75506 Federal Register / Vol. 79, No. 243 / Thursday, December 18, 2014 / Proposed Rules 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Parts 201, 606, and 610 

[Docket No. FDA–2007–N–0363] 

RIN 0910–AG18 

Electronic Distribution of Prescribing 

Information for Human Prescription 

Drugs, Including Biological Products 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Proposed rule. 

SUMMARY: The Food and Drug 

Administration (FDA or the Agency) is 

proposing to amend its prescription 

drug and biological product labeling 

regulations to require electronic 

distribution of the prescribing 

information intended for health care 

professionals, which is currently 

distributed in paper form on or within 

the package from which a prescription 

drug or biological product is dispensed. 

FDA is also proposing that prescribing 

information intended for health care 

professionals will no longer be 

permitted to be distributed in paper 

form with the package from which a 

prescription drug or biological product 

is dispensed, except as provided by this 

regulation. We are proposing these 

actions to help ensure that the most 

current prescribing information is 

publicly accessible for the safe and 

effective use of human prescription 

drugs. 

DATES: Submit either electronic or 

written comments on the proposed rule 

by March 18, 2015. Submit comments 

on information collection issues under 

the Paperwork Reduction Act of 1995 by 

January 20, 2015 (see the ‘‘Paperwork 

Reduction Act of 1995’’ section of this 

document). See section XI for the 

proposed effective date of a final rule 

based on this proposed rule. 

ADDRESSES: You may submit comments, 

by any of the following methods, except 

that written comments on information 

collection issues under the Paperwork 

Reduction Act of 1995 must be faxed to 

the Office of Information and Regulatory 

Affairs, Office of Management and 

Budget (OMB), Attn: FDA Desk Officer, 

FAX: 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 

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Federal Register / Vol. 79, No. 243 / Thursday, December 18, 2014 / Proposed Rules 75507 

1When 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 cellularand tissue-based products licensed under section 

351 of the PHS Act. 

(including patient package inserts and 

Medication Guides), or to prescribing 

information accompanying promotional 

labeling, which would continue to be 

provided in paper form. 

FDA is authorized under various 

sections of the Federal Food, Drug, and 

Cosmetic Act (the FD&C Act) to require 

that prescribing information be 

distributed electronically and to require 

that paper copies of the prescribing 

information no longer be distributed, 

except as provided in this regulation, to 

ensure that human prescription drugs 

have adequate directions for use and to 

ensure the efficient enforcement of the 

FD&C Act. These sections include 

sections 201(n), 502, 503, 505, and 

701(a) of the FD&C Act (21 U.S.C. 

321(n), 352, 353, 355, and 371(a)), and 

section 351 of the Public Health Service 

Act (the PHS Act) (42 U.S.C. 262). The 

electronic distribution of prescribing 

information for human prescription 

drugs would permit the efficient 

enforcement of the misbranding 

provisions in sections 502(a) and (f) of 

the FD&C Act, as well as the safety and 

effectiveness provisions of section 505 

of the FD&C Act. 

Summary of the Major Provisions of the 

Regulatory Action 

The proposed rule would amend the 

labeling regulations to require 

manufacturers to distribute the 

prescribing information electronically, 

instead of in paper form. Manufacturers 

would be required to submit the 

prescribing information to FDA for 

posting on FDA’s publicly available 

labeling repository Web site 

(labels.fda.gov) every time there is a 

change in the labeling. Manufacturers 

would also be required to review the 

labeling posted at FDA’s Web site to 

verify that the correct version of the 

labeling appears in the repository, and 

to promptly notify FDA if the correct 

version is not posted. This would 

ensure that the most up-to-date version 

of the prescribing information is 

available to health care professionals 

and the public. 

The proposed rule would require a 

product’s immediate container label and 

outside package to bear a statement 

directing health care professionals to 

FDA’s labeling repository to view the 

electronic version of prescribing 

information. The statement would also 

provide a toll-free telephone number, 

maintained by the manufacturer, to 

receive requests for the manufacturer to 

send an emailed, faxed or mailed paper 

copy of the prescribing information. The 

manufacturer would be required to 

ensure the toll-free number service was 

available 24 hours a day, 7 days a week. 

This would ensure that the prescribing 

information is accessible in most 

situations when Internet access is not 

available to the health care professional. 

In addition, the proposed rule would 

provide that FDA may grant an 

exemption from the electronic 

distribution of labeling requirements 

when compliance could adversely affect 

the safety, effectiveness, purity, or 

potency of the drug, is not 

technologically feasible, or is otherwise 

inappropriate. Manufacturers of 

exempted products would distribute 

prescribing information in paper form 

on or within the package from which 

the product is dispensed. Examples of 

circumstances where it may be 

appropriate to exempt a product include 

a product intended for use in an 

emergency room or a product that may 

be stockpiled for an emergency. 

Costs and Benefits 

The proposed rule impacts the drug 

and biological products industries that 

supply prescribing information, as well 

as the prescribers, pharmacists and 

other health care professionals who are 

the intended users of the information. 

After initial set-up costs, industry will 

experience net savings by providing the 

prescription information electronically. 

Pharmacies will incur net costs due to 

initial capital costs to access the 

information, increased search time 

when accessing the information and the 

printing cost when a request is received 

for the prescribing information in 

printed form. We estimate no cost 

increases to most health care 

professionals to access the information. 

At a 7 percent discount rate over a 10- 

year period, the annualized cost savings 

range from $52 million to $164 million 

and are predominantly savings to 

industry; the annualized costs range 

from $47 million to $89 million and are 

mainly incurred by pharmacies; and the 

annualized net savings range from $5 

million to $74 million. The public 

health benefits of users having access to 

the most up-to-date version of the 

prescribing information have not been 

quantified. 

SUMMARY OF ANNUALIZED COSTS AND COST SAVINGS OF THE PROPOSED RULE

[$ millions] 

7% discount rate, 10 years 3% discount rate, 10 years 

Low High Low High 

Cost Savings .................................................................................................... $51.8 $163.7 $56.6 $170.8 

Costs ................................................................................................................ 46.8 89.2 46.6 88.6 

Net savings ............................................................................................... 5.0 73.5 10.0 82.2 

I. Background 

We are proposing to amend the 

labeling regulations to require electronic 

distribution of prescribing information 

for human prescription drugs.1 This is 

intended to facilitate the distribution of 

updated prescribing information as new 

information becomes available and as 

changes in prescribing information are 

made. FDA is taking this action so that 

the most current prescribing 

information for distributed prescription 

drugs will be available and readily 

accessible to health care professionals at 

the time of clinical decisionmaking and 

dispensing. 

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 

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75508 Federal Register / Vol. 79, No. 243 / Thursday, December 18, 2014 / Proposed Rules 

2Such labeling is described in § 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 § 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. 

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 

§ 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 §§ 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 (§ 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 § 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 

§ 201.100(d)(4) to make clear that 

prescribing information accompanying 

promotional labeling must be 

distributed in paper form. 

‘‘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 

(§§ 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’’ 

(§§ 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 

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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 (§§ 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 § 201.100, blood and 

blood components intended for 

transfusion are also subject to labeling 

requirements under §§ 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 FDAapproved labeling available in the 

labeling repository or in paper form, as 

appropriate. We invite comment on 

whether the proposed exemptions 

provision provides emergency planners 

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3For 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 

§ 207.3(a)(8)). 

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 FDAapproved 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/GuidanceCompliance

RegulatoryInformation/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 

(§ 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/

GuidanceComplianceRegulatory

Information/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)). 

This proposed rule will complement 

FDA’s other electronic initiatives and is 

intended to improve access to up-todate 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. 

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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 

(§ 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 

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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 

(§ 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 classrelated 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 ultrarapid 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 

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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 onlineonly 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 §§ 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 

(§§ 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 

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distribution, as a Changes Being 

Effected (CBE) supplement, or by 

inclusion of the information in the 

annual report (§§ 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-todate 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 userfriendly. 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. 

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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 §§ 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 peelback 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 § 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 

§ 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 

§ 610.60(c) and (d) and proposed 

§ 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 § 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 peeloff 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 § 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 § 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 § 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 

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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 

§ 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 

§ 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 

§ 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 

(§§ 314.70 and 601.12). Compliance 

with this proposed section would not 

exempt applicants from compliance 

with § 314.70 or § 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 

§ 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 § 201.100 

should be added to § 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 § 207.30(a), 

every manufacturer required to list 

drugs under § 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 § 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 § 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 § 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 § 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 § 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 §§ 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 

§ 201.100(d) would be revised to state 

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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 § 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 

§ 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 § 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 § 1.106 

(21 CFR 1.106)); see also 17 FR 6818 

(July 25, 1952) (final rule amending then 

§ 1.106).) The 1961 amendments to then 

§ 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 

§ 1.106(b)(3).) The relevant provision of 

the exempting regulations is currently 

codified at § 201.100(c)(1). Section 

201.100(c)(1), like its predecessor 

§ 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 

§ 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 

§ 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 

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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 tollfree 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 

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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 

§§ 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 § 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 §§ 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 

§ 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 

§§ 201.100(b)(8), 606.121(c), 

610.60(a)(8), and 610.61(t)) 

Current §§ 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 

§ 201.100(c)(5)) and Exemptions 

(§ 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 

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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 § 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 § 201.100(c)(4)) 

Prescribing information for 

prescription drugs (i.e., content of 

labeling required under § 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 §§ 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/GuidanceCompliance

RegulatoryInformation/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 × 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 × 5.5] 

× 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 (§§ 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 

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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 × 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 × 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 × 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 × 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 § 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 × 1.25 = 1,625) (table 2). 

3. Review of Accuracy and 

Completeness of Posted Prescribing 

Information (Proposed § 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 × 

14.60 × 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 

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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] × 5 = 39,845) (table 1). 

The annual burden of checking the 

circular of information for accuracy is 

estimated to be 6,500 (1,300 × 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 

§ 201.100(b)(8)) 

Under proposed § 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 × 49.3 × 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 § 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 

§ 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 § 201.100(g)) 

Under proposed § 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

Type of reporting and 21 CFR section Number of 

respondents 

Number of 

responses per 

respondent 

Total annual 

responses 

Average 

burden per 

response 

Total hours 

Submission of updated labeling and circular of information under § 201.100(c)(4) ............................................ 3,732 2 .5 9,269 1 .25 11,586 

Review of accuracy of posted labeling and circular of information under § 201.100(c)(4) ................................... 3,732 2 .5 9,269 5 46,345 

Requests for exemptions under § 201.100(g) ................. 10 1 10 1 10 

Requests to receive prescribing information by fax, 

email, or mail when requested (§§ 201.100(c)(5) and 

201.100(g)) ................................................................... 129,090 1 129,090 *0 .25 516,360 

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TABLE 1—ESTIMATED ANNUAL REPORTING BURDEN 1 2—Continued 

Type of reporting and 21 CFR section Number of 

respondents 

Number of 

responses per 

respondent 

Total annual 

responses 

Average 

burden per 

response 

Total hours 

Total .......................................................................... ........................ .......................... ........................ .......................... 574,301 

1Totals may not sum because frequency numbers are rounded. 

2There 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

Type of reporting and 21 CFR section Number of 

respondents 

Number of 

responses per 

respondent 

Total onetime 

responses 

Average 

burden per 

response 

Total hours 

Review for accuracy and completeness of posted prescribing information under § 201.100(c)(4) .................... 3,550 14.60 51,830 5 259,150 

Submission of circular of information by blood establishments under § 201.100(c)(4) .......................................... 1,300 1 1,300 1 .25 1,625 

Total ............................................................................ .......................... ........................ ...................... .......................... 260,775 

1There 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 section Number of 

respondents 

Frequency per 

disclosure 

Total 

disclosures 

Hours per 

disclosure Total hours 

Design, testing, and production of labels for existing products ..................................................................................... 3,550 49.3 175,015 160 28,002,400 

Production of new label statement on immediate container 

label or outside package (Web site and toll-free number) 

under §§ 201.100(b)(8), 606.121(c)(8)(ii), 610.60(a)(8), 

and 610.61(t) ...................................................................... 3,550 49.3 175,015 24 4,200,360 

Total ................................................................................ .......................... ........................ ...................... ...................... 32,202,760 

1There are no capital costs or operating and maintenance costs associated with this collection of information. 

TABLE 4—ESTIMATED ANNUAL THIRD-PARTY DISCLOSURE BURDEN

Type of disclosure and 21 CFR section 

Number of 

disclosures per 

respondent 

Number of 

responses per 

respondent 

Total annual 

disclosures 

Average 

burden per 

disclosure 

Total hours 

Total capital, 

operating 

and maintenance costs 

Distribution of prescribing information by 

fax, email, or mail when requested 

(§§ 201.100(c)(5) and 201.100(g)).

993 130 129,090 1 129,090 $26,500 to 

$90,750. 

Design, testing and production of labels for 

new prescription drug and biological products and blood and blood components.

381 3.80 1,395 160 223,200 

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 (§§ 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 

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75524 Federal Register / Vol. 79, No. 243 / Thursday, December 18, 2014 / Proposed Rules 

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 

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Federal Register / Vol. 79, No. 243 / Thursday, December 18, 2014 / Proposed Rules 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/Reports

ManualsForms/Reports/Economic

Analyses/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 

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75526 Federal Register / Vol. 79, No. 243 / Thursday, December 18, 2014 / Proposed Rules 

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 

■ 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. 

■ 2. Amend § 201.100 as follows: 

■ 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’’; 

■ b. Add paragraph (b)(8); 

■ 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’’; 

■ d. Add paragraphs (c)(3) through (5); 

■ e. Revise the introductory text of 

paragraph (d); 

■ 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’’; 

■ g. Add paragraphs (d)(4) and (g). 

The additions and revisions read as 

follows: 

§ 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 FDAapproved 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 tollfree 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 

§ 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 §§ 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; 

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Federal Register / Vol. 79, No. 243 / Thursday, December 18, 2014 / Proposed Rules 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. 

■ 3. In § 201.306, revise paragraph 

(a)(1)(ii) introductory text and paragraph 

(b)(2) to read as follows: 

§ 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 § 201.100(b)(8) bears 

adequate information for its use by 

practitioners in accord with the ‘‘full 

disclosure’’ labeling requirements of 

§ 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 § 201.100(b)(8) bears 

adequate information for its use by 

practitioners in accord with the ‘‘full 

disclosure’’ labeling requirements of 

§ 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. 

■ 4. In § 201.310, revise the third 

sentence of paragraph (a) to read as 

follows: 

§ 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 

§ 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 

■ 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. 

■ 6. In § 606.121 revise paragraph 

(c)(8)(ii) to read as follows: 

§ 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. 

* * * * * 

§ 606.122 [Amended] 

■ 7. In § 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 

■ 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. 

■ 9. In § 610.60, add paragraph (a)(8) to 

read as follows: 

§ 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. 

* * * * * 

■ 10. In § 610.61, revise paragraphs (k) 

and (n) and add paragraph (t) to read as 

follows: 

§ 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 

ENVIRONMENTAL PROTECTION 

AGENCY 

40 CFR Part 52 

[EPA–R05–OAR–2014–0661; FRL–9920–46– 

Region–5] 

Approval and Promulgation of Air 

Quality Implementation Plans; Indiana; 

Ozone and PM2.5 Standards 

AGENCY: Environmental Protection 

Agency. 

ACTION: Proposed rule. 

SUMMARY: The Environmental Protection 

Agency (EPA) is proposing to approve a 

submission by the State of Indiana as a 

revision to the Indiana State 

Implementation Plan (SIP). The 

mstockstill on DSK4VPTVN1PROD with PROPOSALS