT GOOD MANUFACTURING PRACTICE FOR BLOOD AND BLOOD 
COMPONENTS

0
5. The authority citation for 21 CFR part 606 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 355, 360, 360j, 371, 
374; 42 U.S.C. 216, 262, 263a, 264.

0
6. In Sec.  606.121 revise paragraph (c)(8)(ii) to read as follows:


Sec.  606.121  Container label.

* * * * *
    (c) * * *
    (8) * * *
    (ii) ``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.'' 
This statement must be no smaller than 6-point type.
* * * * *


Sec.  606.122  [Amended]

0
7. In Sec.  606.122 introductory text, remove the words ``must be 
available for distribution'' and add in their place ``must be 
distributed electronically.''

PART 610--GENERAL BIOLOGICAL PRODUCTS STANDARDS

0
8. The authority citation for 21 CFR part 610 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360c, 
360d, 360h, 360i, 371, 372, 374, 381; 42 U.S.C. 216, 262, 263, 263a, 
264.

0
9. In Sec.  610.60, add paragraph (a)(8) to read as follows:


Sec.  610.60  Container label.

    (a) * * *
    (8) The container label for biological products must bear the 
statement: ``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.'' This statement must be no smaller 
than 6-point type. If the container label is incapable of bearing the 
statement due to inadequate space, the statement must be affixed to the 
container by other means, such as a peel-back label.
* * * * *
0
10. In Sec.  610.61, revise paragraphs (k) and (n) and add paragraph 
(t) to read as follows:


Sec.  610.61  Package label.

* * * * *
    (k) The route of administration recommended, or reference to such 
directions in an enclosed circular or the electronic prescribing 
information;
* * * * *
    (n) The inactive ingredients when a safety factor, or reference to 
an enclosed circular or the electronic prescribing information;
* * * * *
    (t) The package label for products must bear the statement: ``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.'' This statement must be no smaller than 6-point type.

    Dated: December 11, 2014.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2014-29522 Filed 12-16-14; 11:15 am]
BILLING CODE 4164-01-P


