[Federal Register Volume 63, Number 230 (Tuesday, December 1, 1998)]
[Rules and Regulations]
[Pages 66378-66400]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-31627]



[[Page 66377]]

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Part V





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



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21 CFR Part 201 et al.



Prescription Drug Product Labeling; Medication Guide Requirements; 
Final Rule

  Federal Register / Vol. 63, No. 230 / Tuesday, December 1, 1998 / 
Rules and Regulations  

[[Page 66378]]



DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 201, 208, 314, 601, and 610

[Docket No. 93N-0371]
RIN 0910-AA37


Prescription Drug Product Labeling; Medication Guide Requirements

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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

SUMMARY: The Food and Drug Administration (FDA) is establishing 
requirements for the distribution of patient labeling for selected 
prescription human drug and biological products used primarily on an 
outpatient basis. The agency is requiring the distribution of patient 
labeling, called Medication Guides, for certain products that pose a 
serious and significant public health concern requiring distribution of 
FDA-approved patient medication information. The intent of this action 
is to improve public health by providing information necessary for 
patients to use their medications safely and effectively. FDA believes 
that this program will result in direct improvements in the safe and 
effective use of prescription medications.

DATES: This regulation is effective June 1, 1999. Written comments on 
the information collection requirements should be submitted by February 
1, 1999.

ADDRESSES: Submit written comments on the information collection 
requirements to the Dockets Management Branch (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT:

Nancy M. Ostrove, Center for Drug Evaluation and Research (HFD-40), 
Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 
301-827-2828, ([email protected]).
Toni M. Stifano, Center for Biologics Evaluations and Research (HFM-
20), Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 
20852, 301-827-3028, ([email protected]).

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of August 24, 1995 (60 FR 44182), FDA 
published a proposed rule entitled, ``Prescription Drug Product 
Labeling; Medication Guide Requirements,'' under which the agency would 
encourage development and distribution of written patient medication 
information by the private sector. This information was intended to 
supplement oral counseling from health care professionals. The agency 
proposed distribution goals and performance standards for this 
information. The agency proposed to survey the marketplace in the years 
2000 and 2006 to determine how much patient medication information is 
being distributed and whether it is useful. The 1995 proposal sought 
comment on two approaches FDA could take if the private sector's 
voluntary program failed to reach the predetermined goals.
    The proposal also included provisions that would permit the agency 
to require FDA-approved written patient information (Medication Guides) 
for distribution with prescription drug and biological products that 
pose a ``serious and significant public health concern requiring 
immediate distribution of FDA-approved patient medication 
information.'' (For the purposes of this document, the shorter term 
``serious and significant concern'' will be used to refer to those drug 
products that FDA determines require Medication Guides for safe and 
effective use by the public.) The agency indicated that it would use 
this authority only on limited occasions.
    In the proposal, FDA stated its position that patient information 
about the risks and benefits of prescription drug and biological 
products is necessary for patients to use these products safely and 
effectively. The overall patient medication information program was 
proposed to provide patients with the information needed to improve 
their use of prescription drug and biological products. Furthermore, 
FDA demonstrated in the preamble to the proposed rule that the program 
could result in substantial health care cost savings by reducing the 
harm caused by inappropriate drug use and enhancing the benefits of 
drugs by facilitating their proper use.
    FDA originally provided 90 days for public comment, and, in 
response to requests, extended the comment period for an additional 30 
days until December 22, 1995 in the Federal Register of November 24, 
1995 (60 FR 58025). In the Federal Register of January 30, 1996 (61 FR 
2971), the agency announced a public workshop to be held on February 14 
and 15, 1996, to discuss issues related to defining the useful 
information that would be provided in the voluntary program. The agency 
also sought written comments on issues raised at the workshop. Comments 
were accepted until March 6, 1996.
    As the agency was reviewing these and other comments on the 
proposed rule, Congress enacted legislation regarding patient labeling. 
This legislation, section 601 of the Agriculture, Rural Development, 
Food and Drug Administration, and Related Agencies Appropriations Act, 
for the fiscal year ending September 30, 1997 (Pub. L. 104-180) (the 
Appropriations Act), established a voluntary private-sector process 
under which national organizations representing health care providers, 
consumers, pharmaceutical companies, and other interested parties were 
to collaborate in the development of a long-range plan to achieve the 
goals of FDA's proposed rule concerning patient labeling as previously 
described. The legislation adopted the distribution and information 
quality goals of the proposed rule. The law further required that the 
plan developed by these organizations be submitted to the Secretary of 
Health and Human Services (the Secretary) for acceptance, rejection, or 
modification before implementation. The collaborative process 
established by this legislation has been completed and the long-range 
private-sector plan has been accepted by the Secretary.
    While section 601 of the Appropriations Act limits the authority of 
the Secretary to implement FDA's proposed rule regarding written 
information voluntarily provided to consumers, there is specific 
legislative history that makes it clear that section 601 does not 
preclude FDA from using its existing authority to implement a mandatory 
program for the small number of products that pose a ``serious and 
significant concern'' and require distribution of patient information. 
That legislative history states that section 601:

[i]s not to be construed as prohibiting the FDA from using its 
existing authority or regulatory authority to require as part of the 
manufacturers' approved product labeling the dispensing of written 
information inserts to consumers on a case-by-case basis with select 
prescription drugs to meet certain patient safety requirements.

Agriculture, Rural Development, Food and Drug Administration, and 
Related Agencies Appropriation Bill, 1997, S. Rept. 104-317, 104th 
Cong., 2d sess., p. 132, July 11, 1996.
    In light of this legislation, the agency is deleting the provisions 
of the proposed rule that dealt with the private sector voluntary 
program, and is limiting this final rule to the mandatory program 
covering products of ``serious and significant concern.'' Because the 
voluntary program is not part of this

[[Page 66379]]

final rule, the agency will not summarize and respond to comments 
relating only to those provisions. Instead, this document will focus on 
the comments concerning the program for products of ``serious and 
significant concern.''
    The final rule incorporates most of the provisions of the proposed 
rule regarding the mandatory program for products of ``serious and 
significant concern'' and provides additional clarification regarding 
how the agency would identify products that require a Medication Guide. 
Additional changes have been made that reflect the narrowed focus of 
the final rule. Highlights of the final rule are summarized, followed 
by a summary and discussion of the comments.

II. Highlights of the Final Rule

    The final rule establishes a patient medication information program 
under which Medication Guides will be required for a small number of 
products that FDA determines pose a serious and significant public 
health concern requiring distribution of FDA-approved patient 
information necessary for the product's safe and effective use. FDA 
anticipates that an average, no more than 5 to 10 products per year 
would require such information.
    The major provisions of the medication information program for 
products of ``serious and significant concern'' and the changes from 
the proposed rule follow.

A. General Provisions (Part 208, Subpart A)

1. Scope and Purpose
    A number of changes have been made to the provisions in part 208 
(21 CFR part 208) to reflect the narrowed focus of this final 
regulation in response to section 601 of the Appropriations Act, and to 
clarify its purpose and scope. Section 208.1(a) has been changed to 
indicate that the final regulation does not cover voluntarily 
distributed patient information for most prescription drugs, but rather 
covers products of ``serious and significant concern.'' The phrase 
``that FDA determines pose a serious and significant public health 
concern requiring distribution of FDA-approved patient information'' 
was added to Sec. 208.1(a) to accomplish this change.
    Section 208.1(a) of the 1995 proposed rule stated that the 
requirements applied to products ``administered primarily on an 
outpatient basis without direct supervision by a health professional.'' 
FDA has changed the term ``administered'' in this context to the term 
``used,'' because ``administered'' is likely to be misinterpreted as 
involving administration by another individual. In addition, the agency 
has determined that Medication Guides may, on rare occasions, be 
required for products of ``serious and significant concern'' that are 
used on an inpatient basis or under the supervision of a health 
professional. This change has been made by moving the word 
``primarily'' to immediately follow the word ``applies'' in the second 
sentence of Sec. 208.1(a). In light of this change, the last sentence 
of proposed Sec. 208.1(a) has been deleted, because it is no longer 
needed.
    Under the proposed rule, the patient information program applied to 
all new prescriptions, but only upon request by the patient for refill 
prescriptions. Because of the narrowed focus of this final rule and 
because the agency believes that the patient information that will be 
provided in Medication Guides is important to the safe and effective 
use of a product, it is necessary to require the distribution of a 
Medication Guide with every prescription for that product. Accordingly, 
Sec. 208.1(a) has been changed so that patient information required 
under this part must be provided for all prescriptions of the drug, 
whether they are new prescriptions or refills and regardless of whether 
the information is requested by the patient.
    Section 208.1(b) as proposed has been deleted because the final 
regulation no longer covers voluntarily distributed patient 
information. This change was made because of the enactment of section 
601 of the Appropriations Act, which created a process under which 
national organizations representing consumers, health professionals, 
pharmaceutical companies, and others developed a plan for the voluntary 
distribution of patient information. This legislation specifically 
prohibits the implementation of the proposed rule if a plan acceptable 
to the Secretary is developed and submitted within the statutory time 
period. The accompanying legislative history makes it clear, however, 
that the agency was not precluded from requiring FDA-approved patient 
leaflets for drugs of serious and significant concern under its 
existing authority. New Sec. 208.1(b) describes the purpose of patient 
labeling required under the final regulation.
    The information will be required if the agency determines that it 
is necessary to patients' safe and effective use of the drug product. 
The agency added this provision to clarify the regulations when it will 
require Medication Guides and to reflect the agency's intention to make 
the decision to require a Medication Guide carefully and on a case-by-
case basis. This approach to Medication Guides is consistent with the 
legislative history of the Appropriations Act discussed earlier in this 
preamble. The new language in Sec. 208.1(b) also helps differentiate 
required Medication Guides from the voluntary private sector program.
    Section 208.1(c) as proposed has been deleted. Its primary purpose 
was to provide a standard against which voluntarily distributed patient 
information would be evaluated. However, the voluntary program is no 
longer part of this regulation. The agency believes that the substance 
of this provision is valuable, however, and has therefore changed 
Sec. 208.20, Content and format of a Medication Guide, to include all 
of the elements of proposed Sec. 208.1(c). These elements are also 
closely related to the criteria adopted during the collaborative 
private-sector process.
    New Sec. 208.1(c) of the final rule describes when FDA may require 
a Medication Guide. Patient labeling will be required if the agency 
determines that one or more of the following circumstances exists:
    (1) The drug product is one for which patient labeling could help 
prevent serious adverse effects.
    (2) The drug product is one that has serious risk(s) (relative to 
benefits) of which patients should be made aware because information 
concerning the risk(s) could affect patients' decision to use, or to 
continue to use, the product.
    (3) The drug product is important to health and patient adherence 
to directions for use is crucial to the drug's effectiveness. FDA 
believes that these circumstances will apply to a very small group of 
products. These circumstances have been clarified to address comments 
that they were overly broad.
    Proposed Sec. 208.1(d) has been deleted as unnecessary because the 
final regulation applies only to ``serious and significant'' products.
2. Definitions
    Section 208.3 contains definitions of important terms used in part 
208. Several changes have been made in this section to help clarify the 
Medication Guide program. Numerous comments conveyed confusion about 
what constitutes a ``Medication Guide,'' for example, whether the term 
refers to voluntary private sector patient information or mandated FDA-
approved patient information. Therefore, in the final rule new 
Sec. 208.3(h) defines ``Medication Guide'' to mean FDA-approved patient 
labeling conforming to

[[Page 66380]]

the specifications set forth in part 208 and other applicable 
regulations. This term now applies only to patient information required 
for products of ``serious and significant concern.''
    The agency on its own initiative added new Sec. 208.3(e) to include 
a definition of the term ``drug product.'' The purpose of adding this 
new definition is to make it clear that the term, as it is used in this 
final regulation, applies to the finished dosage form of both drug and 
biological products. Because of the addition of this definition, the 
subsequent provisions in Sec. 208.3 have been renumbered.
    In preparing the final rule, the agency revised the definition of 
the ``manufacturer'' of a drug product to be consistent with the 
definition of the ``manufacturer'' of a biological product. The 
definition of a ``manufacturer'' in the proposed rule inadvertently 
referred only to the person who actually produced the drug product, 
while the definition for biologicals included both the actual producer 
of the product as well as the person who is an applicant for a license 
where the applicant is responsible for complying with the product and 
establishment standards. This latter meaning of the term corresponds 
most closely to the definition of an ``applicant'' as that term is used 
in the new drug regulations in part 314 (21 CFR part 314). Therefore, 
FDA has included the definition of ``applicant'' in Sec. 314.3(b) in 
the definition of a drug product manufacturer in Sec. 208.3(g). It is 
important for two reasons that both meanings of ``manufacturer'' be 
included in the definition of the term for purposes of this final rule. 
First, FDA intends that each person potentially or actually in the 
chain of distribution of a product be subject to the distribution 
requirements in Sec. 208.24 and for that reason both the producer of 
the product and the person responsible for the product application must 
be included. Second, for purposes of identifying the person who is 
responsible for the content and format requirements in Sec. 208.20 and 
the requirement of obtaining FDA approval of the Medication Guide in 
Sec. 208.24(a), the agency wishes to clarify that it is the person who 
is responsible for the product application.
    The agency has also added a definition of the term ``packer'' in 
new Sec. 208.3(i). Packers are subject to the provisions of this final 
rule and a definition was needed to distinguish a packer from a 
manufacturer or distributor.
    Section 208.3(k) of this final regulation provides a definition of 
the terms ``serious risk'' and ``serious adverse effect'' that states 
that these terms mean an adverse drug experience, or the risk of such 
an experience, as that term is defined elsewhere in the regulations 
governing drug and biological products. The purpose of adding this 
definition is to further narrow the scope of this regulation in 
response to many comments complaining of the breadth of the agency's 
proposed criteria for identifying products of ``serious and significant 
concern.'' (See previous discussion of Sec. 208.1 (b) and (c).)

B. General Requirements for a Medication Guide (Part 208, Subpart B)

1. Content and Format of a Medication Guide
    Section 208.20 now contains the requirements for both the content 
and format of Medication Guides. This section sets forth the specific 
categories of information about a product that a Medication Guide shall 
contain, as well as statements that shall appear on a Medication Guide. 
The agency has generally retained from the proposal the text and order 
of the headings under which the information shall appear and has also 
now grouped the information under the appropriate heading. This section 
also includes specifications for minimum letter height or type size, 
legibility, and presentation considerations. The combined provision is 
more concise and the reorganization makes the requirements clearer. The 
agency notes that the content and format criteria in the final rule are 
virtually the same as those adopted in the private sector plan 
discussed earlier.
    The order specified in Sec. 208.20(b) starts with a presentation of 
the most important information patients should know about the product 
to use it safely and effectively, i.e., why the product poses a serious 
and significant public health concern requiring distribution of FDA-
approved written patient information. This section is being included in 
place of the summary section originally proposed by FDA. The agency 
made this change because it believes that it is redundant to include in 
such a short document a summary section containing information 
elaborated in other sections.
    This section is followed by sections addressing the product's 
indications for use, contraindications, directions for use, 
precautions, and possible side effects. The final rule does not specify 
where in this order other information (e.g., storage instructions and 
specific instructions for using products that are not orally 
administered (e.g., injectables, patches)) may be placed. As reflected 
in Sec. 208.20(b)(9), the rule permits the insertion of additional 
headings or subheadings as appropriate for specific Medication Guides.
    Other changes have been made in Sec. 208.20 of the final rule. As 
mentioned above, the agency believes that the criteria for determining 
useful information that were proposed in Sec. 208.1(c) are important 
and has retained them in the final rule. All of the criteria that 
Medication Guides must meet, however, are now contained in a single 
section of this final rule (Sec. 208.20(a)).
    The agency on its own has added language to Sec. 208.20(a)(2) to 
reinforce the fact that a Medication Guide, while based on the approved 
labeling, should be understandable to laypersons and therefore need not 
use the identical language in the approved labeling.
    Other small changes have been made in Sec. 208.20 as well. Section 
208.20(a)(7) and (b)(1) now require that a Medication Guide contain the 
established or proper name of the drug in order to recognize the 
terminology used for biologicals. (See 21 CFR 600.3(k)). The 
introductory sentence of Sec. 208.20(b) has been changed to make it 
clear that only the headings that have relevance to the drug product 
should be included in a Medication Guide. Other changes have been made 
throughout Sec. 208.20(b) to emphasize that only specific, important 
information about the drug product should be included in a Medication 
Guide. These changes are being made so that the effectiveness of the 
patient labeling is not reduced by its being too long or including 
irrelevant information.
    FDA has added the following language to Sec. 208.20(b)(3) relating 
to the product's indications: ``In appropriate circumstances, this 
section may also explain the nature of the disease or condition the 
drug product is intended to treat, as well as the benefit(s) of 
treating the condition.'' This addition is designed to allow, when 
relevant, a fuller discussion that could include the benefits of 
treatment.
    Finally, FDA has made two changes to Sec. 208.20(b)(8). First, 
Sec. 208.20(b)(8)(ii) has been changed to make it clear that a 
Medication Guide must contain a statement that a drug product should 
not be used for a condition other than that for which it is prescribed. 
This change is made to avoid any confusion with the statement that 
drugs may sometimes be prescribed for uses not described in the 
Medication Guide. Second, Sec. 208.20(b)(8)(iii) has been changed to 
make it clear that the name and address of the dispenser may be 
included in a Medication Guide. The

[[Page 66381]]

name and address of the manufacturer, distributor, or packer of a drug 
product that is not also a biological product or of the manufacturer or 
distributor of a drug product that is also a biological product is 
required. This change was made to correct a drafting error in proposed 
Sec. 208.20(b)(8)(iii) that would have allowed the dispenser's name 
alone to appear on a Medication Guide.
2. Distributing and Dispensing a Medication Guide
    Section 208.24 sets forth the requirements for distributing and 
dispensing Medication Guides. The agency has made several changes to 
this section to make clear the responsibilities of each person 
distributing a drug product subject to this part. The agency has added 
new Sec. 208.24(a) that explicitly requires the manufacturer to obtain 
FDA approval of the Medication Guide before it can be distributed. 
Although this requirement had been stated indirectly in the proposed 
rule regarding products of ``serious and significant concern,'' the 
agency believed it should be stated clearly in the final rule. Because 
the majority of Medication Guides will be required at the time of 
approval, it is appropriate for FDA to approve the text of both patient 
labeling and professional labeling at the same time.
    Section 208.24(b) states the manufacturer's basic responsibility 
for ensuring that Medication Guides are available for distribution to 
patients. Under Sec. 208.24(b), a manufacturer shall provide to 
distributors, packers, or authorized dispensers to which it ships the 
drug product, either Medication Guides in sufficient numbers, or the 
means to produce Medication Guides in sufficient numbers, to permit the 
authorized dispenser to provide a Medication Guide to each patient who 
receives a prescription for the drug product. The agency generally 
expects that the ``means to produce'' shall include a computer file of 
the Medication Guide for use with a computerized patient medication 
information program. Section 208.24(c) states the responsibility of the 
distributor or packer that receives Medication Guides, or the means to 
produce Medication Guides, to provide them to each authorized dispenser 
to whom it ships a container of drug product.
    FDA has changed Sec. 208.24 in several places to make it clear that 
packers are covered by this final regulation. It appears that packers 
had been inadvertently omitted from the proposal. The change is 
intended to make it clear that, in situations where a Medication Guide 
is distributed with the product, each person in the distribution chain 
has the responsibility of ensuring that the Medication Guide remains 
with the product so that it can reach the authorized dispenser.
    FDA has also deleted the phrase ``finished dosage form'' from 
several places in Sec. 208.24 of this rule. This phrase is no longer 
needed because the agency has added a definition of ``drug product'' in 
Sec. 208.3(e) that clarifies that the term refers to products in 
finished dosage form.
    Section 208.24 has been changed in several places to reflect the 
fact that Medication Guides must be dispensed with every prescription 
for a drug product subject to this part, and not just with new 
prescriptions or if requested by a patient for a refill prescription. 
This change is needed because it will be necessary for patients to have 
the information in a Medication Guide in order to use a product of 
``serious and significant concern'' safely and effectively. It is 
therefore important for patients to receive this information each time 
they obtain the drug product.
    Some comments noted that dispensers may not know if Medication 
Guides are provided with the product, affixed on the container, or 
contained within the package. Therefore, in the final rule, a new 
Sec. 208.24(d) has been created that states that the label of each 
container of drug product (which now, because of the added definition 
of drug product, includes both large volume containers of finished 
dosage form and unit-of-use containers) shall instruct the authorized 
dispenser to provide a Medication Guide to each patient to whom the 
drug product is dispensed, and shall state how the Medication Guide is 
provided. This new section also requires that these statements be made 
in a prominent and conspicuous manner. The agency on its own initiative 
has amended both Sec. 208.24(d) and the regulations governing labeling 
of biological products to make clear how manufacturers can comply with 
the requirements of Sec. 208.24(d) if a container label is too small 
for the required statement. (See Sec. 610.60(a)(7).)
    Section 208.24(c) of the proposed rule required the manufacturer 
and distributor to provide a Medication Guide with each unit-of-use 
container intended to be dispensed to a patient. FDA has omitted this 
paragraph from the final rule. This provision is not necessary because 
the responsibility to provide Medication Guides to the authorized 
dispenser is clear from the other changes to Sec. 208.24. Further, FDA 
wishes to provide manufacturers, distributors, and packers flexibility 
in the ways that they can meet that responsibility. If a manufacturer 
chooses to provide Medication Guides electronically for a product in a 
unit-of-use container, they may now do so because of this change.
    Proposed Sec. 208.24(d) stated that the requirements of part 208 
could be met by the manufacturer, distributor, or any other person 
acting on behalf of the manufacturer or distributor. This section 
further provided that a manufacturer or distributor could satisfy the 
requirements of part 208 with a Medication Guide printed by a 
distributor or authorized dispenser. This provision was intended to 
enable manufacturers and distributors to make use of third-party 
information systems that could simplify the process of dispensing 
patient information leaflets to patients. The proposal envisioned that 
third parties would most likely both create and distribute Medication 
Guides to authorized dispensers under the voluntary private-sector 
program. Proposed Sec. 208.24(d) has been deleted from this final rule. 
The agency believes that it is no longer necessary because the final 
rule applies only to Medication Guides for products of ``serious and 
significant concern'' that will be approved by the agency and will be 
part of these products' approved labeling.
    Section 208.24(f) was modified in response to several comments. A 
change has been made to make it clear that wholesalers, as well as 
authorized dispensers, are not subject to section 510 of the Federal 
Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 360) that requires 
registration of producers of drugs and listing of drugs in commercial 
distribution if they change the container, wrapper, or labeling of any 
drug product, as long as the change is due solely to an act performed 
under part 208.
3. Exemptions and Deferrals
    Section 208.26 provides the circumstances under which there may be 
exemptions from, or deferrals of, content and format requirements for 
Medication Guides, and exemption from the distribution of Medication 
Guides to patients under certain circumstances.
    Proposed Sec. 208.26(b) provided, in part, that a licensed 
practitioner or an authorized dispenser could determine that it is not 
in the best interests of a patient to receive a Medication Guide. FDA 
has changed this provision to allow only the licensed practitioner who 
prescribes a drug product to direct that a Medication Guide be withheld 
from a patient.
    Section 208.26(b) has also been modified to address concerns about

[[Page 66382]]

possible perceived interference by FDA in the judgments of health care 
professionals with respect to withholding a Medication Guide from a 
patient. The final rule does not contain the proposed sentence that 
would have required authorized dispensers to provide Medication Guides 
for a particular product under all circumstances. Consequently, only 
the patient, and not FDA, can overrule the licensed practitioner's 
decision to withhold a Medication Guide from that patient.
    Section 208.26(c) as proposed provided that a Medication Guide was 
not required to be dispensed in an emergency, or where the 
manufacturer, distributor, or authorized dispenser did not have a 
Medication Guide available and could document a good faith effort to 
provide one. Section 208.26(d) as proposed set forth a small business 
exemption for certain authorized dispensers. However, this exemption 
only applied to the broad comprehensive program of distribution of 
patient information. It did not apply to Medication Guides for products 
of ``serious and significant'' concern.
    The agency has deleted both proposed Sec. 208.26(c) and (d) from 
this final rule. FDA does not believe that such exemptions are 
appropriate for Medication Guides that are required for a very small 
number of products of ``serious and significant concern'' and that 
provide information necessary to the safe and effective use of the 
product.

III. Comments on the Proposed Rule

    FDA received approximately 100 comments in response to the 1995 
proposed rule and the request for comments associated with the February 
1996 public workshop. The comments came from individual consumers and 
consumer organizations, academics, individual pharmacists, physicians, 
and other health care professionals, health professional associations, 
trade associations, and prescription drug and biological product 
manufacturers, attorneys, and others. A number of comments submitted 
examples of patient information leaflets currently being distributed. 
Several comments misunderstood the proposed rule and commented as 
though FDA was seeking to immediately establish a mandatory Medication 
Guide program to provide patient labeling for all prescription drug and 
biological products.

A. Patient Information--Legal Authority

    1. Some comments stated that the proposal regulates the 
professional practice of pharmacy, which is the purview of the State 
boards of pharmacy. The comments stated that FDA cannot extend its 
statutory authority to regulate product labeling to require that 
pharmacists distribute information about prescription medications that 
they dispense. One comment added that this initiative would set a 
precedent for FDA to impose other regulations on individual health care 
professionals.
    Both the proposal and the final rule seek to assure that patients 
receive information necessary to the safe and effective use of 
prescription drug products. Federal courts have affirmed FDA's 
authority to require the dispensing of patient labeling for 
prescription drugs, and that such requirement does not interfere with 
the practice of medicine (Pharmaceutical Mfr. Ass'n (PMA) v. FDA, 484 
F. Supp. 1179 (D. Del. 1980), aff'd per curiam, 634 F. 2d 106 (3d Cir. 
1980)).
    In PMA v. FDA, the court stated that ``[t]he fact that the practice 
of medicine is an area traditionally regulated by the states does not 
invalidate those provisions of the act which may at times impinge on 
some aspect of a doctor's practice'' (Id. at 1188). The court reasoned 
that the regulation at issue, which required pharmacists and dispensing 
physicians to distribute patient labeling with prescription drugs 
containing estrogens, did not forbid a physician from prescribing a 
prescription drug product, nor did it limit the physician's exercise of 
professional judgement (Id.). Moreover, the court stated that the 
regulation not only did not limit the information that a physician may 
provide to his or her patients, but rather it fostered open discussions 
between physicians and patients (Id.). Similarly, this final rule does 
not inhibit a prescriber or pharmacist from exercising his or her 
professional judgement, nor does it limit the information that can be 
given to the patient. The prescriber or pharmacist may add to the 
information and discuss any aspect of the product with the patient, 
thereby promoting better communication between health care 
professionals and their patients.
    FDA also does not agree that it lacks statutory authority over 
written information about prescription drug products that is dispensed 
by pharmacists. The agency's authority for this final rule was set 
forth in the proposed rule (60 FR 44182 at 44210). In short, under 
section 502(a) of the act (21 U.S.C. 352), a drug product is misbranded 
if its labeling is false or misleading in any particular. Further, 
under section 505 (d) and (e) of the act (21 U.S.C. 355 (d) and (e)), 
FDA must refuse to approve an application and may withdraw the approval 
of an application if the labeling for the drug is false or misleading 
in any particular.
    Section 201(n) of the act (21 U.S.C. 321) describes the concept of 
``misleading'' and specifically provides that in determining whether 
the labeling of a drug is misleading, there shall be taken into account 
not only representations or suggestions made in the labeling, but also 
the extent to which the labeling:

[f]ails to reveal facts material in the light of such 
representations or material with respect to consequences which may 
result from the use of the [drug] * * * under the conditions of use 
prescribed in the labeling * * * or under such conditions of use as 
are customary or usual.

    These provisions, along with section 701(a) of the act (21 U.S.C. 
371), authorize FDA to issue regulations designed to ensure that 
patients using prescription drug products receive information that is 
material with respect to the consequences which may result from the use 
of these products under labeled conditions. The proposed rule also 
described the agency's authority for requiring Medication Guides for 
generic drugs and biological products.
    The act authorizes FDA to regulate the marketing of drug products 
so that they are safe and effective for their intended uses and are 
properly labeled. As previously stated, FDA has determined that written 
patient labeling containing information on warnings, precautions, 
contraindications, side effects, directions for use, and other 
information is necessary for the safe and effective use of prescription 
drug products of ``serious and significant concern.''
    2. Several comments contended that FDA lacks the legal authority to 
request (or require) patient labeling for prescription drug products. 
One comment cited section 503(b)(2) of the act (21 U.S.C. 353), which 
expressly exempts prescription medications from the requirement for 
``adequate directions for use.''
    FDA does not agree with these comments. As previously discussed in 
response to comment number 1 of this document, the agency's authority 
to require patient labeling for prescription drugs has been upheld by 
the courts (PMA v. FDA, 484 F. Supp. 1179 (D. Del. 1980), aff'd per 
curiam, 634 F. 2d 106 (3d Cir. 1980)).
    Section 503(b)(2) of the act exempts dispensed prescription drugs 
from the ``adequate directions for use'' requirements under section 
502(f) of the act, but does not prohibit FDA from imposing a 
requirement under section 502(a) that pharmacists dispense labeling 
directed to the patient that is

[[Page 66383]]

intended to promote the safe and effective use of these products. In 
fact, section 503(b)(2) of the act specifically makes labeling 
dispensed by pharmacists subject to section 502(a) of the act. Section 
503(b)(2) of the act was intended to clarify certain statutory 
requirements of the 1938 act related to the dispensing of prescription 
drug products. Section 503(b)(2) of the act was not directed toward 
limiting the Government's authority to require that pharmacists 
dispense labeling specifically directed to patients. This 
interpretation of the act was upheld in PMA v. FDA at 1185-1186.
    3. One comment contended that FDA is proposing to create a new 
subcategory of prescription drugs--those that pose a ``serious and 
significant public health concern''--and that it lacks statutory 
authority to do so. The comment contended that the act does not grant 
FDA the authority to instruct manufacturers after approval of what the 
contents of their labeling must be.
    FDA does not agree that it is creating a new subcategory of 
prescription drugs. The final rule will merely require that those 
prescription drugs deemed to pose a serious and significant public 
health concern be dispensed with patient information to ensure they are 
used safely and effectively.
    Under section 502(a) of the act, a product is misbranded if its 
labeling is false or misleading in any particular. Section 201(n) of 
the act provides that labeling may be misleading if it fails to reveal 
facts that are material with respect to the consequences which may 
result from the use of the product under customary or usual conditions 
of use. In addition, under section 505(e) of the act, FDA may withdraw 
the approval of an application if, on the basis of new information, the 
labeling for the drug is false or misleading in any particular and was 
not corrected by the applicant within a reasonable time after written 
notice from the agency.
    Accordingly, manufacturers have a continuing obligation to assure 
that their drugs' labeling is not false or misleading. Thus, if FDA 
determines that information about the use of a product should be 
included in the labeling to prevent the product from being misbranded, 
it is irrelevant whether FDA makes that determination before or after 
approval. Oftentimes, after an approved product gains widespread use in 
the general population, adverse events or other consequences regarding 
the use of the product are discovered. If the agency were not permitted 
to revise required labeling based on the product's market experience, 
its ability to protect the public health would be seriously undermined.
    4. One comment noted that FDA has authority to determine that the 
product as labeled is unsafe or ineffective based on information before 
the agency, and if it so determines, it may withdraw approval, under 
section 505(e) of the act. In the case of this rule, the comment stated 
that FDA has not articulated what procedures it expects to follow to 
make the determination under section 505(e) of the act.
    If such a case arises, FDA will use the procedures set forth in the 
act and the Public Health Service Act, and their implementing 
regulations.
    5. Several comments stated that FDA has the authority to establish 
a mandatory patient labeling program only after notice and comment 
rulemaking on a drug-by-drug basis, and that one regulation requiring 
patient labeling for all products denies manufacturers due process.
    It is well settled that the act authorizes FDA to require patient 
labeling for prescription drugs (PMA v. FDA, 484 F. Supp. 1179 (D. Del. 
1980), aff'd per curiam, 634 F. 2d 106 (3d Cir. 1980); ``Agriculture, 
Rural Development, Food and Drug Administration, and Related Agencies 
Appropriation Bill, 1997,'' S. Rept. 104-317, 104th Cong., 2d sess., p. 
132, July 11, 1996). FDA does not believe that the Medication Guide 
rulemaking raises any due process issues. First, FDA provided notice 
and opportunity for public comment on the proposed program. Second, 
unlike the proposal, the final rule only applies to prescription 
products that pose a serious and significant public health concern 
requiring distribution of necessary patient information. In terms of 
the specific information required in Medication Guides, sponsors will 
have an opportunity to discuss the specific content with the agency, to 
request an exemption or deferral of certain Medication Guide 
requirements (see Sec. 208.26(a)), and to appeal an agency decision if 
the sponsor disagrees. (See 21 CFR part 10, Administrative Practices 
and Procedures.) Third, the agency has set forth the circumstances in 
which it will determine which products pose a serious and significant 
public health concern requiring distribution of written patient 
information (see Sec. 208.1(c)). This decision may be challenged as 
well.
    Although FDA used notice and comment rulemaking to require patient 
package inserts for certain prescription drug products in the 1960's 
and 1970's, this proved to be overly cumbersome and impractical. The 
agency notes that in the 1980's and 1990's, the vast majority of 
patient package inserts were instituted on a voluntary basis by the 
sponsor or incorporated as part of the approved product labeling at the 
time of initial approval of the product. FDA did not engage in notice 
and comment rulemaking for any of these patient package inserts.
    Furthermore, the agency notes that individual notice and comment 
rulemaking is not required for changes to the labeling of FDA-regulated 
products. FDA has the statutory authority to regulate prescription 
product labeling, while holders of new drug applications (NDA's), 
abbreviated new drug applications (ANDA's), and product license 
applications (PLA's) have the continuing obligation to ensure that 
their products' labeling does not cause the product to be misbranded.
    Moreover, general patient medication information requirements need 
not be based on a drug-by-drug identification of specific hazards. 
Rather, general requirements are amply justified by the data presented 
in the 1995 proposed rule demonstrating that there is substantial 
noncompliance by patients with drug therapy, that providing patients 
with information about drugs increases the degree to which they use 
them properly, and that existing drug-dispensing mechanisms are not 
adequately providing the information to patients.
    6. Some comments contended that the provision of patient labeling 
would adversely affect the legal liability of manufacturers, 
physicians, pharmacists, and other prescribers or dispensers of 
prescription drug products by abrogating the ``learned intermediary 
doctrine.'' Some comments urged that FDA provide for Federal preemption 
of State regulation with respect to civil tort liability claims and 
other labeling requirements. The comments claimed that without 
preemption, FDA regulation would encourage ``failure to warn'' claims 
and challenges to the adequacy of the patient labeling, especially 
compared to professional labeling.
    Tort liability can not be a major consideration for FDA which must 
be guided by the basic principles and requirements of the act in its 
regulatory activities. Nevertheless, FDA does not believe that this 
rule would adversely affect civil tort liability for several reasons. 
First, tort liability depends on a number of factors surrounding the 
manufacture, distribution, sale, and use of a product, and the nature 
of the injury, and not just on the information provided or not provided 
to patients. Second, the agency believes that

[[Page 66384]]

providing patients with written information about the proper use of 
prescription drug products of ``serious and significant concern'' could 
reduce potential liability by improving patient compliance and patient 
monitoring of serious adverse events, thus decreasing drug-induced 
injuries and hospitalizations. Written information could also represent 
a clear opportunity for patients to be made aware that certain risks 
accompany drug therapies, and that not all serious adverse events are 
caused by deficiencies in the drug product or actions of the health 
professional. Third, the written patient medication information 
provided does not alter the duty, or set the standard of care for 
manufacturers, physicians, pharmacists, and other dispensers. Fourth, 
no evidence has been presented that patient labeling currently required 
by FDA regulation has caused a noticeable change in tort rules 
affecting civil liability. The courts have not recognized an exception 
to the ``learned intermediary'' defense in situations where FDA has 
required patient labeling, and the courts seem increasingly reluctant 
to recognize new exceptions to this defense.
    FDA believes that the information required under these regulations 
is necessary for patients to safely and effectively use prescription 
drug products that have been determined to be of ``serious and 
significant concern.'' In most cases, the information required by FDA 
will be such that States will have little reason to impose additional 
labeling requirements. Additionally, Federal preemption could unduly 
interfere with the goals and objectives of existing State programs 
imposed under the Omnibus Budget Reconciliation Act (OBRA) of 1990, 
which requires that pharmacists offer to counsel Medicaid patients 
about their prescription drugs. Many States have extended this 
requirement to all patients who receive prescription drugs, and some 
States have required that patients receive written medication 
information. This final rule is intended to complement these State 
efforts, not replace or hinder them.
    FDA does not believe that the evolution of state tort law will 
cause the development of standards that would be at odds with the 
agency's regulations. FDA's regulations establish the minimal standards 
necessary, but were not intended to preclude the states from imposing 
additional labeling requirements. States may authorize additional 
labeling but they cannot reduce, alter, or eliminate FDA-required 
labeling.
    To reduce liability concerns brought about by the perception that 
medication information must be tailored to each individual patient, the 
final rule has been changed to eliminate references to individual 
patients. FDA believes that Medication Guides for products of ``serious 
and significant concern'' should provide important and specific risk 
and benefit information that is applicable generally to the largest 
number of patients. Health care professionals bear the primary 
responsibility for informing individuals about patient-specific 
benefits, risks, and directions for using prescription medication.
    7. Some comments stated that manufacturers should be responsible 
only for providing medical and scientific information about their 
products to health care professionals. Several comments stated that the 
health care provider is in the best position to supply personalized 
information because the manufacturer's advertising, medical, or legal 
departments cannot possibly craft patient-specific information.
    As previously indicated, FDA agrees that health care providers who 
directly communicate with patients are in the best position to educate 
patients by personalizing oral and written information. However, FDA 
does not agree that manufacturers should not be responsible for 
informing patients about their products when circumstances make this 
important. Thus, manufacturers have been required to provide patients 
with information about certain products, such as oral contraceptives. 
Likewise, the final regulations will require that manufacturers develop 
and disseminate patient information only for selected medications that 
the agency has determined cannot be used safely and effectively without 
patient information.
    8. Some comments stated that Executive Order 12866 permits FDA to 
issue only such regulations as are ``necessary by compelling public 
need, such as material failures of private markets to protect or 
improve the health and safety of the public.'' Noting FDA's assertion 
that numerous sources of prescription medication information suitable 
for distribution to patients have been developed, the comments 
concluded that the regulation would violate Executive Order 12866.
    FDA believes that the final rule is in compliance with Executive 
Order 12866. To date, the private sector has not succeeded in providing 
prescription medication information to a large portion of Americans. 
Section 601 of the Appropriations Act will provide the private sector 
with sufficient time to meet the legislation's goal of distributing 
high quality information to a large number of consumers. These goals 
permit significant variability in the content of patient information. 
This final regulation applies only to a small number of products that 
are of ``serious and significant concern.'' Therefore, these 
regulations are consistent with section 1(b)(8) of Executive Order 
12866, which states that ``Each agency shall identify and assess 
alternative forms of regulation and shall, to the extent feasible, 
specify performance objectives, rather than specifying the behavior or 
manner of compliance that regulated entities must adopt'' (58 FR 51735, 
October 4, 1993). The final rule requires the development of Medication 
Guides only for those few medications where the need for patient 
information is critical to proper use of the drugs. In those cases, a 
voluntary system will not suffice because it would not satisfy the 
``compelling public need'' for good patient guidance.
    9. One comment insisted that the entire proposed rule and preamble 
is too vague and as such cannot be commented on in a meaningful manner.
    The agency has reviewed both the proposed rule and public comments 
and has concluded that the proposed rule is sufficiently clear. 
Moreover, no other comment stated that the proposed rule was either 
vague or ambiguous. Despite this consensus, FDA has made changes in the 
final rule to make the program clearer, in particular more specifically 
defining the circumstances under which a Medication Guide will be 
required for a drug product.

B. Medication Guide

    10. Several comments argued that providing written information is 
not an effective intervention, citing a number of studies indicating no 
significant changes in compliance with medication instructions. Other 
comments stated that FDA makes a number of ``unsubstantiated'' 
assumptions regarding the impact of written material on improved 
interaction with health care professionals, on decreased unnecessary 
physician visits, and on improved quality of health care. Some comments 
argued that FDA erroneously assumes that a direct relationship exists 
between providing patient information and improved health outcomes.
    FDA believes that the research consistently concludes that written 
information can improve patient knowledge, and that improved patient 
knowledge about how and when to take medication, and what to expect 
from taking the medication, contributes to

[[Page 66385]]

better medication-taking behavior, including regimen adherence. The 
agency's conclusions are based upon published literature cited in the 
August 24, 1995, proposal (60 FR 44182 at 44233 through 44235). For 
example, estimates of hospital admissions caused by preventable adverse 
drug reactions (ADR's) and noncompliance were based upon a thorough 
literature review. To achieve the most accurate estimate, FDA relied 
upon a meta-analysis of this literature and upon additional studies 
that directly examined the cause of hospitalizations (Ref. 1). 
Estimates of the number of preventable ADR's, as distinguished from 
nonpreventable ADR's, were based upon an analysis made by the study's 
authors.
    FDA agrees that health care problems are multifaceted, requiring a 
number of interventions. FDA maintains, however, that patients' 
knowledge about their treatments (which is consistently improved by 
written information) can and will contribute to such improvement. The 
experience FDA has had with written information (evaluated by Rand and 
oral contraceptive studies) (Refs. 2 and 3), with voluntarily supplied 
information (cited in the proposal in 60 FR 44182 at 44187), and the 
experiences in other nations with patient package inserts (Ref. 4) 
demonstrate that patient information does generally contribute to 
improvements in the parameters measured. Although it is true that FDA's 
analysis makes certain assumptions, the agency believes that they are 
valid. For example, patients who discuss the utilization of medications 
in a more informed manner have better quality interactions with a 
health care professional.
    11. Several comments stated that a ``one size fits all'' mentality 
will not work because different patients have different needs in 
acquiring and understanding medication information. In contrast, one 
comment pointed to research indicating that many groups share 
preferences for quality information. For example, older and younger 
adults share preferences regarding how medication information should be 
organized (which was in a manner similar to the suggested Medication 
Guide format), and better remember instructions if they are presented 
in the preferred grouping and order.
    The final rule specifies both content and format requirements to 
ensure that every affected patient receives certain basic information, 
the content of which is tailored to the individual drug. The modest 
format requirements are based on the best available research and 
contain such common sense provisions as a minimum type size generally 
readable even by older individuals with reduced visual abilities. The 
content provisions are more extensive and contain every category of 
information that might be needed for any drug requiring patient 
labeling. FDA notes, however, that it does not expect each Medication 
Guide to contain information in all of the categories specified in 
Sec. 208.20 because not every category will be relevant to every drug. 
Rather, the agency expects that a Medication Guide will contain only 
that information that is necessary for the safe and effective use of 
the particular drug. In recognizing the need for a certain amount of 
flexibility in the design and content of Medication Guides, the final 
rule provides in Sec. 208.26(a) that FDA will consider changes to any 
Medication Guide requirement, except those contained in 
Sec. 208.20(a)(2) and (a)(6), on the basis that the requirement is 
inapplicable, unnecessary, or contrary to patients' best interests. FDA 
has determined that it would never exempt a Medication Guide from the 
requirements that it be scientifically accurate and based on the 
product's approved professional labeling, or that it contain the legend 
identifying it as a Medication Guide. The agency anticipates exempting 
Medication Guides from specific content requirements that are shown to 
be inapplicable, unnecessary, or contrary to patients' best interests. 
The agency believes that this approach provides sufficient 
standardization to ensure uniform quality of Medication Guides, while 
also providing the flexibility to allow each Medication Guide to be 
tailored to the specific product and its population.
    FDA agrees with the comment concerning the value of instructions 
presented in a preferred grouping and order. Accordingly, the final 
rule continues to require the order of presentation of certain specific 
headings. This was discussed more fully in section II of this document.
    12. Some comments stated that medication information could, through 
suggestion, cause patients to develop the side effects listed, while 
other comments disagreed with this view. Some comments cited studies 
(Ref. 5) indicating that patient leaflets would increase patients' 
anxiety, causing them either not to initiate therapy or to discontinue 
it. One comment asserted that previous government-mandated patient 
leaflets have overemphasized risks, leading to decreased compliance.
    The effect of receiving written information on patients' propensity 
to report side effects has been evaluated in several studies (Refs. 6 
and 7), most of which have not found an increase in suggestion-induced 
side effects. For example, in a study by Morris and Kanouse (Ref. 8), 
patients taking thiazide medication were asked to report any health 
problems they experienced. The patients who were given a leaflet 
mentioning side effects were no more likely to report ``health 
problems'' following the initiation of the regimen than those who did 
not receive a leaflet. However, those who received the leaflet were 
more likely to say that the health problem was caused by the 
medication. The authors concluded that the leaflet did not cause 
suggestion-induced side effects, but did increase the attribution of 
reactions to the action of the medication. It is unclear how many of 
these side effects attributions were warranted by the action of the 
ingested medication or some other factor. However, the authors noted 
that if leaflets help patients understand the causes of their 
reactions, patients can better decide how to respond to these 
reactions.
    Although there have been anecdotal reports of increases in anxiety 
and deterrence in taking medications, FDA is not aware of any studies 
that document such an effect and therefore disagrees with the comments 
on this point. An FDA-sponsored study reported by the RAND corporation 
in 1981 measured the broad-scale impact of a variety of patient 
leaflets (Ref. 2). The postulated negative effects did not occur. Few 
patients demonstrated increased anxiety, there was no significant 
decrease in reported compliance, and few (3 of 2,000) patients returned 
their medication.
    FDA does not agree that patient leaflets already in use have 
overemphasized risks. These patient leaflets, such as those for oral 
contraceptives, have been written for medications that pose significant 
risks to patients. It is essential that the healthy young women who use 
oral contraceptives be informed that the products can increase the 
risks of sudden life-threatening outcomes, especially when the risks 
can be avoided or reduced by the patient (e.g., by not smoking). The 
agency strives for a balanced description of the benefits and risks of 
taking the medication in the patient leaflets it approves. To reinforce 
that balance, the agency has changed Sec. 208.20(b)(3) to allow 
discussion of the benefits of treatment.
    13. Some comments stated that patient information would 
detrimentally affect patients' relationships with health care 
providers. These comments

[[Page 66386]]

variously suggested that patient information would reduce incentives 
for health care providers to communicate with patients, or would 
inappropriately increase the number or length of patients' contacts 
with health care providers because the information could confuse or 
alarm patients. Other comments stated that FDA did not properly 
emphasize the importance of the physician in the patient encounter, 
arguing that physicians should decide if and when the patients should 
receive a Medication Guide.
    FDA agrees that health care providers should be the primary source 
of information about medications for their patients. The purpose of 
written information is to reinforce and supplement, not to interfere 
with, the doctor-patient relationship. This final rule is intended to 
help ensure that patients receive accurate and easy-to-understand 
information necessary for the safe and effective use of their 
medications, and to provide pharmacists, physicians, nurses, and other 
counselors with information that can supplement oral counseling. As 
discussed in the proposal (60 FR 44182 at 44188 through 44189), 
virtually all studies indicate that a combination of written and oral 
information works better than either of these interventions alone to 
increase patients' knowledge about their medications.
    FDA does not believe that written information will be detrimental 
to patients' relationships with their health care providers. Rather, 
written information should improve this relationship by improving 
patients' ability to communicate about their medications. Improved 
education should also increase patients' ability to take care of 
themselves and to make more knowledgeable inquiries of health 
professionals. Research indicates that for most patients the 
information in the patient leaflet for oral contraceptives did not 
change the length of patients' visits. It did, however, influence the 
content of the interaction, focusing more of the interaction on the 
medication (Ref. 3).
    FDA's 1992 and 1994 surveys of people initiating prescription 
medication treatment (Refs. 9, 10, and 11) indicated that the increased 
use of written patient information did not decrease the amount of 
orally supplied information.
    14. One comment pointed out that labeling changes occur frequently 
during the life cycle of a product. Thus, distribution of revised 
Medication Guides resulting from these changes will need to be 
carefully controlled to ensure that the most up-to-date information is 
available for dissemination to the patient.
    Section 208.20(b)(8)(iv) of the final rule requires that the date 
of the most recent revision be printed on the Medication Guide so that 
patients who receive multiple materials can identify the most recent 
information. FDA does not contemplate that changes in professional 
labeling would necessarily require changes in patient information. 
However, if changes in the professional labeling are significant enough 
to affect a product's Medication Guide, the manufacturer would be 
required to make related changes at the same time.
    15. Some comments stated that the final rule should not require 
approval of all written information prior to its use. Instead, they 
urge that the rule should simply specify topics to be included and 
require clarity, but that FDA audit, as opposed to preapprove, such 
information. Similarly, one comment suggested that prior approval 
should not be required for ``minor changes,'' such as the company name 
or address.
    The final rule requires that FDA approve a Medication Guide prior 
to distribution to ensure that it is consistent with the package insert 
and is adequate to help ensure safe and effective product use. Because 
Medication Guides will be required only for drug products of ``serious 
and significant concern,'' FDA believes that prior approval of the 
information necessary to the safe and effective use of the product is 
especially important. The agency will allow only very minor changes to 
be made without prior approval and has accordingly revised 
Sec. 314.70(b)(3)(ii) (21 CFR 314.70(b)(3)(iii)) and Sec. 601.12(f) (21 
CFR 601.12(f)) to indicate that. The agency has added the change to 
Sec. 601.12(f), which was not included in the proposal, to make the 
requirements for drug and biological products the same.
    16. One comment suggested that FDA be held to a 30-day approval 
time on NDA supplements for patient labeling, and that if 30 days pass 
without comment by FDA, the patient labeling should be automatically 
approved.
    As discussed previously in this document, Medication Guides would 
most often be required at the time of product approval. Thus, most 
Medication Guides would be covered under the timeframes designated 
under the Prescription Drug User Fee Act (PDUFA) (21 U.S.C. 379).
    However, for the rare situations in which Medication Guides are 
required subsequent to product approval, PDUFA timeframes are not 
relevant unless new clinical information is submitted in support of the 
labeling changes. Under these circumstances, FDA will endeavor to 
approve these changes as quickly as possible.
    17. Some comments urged that the regulations require patient 
labeling to be standardized in format and content, much like food 
labeling requirements, and be harmonized with international 
requirements.
    Consistent with the views of many consumer groups, FDA agrees that 
a standard format would be extremely helpful in aiding readers to 
quickly find information of particular interest. However, the agency 
was persuaded by the written comments and presentations at the February 
1996 public workshop that flexibility should be afforded in the design 
of Medication Guides. Different medications and patient populations may 
require somewhat different presentations to ensure that information is 
effectively communicated.
    FDA has determined that the best approach is to retain the 
standardized format but be flexible enough to allow changes when they 
are needed to more effectively communicate with a special population or 
to permit innovation. The final rule specifies the order of topics, the 
text of the headings to be used, and the location of required contents 
within the headings. FDA will consider changes to the format and 
content if the requirements are inapplicable, unnecessary, or contrary 
to patients' best interests. In reviewing requests for changes, the 
agency will be interested in receiving any data regarding more 
effective design or methods of communication.
    FDA believes that Medication Guides are different from the 
numerical listings of food labels because of the wider variety of 
issues and more complex meanings covered in a patient leaflet. The 
greater difficulty of communicating medication information justifies 
departure from the standard format.
    Regulations in Europe standardize the formats of patient leaflets 
within but not across countries. Therefore, the extent to which U.S. 
standards for Medication Guide formats would be consistent with 
evolving format standards being developed through the International 
Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use (ICH) is unclear at this time.
    18. One comment suggested that Sec. 208.1(a) be revised to read 
that ``[t]his part does not apply to prescription drug products 
administered in an institutional setting (such as hospitals, nursing 
homes, doctors' and dentists' offices, or other health care facilities 
such as clinics), or in emergency

[[Page 66387]]

situations.'' [Emphasis in original comment.]
    FDA does not agree with this comment. Section 208.1(a) states that 
part 208 applies primarily to medications used on an outpatient basis 
without direct supervision by a health professional. In addition to the 
wording change in Sec. 208.1(a) of the final rule that reflects the 
regulation's focus on providing Medication Guides for all prescriptions 
for drug products of ``serious and significant concern,'' the agency 
made the small change of moving the word ``primarily'' in the second 
sentence of Sec. 208.1(a) to immediately follow the word ``applies.'' 
This was done to make it clear that Medication Guides will usually be 
required for products used on an outpatient basis without the direct 
assistance of a health care provider.
    The agency believes that on rare occasions it may be necessary to 
require a Medication Guide for a product that is used in a physician's 
office or other health care facility, and this change reflects the 
agency's desire for the flexibility to accomplish this. The agency 
notes that prescribers would not be exempt from providing mandatory 
Medication Guides if they dispense a product to patients for outpatient 
use.
    19. One comment disagreed with FDA's reasoning as to why the 
Medication Guide proposal relates to prescription products that are 
used ``primarily on an outpatient basis without direct supervision by a 
health care professional.'' The comment asserted that this reasoning is 
incorrect in that these outpatients are, indeed, under the direct 
supervision of a physician or pharmacist.
    The comment misunderstands FDA's use of the phrase ``direct 
supervision.'' The agency uses the phrase to describe situations in 
which a health professional is administering the medication on site, 
whether it is at a physician's office or at a health facility.
    20. One comment stated that FDA should clearly define how it 
identified, developed, and tested the seven components of ``useful'' 
information.
    To identify and develop the seven components, FDA relied on several 
studies it conducted involving various aspects of patient information 
(Refs. 2, 12, 13, and 14), as well as other published studies (Ref. 
15). Additionally, FDA relied on a number of clear writing manuals 
(Refs. 16, 17, 18, and 19) and legibility guidelines used by the 
nonprescription drug industry (Ref. 20). FDA also relied on its 
extensive experience gained over the past two decades developing and 
approving patient labeling, as well as preliminary advice obtained from 
the pharmaceutical industry, pharmacy and medical professional 
organizations, and consumer groups. All of this information and 
guidance was combined to create the list of seven components. This list 
was published in the 1995 proposed rule to obtain public comment. 
Furthermore, the agency held a public workshop in February 1996 to 
obtain additional comment on the seven components. The agency 
maintained a public docket for comment until March 6, 1996, to accept 
comments specific to these seven components (Ref. 9). Based on 
information and comments received during the workshop and comment 
period, the agency made certain changes to the components.
    FDA proposed these criteria for identifying and evaluating the 
quality of the information included in leaflets voluntarily distributed 
to patients. While the voluntary private-sector program for which the 
seven components were originally developed is outside the scope of this 
final rule, the agency believes that these criteria are important and 
has therefore retained them as requirements for Medication Guides. The 
broad acceptance of these components has been affirmed by Congress by 
their inclusion in the Medication Guide language contained in the 1997 
Appropriations Act and their use in the voluntary private-sector 
program.
    21. The 1995 proposed rule defined the criterion of scientific 
accuracy to mean consistency with FDA-approved product labeling, and 
proposed requiring that Medication Guides include the verbatim 
statement ``Medicines are sometimes prescribed for purposes other than 
those listed in a Medication Guide.'' Many comments stated that 
patients could become confused and experience problems if a product was 
prescribed for an off-label use or regimen that was not described in 
their medication information sheet.
    The agency does not believe that a change in response to these 
comments is warranted. The comments did not explain why patients would 
become confused or elaborate on the problems that might ensue. 
Moreover, the agency believes that the statement to be included in 
Medication Guides is sufficiently clear and will be helpful to 
patients. If patients have questions about the product's use, this may 
stimulate profitable discussion with an appropriate health care 
professional.
    22. Several comments stated that FDA's criteria for determining 
whether a product would be designated as being of ``serious and 
significant concern'' and hence that it would be accompanied by a 
Medication Guide are so broad as to include all pharmaceutical 
products, providing little or no guidance to manufacturers. Some 
comments stated that FDA's purpose in requiring 10 drugs or drug 
classes each year was to eventually require Medication Guides for all 
prescription drugs.
    FDA agrees that the proposed criteria for determining whether 
products or classes of products must be accompanied by Medication 
Guides can be more narrowly defined. Although the agency asked for 
comments on the appropriateness of the criteria, there were no 
suggestions made for improving them. Therefore, FDA has made several 
changes of its own in the final rule to clarify the purpose of 
Medication Guides and to describe more clearly the circumstances in 
which medications will be determined to be of ``serious and significant 
concern'' requiring Medication Guides.
    The agency has rewritten Sec. 208.1(b) describing the informational 
goals of Medication Guides. This section states that the agency must 
determine that information is ``necessary'' to patients' safe and 
effective use of the product. This is a high standard that will be met 
in only a small number of cases.
    To conclude that the information is necessary, the agency must find 
that one or more of the three circumstances in Sec. 208.1(c) exists. 
The four cases discussed in the preamble to the proposed rule have been 
condensed to three circumstances in order to avoid redundancy and to 
further clarify the circumstances in which FDA will require a 
Medication Guide. The three circumstances are: (1) The drug product is 
one for which patient labeling could help prevent serious adverse 
effects; (2) The drug product is one that has serious risk(s) (relative 
to benefits) of which patients should be made aware because information 
concerning the risk(s) could affect patients' decisions to use, or to 
continue to use, the product; or (3) The drug product is important to 
health and patient adherence to directions for use is crucial to the 
drug's effectiveness. These circumstances describe those situations in 
which patients must have information to use their medications safely 
and effectively.
    FDA does not expect that these circumstances will be regularly 
presented and thereby determine that Medication Guides are required for 
many or most medications. Rather, the agency intends to require patient 
labeling only if it is needed for the safe use of the product or 
critical to the effective use of the drug, and expects that this will 
be infrequent. In reviewing its past recommendations that

[[Page 66388]]

manufacturers prepare patient labeling for particular products, FDA has 
determined that it initially overestimated the number of products or 
product classes per year that would be required to have a Medication 
Guide. FDA now estimates that on average no more than 5 to 10 products 
per year would be determined to be of ``serious and significant 
concern'' and would thus require Medication Guides.
    The following examples will illustrate in more detail each of the 
three circumstances in which a Medication Guide will be required:
    (1) Where patient labeling could prevent serious adverse effects:
    These are cases in which there is a known ``risk control strategy'' 
(e.g., recognition of the early warning signs of lactic acidosis, a 
potentially fatal side effect, during metformin treatment so that the 
drug can be stopped and a physician contacted immediately) or where 
easily taken preventive measures can prevent harm, such as using sun 
block to avoid serious photosensitivity reactions with photofrin, or 
avoiding a concomitant therapy that can lead to a dangerous 
accumulation of the drug.
    (2) Where there are serious risks (relative to benefits) of which 
patients should be made aware because the information could affect 
patients' decisions to use, or continue to use, the drug:
    This is a case where the risk of a drug is relatively great, 
greater than a patient would anticipate given the relatively benign 
condition being treated (e.g., isotretinoin is used to treat acne, not 
usually considered a seriously morbid condition, but the drug can cause 
severe birth defects in an exposed fetus), where understanding the 
adverse effects is critical to a choice among alternative treatments 
with different safety and effectiveness profiles (e.g., choice of 
barrier contraception versus oral, injectable, or implantable birth 
control), or where there is an important relation of duration of use to 
risk (e.g., increased risk of endometrial cancer with chronic 
administration of oral estrogens, or increased risk of habituation with 
prolonged use of benzodiazepine hypnotics).
    (3) Where the drug product is important to health and patient 
adherence to directions for use is crucial to the drug's effectiveness:
    This is a case where nonadherence could compromise patients' health 
by interfering with effectiveness; e.g., labeling could remind people 
that taking alendronate sodium at least one-half hour before the first 
food, beverage, or medication of the day with plain water only (other 
beverages, food, and some medications are likely to reduce the 
absorption of alendronate), is essential to the drug's effectiveness in 
treating osteoporosis.
    Medication Guides would not be required for general admonitions, 
such as, ``Remember to take your antihypertensive medication daily.'' 
Rather, Medication Guides would be used to communicate messages 
specific to the serious risks associated with certain medications.
    FDA wishes to note its expectation that the vast majority of 
Medication Guides will be required when a product is first approved. 
Consistent with past procedures when recommending that certain products 
should include FDA-approved patient labeling, FDA intends to notify 
sponsors by letter, during the product's review process, that a 
Medication Guide is required for the product.
    In general, FDA does not anticipate determining that currently 
marketed products are of ``serious and significant concern,'' unless 
there is a compelling public health need. At this time, the only 
currently marketed products for which FDA intends to require Medication 
Guides are products in classes for which FDA has requested that 
manufacturers supply patient labeling, but where some manufacturers 
have failed to provide this information (e.g., benzodiazepine hypnotics 
and nonsedating antihistamines with boxed warnings). FDA believes that 
patients receiving similar medications, with similar risks, should 
receive similar approved patient labeling for all products in the 
specific pharmacologic class. A Medication Guide will also be required 
when new information becomes available raising a serious safety or 
efficacy concern about an FDA-approved drug.
    Over the years, FDA has approved a number of patient information 
leaflets. Some of these leaflets concerning a class of drugs (e.g., 
oral contraceptives, estrogen replacement products) have been required 
under notice and comment rulemaking. In addition, some manufacturers 
have supplied, and FDA has approved, patient information leaflets for 
several other drug products (e.g., isotretinoin, metformin, alendronate 
sodium, and epoetin alpha).
    Manufacturers whose approved labeling already includes patient-
directed labeling must continue to distribute such labeling. FDA 
believes that this information provides a valuable service to patients 
that should not be disrupted. In time, FDA intends to review all 
existing patient labeling to determine whether it is subject to this 
part. If existing patient labeling is found to meet the circumstances 
in Sec. 208.1(c), FDA will notify sponsors directly of such 
determinations and will allow them sufficient time to conform such 
labeling to the requirements of this final rule.
    23. One comment argued that because prescription drug wholesalers 
have no contact with patients they satisfy the definition of 
``distributors'' under proposed Sec. 208.3. Consequently, the comment 
suggests that FDA more clearly define the roles of dispensers and 
distributors.
    FDA agrees that drug wholesalers should not be considered 
dispensers under proposed Sec. 208.3(a), but rather as distributors 
under Sec. 208.3(d). FDA acknowledges that in several places in the 
proposal, the term ``distributor'' was used when, in fact, the term 
``dispenser'' should have been used. These inconsistencies have been 
corrected in the final rule.
    24. A number of comments addressed the relatively large number of 
Spanish-speaking individuals in the United States and the need for 
Spanish (and other language) Medication Guides. One comment suggested 
that existing computer data bases could be adapted easily to translate 
patient information into foreign languages commonly spoken in the 
United States. One comment claimed that proposed Sec. 208.20(a), 
mandating that Medication Guides be in English, is inconsistent with 
FDA's request for comments on how best to provide information to 
populations who do not speak English. One comment stated that FDA 
should permit verbatim translations of Medication Guides without 
requiring a submission for approval.
    FDA encourages, but the final rule does not require, the dispensing 
of patient information in foreign languages, in low literacy formats, 
or in braille for visually impaired consumers. Given the development of 
technology, translations and Medication Guides in other formats may 
become easier to distribute. However, FDA believes that most of these 
populations still could benefit from English language leaflets because, 
for example, a relative or friend could translate the information.
    Section 208.20(a)(1) does not prohibit, in addition to English 
language leaflets, either the distribution of faithful translations, 
such as materials in other languages or braille, or materials in 
simplified texts, or using icons or symbols. FDA continues to believe 
that a multifaceted communications system would help ensure that all 
consumers receive meaningful patient information.
    FDA believes that due to sometimes subtle differences among 
languages,

[[Page 66389]]

including syntax and connotation, translation requires judgment and 
expertise. While the distribution of translations is encouraged, 
translations would not satisfy Sec. 208.20(a)(1). Moreover, FDA 
frequently disagrees with sponsors about the appropriate translation of 
labeling language. The final rule does not require that translations 
receive FDA approval, but Sec. 208.20(a)(1) requires, that when they 
are used, they be distributed along with English language texts.
    25. Several comments suggested that Sec. 208.20(b)(1) be modified 
to permit the established name to be used as the most prominent product 
name and permit the trade name(s) to be listed secondarily.
    Application of Sec. 208.20(a)(7) and (b)(1) of the final rule would 
permit the established name of the product to be more prominent than 
the brand or trade name. Implementing section 502(e)(1)(B) of the act, 
Sec. 208.20(a)(7) of the final rule requires that the established name 
be printed in type at least one-half the height of that used for any 
proprietary name. Consequently, the established name can be as large as 
desired, provided that it is no less than one-half the height of the 
brand or trade name.
    26. Several comments suggested that Sec. 208.20(b)(5)(iv) be 
modified to include what the patient should do if several doses of the 
drug are missed or if the patient discontinues the regimen.
    No change is necessary to Sec. 208.20(b)(5)(iv) in response to 
these comments. The provision gives manufacturers the ability to 
include information on missed doses of a medication of ``serious and 
significant concern.'' The agency has modified this provision to 
include the phrase ``where there are data to support the advice.'' This 
change was made to emphasize that any advice of this type must be based 
on appropriate data or information.
    27. Several comments claimed that the required content of a 
Medication Guide emphasizes the presentation of risks without similar 
stress on benefits. Some pointed out, for example, that one of the 
prototype Medication Guides in the proposal includes information that 
overemphasizes the risks associated with the medication.
    FDA has long maintained that patients need to receive a fair 
balance of risk and benefit information. FDA does not object to the 
presentation of product benefit information if it is supported by 
scientific evidence and is consistent with approved professional 
labeling. In fact, the agency has added a new sentence to 
Sec. 208.20(b)(3) to make it clear that, when appropriate, a discussion 
of benefits of treatment can be included in a Medication Guide. On the 
other hand, because some medications have potentially serious effects, 
FDA believes that it is vitally important for patients to receive a 
truthful description of products' risks.
    While FDA believes that benefit information is often understood, 
the agency is open to learning more about how to communicate risk and 
benefit information so that patients receive a fair and balanced 
picture of their medications, without undue emphasis on either risks or 
benefits.
    28. Several comments urged that FDA avoid class labeling, i.e., 
providing the same information for various products within a class of 
drugs. Medication Guides, they argued, should be product-specific, 
rather than class-specific, to address issues unique to particular 
products.
    FDA has accepted both product-specific and class labeling 
approaches in its past approval of patient labeling and believes that 
class labeling can be appropriate for products in narrowly-defined 
pharmacologic classes. FDA will review drug product labeling when the 
agency believes that information can be safely applied to the specific 
covered product.
    29. Several comments suggested that the currently available 
``imprint system,'' or other descriptors of color, shape, markings, 
etc., be incorporated in the patient information to facilitate 
patients' coordinating their medication with the proper patient 
information. Other comments noted that these descriptors would be 
excessive.
    FDA encourages systems that ensure that the patient is able to 
identify the individual products dispensed. However, a single system 
may be difficult to implement. For example, in large pharmacies, 
dispensers may be unaware when generic suppliers with a different 
imprint are switched, necessitating a corresponding change in the 
patient information. Because of the excessive burden that would be 
imposed, FDA will not require that imprints or other descriptors be 
included in patient information.
    30. One comment asked that the medicine's expiration date be 
stamped on the patient information. Another comment suggested that 
patient information sheets include the pharmacist's or provider's 
telephone number so that patients will know where to call to get their 
follow up questions answered.
    The medicine's expiration date applies only to products stored in 
the manufacturer's container. Once the product is removed from the 
pharmacy's storage conditions, the original expiration date may no 
longer be valid. Further, many state pharmacy laws require that an 
expiration date appear on the medication vial dispensed to the patient. 
Generally, this date is 1 year from the time of dispensing. FDA will 
not require that patient information include the medicine's expiration 
date because it is not possible for the dispenser to know the 
medication's true expiration date.
    FDA encourages pharmacists or providers to include their telephone 
number in the information they give to patients. Many State Boards of 
Pharmacy rules require that the label on the medication container 
include the pharmacy's name, address, and telephone number.
    31. A number of comments suggested the use of pictograms or icons 
in addition to text, especially for patients with limited reading 
skills.
    FDA believes that, while pictograms may be helpful in explaining 
concepts, and icons helpful in providing graphically pleasing and 
memorable text, it is not clear that these devices are able to 
communicate concepts adequately regarding the use of prescription 
medications without the addition of the textual material. Accordingly, 
FDA will not require the incorporation of icons or pictograms in 
Medication Guides. However, the agency believes that icons or 
pictograms, when used in addition to text, are useful and may permit 
their incorporation on a case-by-case basis if requested by the 
manufacturer.
    32. The proposal solicited comments on page limits (60 FR 44182 at 
44208). One comment noted that it may be difficult to explain technical 
information in consumer language if the page length is limited, 
especially because page size and length will vary with the computer 
equipment used by the dispenser. Another comment argued that the rule 
should not specify page dimensions because the amount and type of 
information will vary from product to product.
    FDA agrees that a required page limit could put unnecessary 
constraints on the communication of important information. However, it 
is important to note that FDA expects that Medication Guides will 
include only the information necessary for the safe and effective use 
of the product and other information required to provide needed 
context. Medication Guides should not exhaustively detail all 
information known about the product. FDA is concerned that, if 
unrestrained, lengthy information could result in unnecessary or even 
dangerous barriers to the

[[Page 66390]]

effective communication of important concepts. Therefore, the agency 
will establish a two-page limit as a goal for the communication of the 
essential information to be included in Medication Guides. Graphic 
representations, charts or other material supportive of, or in addition 
to, the essential information should be placed in an ``appendix'' 
located at the end of the leaflet. The agency will consider overall 
length and the inclusion of supportive material in its evaluation of 
the understandability and legibility of the Medication Guide.
    33. Several comments suggested that Sec. 208.20(a)(4) 
(Sec. 208.22(a) of the proposed rule) be modified to require at least 
12 point type size, rather than 10 point, as proposed.
    FDA acknowledges that many prescription drug users are elderly and 
may have difficulty discerning words written in small type sizes. Ten 
point minimum type is larger than that used in many commonly read 
materials, e.g., newspapers. FDA notes that legibility is determined by 
a number of factors other than type size. The 10 point minimum was 
based on the need to balance legibility concerns and patients' 
reluctance to read longer materials.
    34. A number of comments made suggestions for: (1) Optimal 
presentation of information for patients (e.g., bulleting, outlines, 
contrast, typeface, leading); (2) the inclusion of specific types of 
information (e.g., potential treatment outcomes, managing side 
effects); and (3) providing greater flexibility in the presentation and 
language used in patient information.
    FDA appreciates the comments and suggestions and believes that the 
final rule provides an appropriate amount of flexibility. The final 
rule contains a minimum type size in Sec. 208.20(a)(4) and also 
requires in Sec. 208.20(a)(5) that the information be legible and 
clearly presented, and, where appropriate, use boxes, bolding, and 
other highlighting techniques to emphasize portions of the text. In 
addition, Sec. 208.20(b) of the final rule contains general content 
requirements for Medication Guides which the agency has said should be 
tailored to include only those categories of information relevant to 
the drug product and the need for the Medication Guide. Furthermore, 
Sec. 208.26(a) provides that changes from the format (and content) 
requirements will be considered when the requirements are inapplicable, 
unnecessary, or contrary to patients' best interests. These provisions 
will provide sufficient flexibility in the design of Medication Guides.
    35. One comment recommended that the final rule require that 
patient information accompany all medication samples distributed by 
health care providers.
    Under the final rule, Medication Guides are to be dispensed with 
all prescriptions of drug products that the agency determines are of 
``serious and significant concern.'' Prescription drug samples are 
dispensed under an oral or written prescription of a licensed 
practitioner. Accordingly, a Medication Guide must be provided with 
samples of prescription drug products that FDA determines are of 
``serious and significant concern.''
    36. Some comments questioned manufacturer compliance under a 
variety of conditions, such as when changes are made to the Medication 
Guide, especially for products that are not in unit-of-use packaging. 
Others questioned whether the agency would request a recall of 
Medication Guides if important changes are needed. The comments also 
questioned how the manufacturer could be held accountable or be allowed 
to confirm the accuracy of the information if third parties are able to 
make changes to the Medication Guide. Some comments also asked about 
what criteria must be met for personalized Medication Guides.
    In general, FDA intends that changes in Medication Guides be 
incorporated into the next printing of labeling. If clinically 
significant information necessitates a change in a Medication Guide, 
FDA will ask that manufacturers expedite the next printing to 
incorporate the change as rapidly as is reasonably possible. In 
addition, FDA could request that manufacturers notify health care 
professionals, such as by sending ``Dear Health Professional'' letters, 
and rapidly distribute replacement patient information. FDA would also 
expect manufacturers to use or adapt whatever systems are already in 
place for making changes to the professional labeling to make changes 
to Medication Guides.
    In response to the comment on personalized information, written 
medication information may be customized by individual health care 
practitioners for individual patients by including, for example, the 
prescription number, the name, address, and/or telephone number of the 
authorized dispenser and/or licensed practitioner, the specific dosage 
regimen prescribed, or by including other patient-specific information 
on leaflets. This information may precede or follow the required 
information in the Medication Guide, but in no case should the 
information be more prominent than, or obscure, any required 
information. FDA believes that such personalization falls within the 
practice of medicine and pharmacy. However, this final rule pertains 
only to Medication Guides for drug products of ``serious and 
significant concern,'' and the information in them must be approved by 
the agency before they can be distributed. Thus, third parties cannot 
make substantive changes to a Medication Guide, except in the limited 
context of personalizing it. Finally, under Sec. 314.70(b)(3) and 
Sec. 601.12(f), FDA will permit manufacturers to make only very minor 
changes to Medication Guides without submission of a labeling 
supplement.
    37. One comment stated that the distribution of Medication Guides 
by drug manufacturers to pharmacies, directly or through drug 
wholesalers, is not feasible because pharmacies use a variety of 
operating system platforms and proprietary software. The comment 
claimed that disks provided by manufacturers or wholesalers may not be 
compatible with existing systems because, for example, information may 
be formatted inconsistently with the printing specifications. The 
comment argued, therefore, that the rule would require that suppliers 
individualize disks for dispensers, and that such a requirement is 
overly burdensome.
    FDA agrees with the comment that pharmacies use a variety of 
computer systems. The final rule, in Sec. 208.24(b), however, permits 
manufacturers and distributors to provide either hard copies of patient 
information or the ``means'' for disseminating information. FDA 
believes that providing manufacturers and distributors with this degree 
of flexibility will encourage them to develop readily adaptable systems 
for distributing required Medication Guides. FDA believes that some 
manufacturers will choose to package certain products in unit-of-use or 
bulk containers with hard copies of the Medication Guides affixed to 
the product container. Other manufacturers will work with information 
system vendors to incorporate Medication Guides into existing pharmacy 
software systems.
    The agency wishes to emphasize that it is ultimately the 
responsibility of manufacturers to ensure that authorized dispensers 
receive sufficient numbers of Medication Guides that can, in turn, be 
dispensed to patients with selected products that pose a ``serious and 
significant'' public health concern. This requirement would not be 
fulfilled, for example, by a manufacturer providing a pharmacy with 
Medication Guides in a form that the pharmacy could not use. In cases 
where unit-of-use packaging or

[[Page 66391]]

printed copies of Medication Guides attached to bulk packages are not 
used, the agency feels that market forces will contribute to 
manufacturers working with the various third-party information 
providers to ensure that their computerized systems can provide 
printouts of Medication Guides.
    38. One comment argued that the rule would require that 
manufacturers ``provide the dispensers with the means to ensure 
distribution'' of Medication Guides to each patient without adequately 
defining ``the means.'' The comment asked whether manufacturers would 
be required to pay dispensers, provide computer equipment, or develop 
some other mechanism to ensure that dispensers could distribute 
Medication Guides. The comment also asked whether manufacturers would 
be liable for pharmacists' failure to distribute, or distributing the 
wrong Medication Guide, and whether drug manufacturers have a duty to 
educate pharmacists about the information contained in the leaflet. 
Other comments noted that pharmacists currently rely on patient 
information data bases developed by others, and argued that it would be 
excessively burdensome to require that pharmacists maintain hard copies 
of every manufacturer's Medication Guide.
    Section 208.24 of the final rule requires that manufacturers 
provide distributors and authorized dispensers with the means to 
distribute Medication Guides to patients. To allow for flexibility, FDA 
did not specify the means, but instead provided examples of effective 
means, such as providing authorized dispensers with patient information 
software. As suggested by some comments, FDA believes that most 
manufacturers will contract with third parties or large pharmacy chains 
who would develop acceptable dispensing mechanisms that pharmacists 
could easily incorporate into their practice. The final rule does not 
specify additional requirements because the agency wants to encourage 
private-sector innovation.
    Section 208.24(e) requires that authorized dispensers provide 
Medication Guides to patients. A manufacturer has fulfilled its 
obligation under the final rule by providing those who dispense its 
products with Medication Guides in sufficient numbers or the means to 
produce Medication Guides.
    39. Several comments objected to the requirement in proposed 
Sec. 208.24(c) that patient information be distributed with each unit-
of-use package, for both new prescriptions and refills, arguing that 
manufacturers should be allowed the same options of either providing 
sufficient paper copies with each shipment, or providing the dispenser 
with the means to supply Medication Guides without the use of paper, 
regardless of how the product is packaged.
    FDA has accepted the comment's suggestion that the agency exercise 
greater flexibility in the distribution of patient information for 
unit-of-use packaged medications. This was not an easy decision and may 
be reconsidered if alternatives do not succeed in regularly providing 
patients with the needed information. A unit-of-use package with 
enclosed patient information guarantees that patients receive the 
information. No alternative system does so. Although unit-of-use 
packaging is not the usual packaging in the United States, it is the 
standard in Europe and thus familiar to any sponsors with international 
experience.
    Proposed Sec. 208.24(c), which would have required the distribution 
of Medication Guides with each unit-of-use package intended for 
distribution to patients, has been deleted. This deletion will permit 
manufacturers the same options for distributing Medication Guides for 
unit-of-use and bulk dispensed medications. However, to ensure that 
authorized dispensers know which unit-of-use packaged products contain 
Medication Guides (so dispensers will know whether or not to dispense a 
separate Medication Guide), the term ``large volume'' as a modifier of 
the term ``container'' has been deleted every place it appeared in 
Sec. 208.24. In addition, the agency has made changes to Sec. 208.24(d) 
to require that the label of each container of drug product for which a 
Medication Guide is required instruct the authorized dispenser to 
provide a Medication Guide and tell the dispenser how the Medication 
Guide is provided. Because this information is so important, the agency 
has also added the requirement that these statements appear on the 
label in a prominent and conspicuous manner.
    40. One comment noted that proposed Sec. 208.24(f) specifically 
exempts authorized dispensers who print Medication Guides from the 
establishment registration and drug listing requirements of section 510 
of the act. The comment contended that this exemption should also apply 
to prescription drug wholesalers who have never been required to 
register and list their products with FDA.
    Section 510 of the act requires any person (including prescription 
drug wholesalers), unless exempt by statute (section 510(g)) or by 
regulation (21 CFR 207.10), who, among other things, changes the 
container, wrapper, or labeling of any drug product in furtherance of 
its distribution to register with the agency, as well as to list the 
product with the agency. FDA does not believe that section 510 of the 
act would apply to wholesalers who serve merely to pass on Medication 
Guides from manufacturers to authorized dispensers. On the other hand, 
if drug wholesalers make changes to the content of a Medication Guide, 
just as if they had made changes to the content of the professional 
labeling, they would be required to register and list their products 
with FDA.
    41. One comment suggested that proposed Sec. 208.26(b), which 
permitted physicians and pharmacists to withhold a Medication Guide 
from a patient, be amended to permit the withholding of Medication 
Guides only if the information ``would harm the patient or interfere 
with the course of treatment.'' The comment also suggested that the 
rule require that the prescriber note the reason for withholding the 
Medication Guide in the patient's record, and that only physicians, not 
pharmacists, should determine whether Medication Guides should be 
withheld.
    The agency agrees with this comment in part. Section 208.26(b) has 
been changed to permit only the licensed practitioner who prescribes a 
drug to direct that a Medication Guide be withheld if it is not in the 
patient's best interest because of significant concerns about the 
effect of the information on the patient. Authorized dispensers who are 
not licensed practitioners may not withhold a Medication Guide. If the 
patient requests information about a prescription drug subject to this 
final rule, however, Sec. 208.26(b) requires that the dispenser provide 
one, regardless of the licensed practitioner's concern. Licensed 
practitioners may include, depending on the jurisdiction, pharmacists, 
nurses, physician assistants, and other health professionals, as well 
as physicians. Any of these practitioners who have prescribing 
authority may direct that a Medication Guide be withheld. FDA does not 
believe that practitioners should be required to document the reason 
for directing that a Medication Guide be withheld when such decision is 
deemed to be in a patient's best interest.
    FDA believes that it is appropriate to limit this authority because 
Medication Guides required under this final rule will contain 
information of crucial importance for the safe and effective use of the 
product. The agency expects that licensed practitioners will direct 
that Medication Guides be withheld

[[Page 66392]]

relatively rarely, and that the decision will be based on special 
individual circumstances or characteristics of their patients.
    42. Several comments stated that the proposed regulations 
substitute the agency's judgment for that of the health care 
professional regarding the information individual patients need. Some 
comments argued that practitioners should decide if and when a patient 
should receive a Medication Guide, or relevant part(s) thereof. The 
comments maintain that the rule interferes with the practice of 
medicine by requiring that Medication Guides be distributed to all 
patients, even when a health care professional has determined that an 
individual patient should not receive such information.
    The final rule is limited to requiring Medication Guides for 
products FDA determines present health care concerns so significant 
that patients must have written information about the products. 
Medication Guides under this rule will contain information necessary to 
patients' safe and effective use of the products. FDA does not believe 
that providing such information interferes with the practice of 
medicine. The final rule does not limit the information that health 
care providers may impart to patients concerning prescribed 
medications. If physicians disagree with specific aspects of the 
patient labeling supplied by the manufacturer, they are free to discuss 
the matter fully with patients, noting their concerns and views. FDA 
believes the final rule encourages patients to engage in this kind of 
open discussion with their health care provider. Also, as noted above, 
the final rule permits a licensed practitioner to instruct that a 
Medication Guide be withheld from an individual patient if the 
practitioner believes that it would not be in the patient's best 
interest to receive the information. Only the patient can overrule this 
instruction by specifically requesting the Medication Guide.
    43. One comment suggested that the final rule exempt only those 
medications administered under emergency conditions. Another comment 
suggested that while the distribution of Medication Guides in emergency 
situations would be impractical, a good faith effort should be made by 
health care professionals to assure that the patient receives a copy as 
soon as practicable. In the case of hospitals, one comment advocated 
that Medication Guides be given to patients upon discharge, if not 
before. Others argued that Medication Guides should be given to 
institutionalized patients or their designees, including those in 
hospitals, long-term care facilities, and prisons. Still others stated 
that Medication Guides should be made available in physicians' offices.
    FDA has determined that routinely distributing Medication Guides to 
institutionalized patients is unnecessary because medications dispensed 
in such facilities are usually administered directly by health care 
professionals who are readily available to answer patients' questions 
about their medications. FDA encourages health care institutions to 
make copies of Medication Guides available to patients who request 
them, and to maintain compilations of Medication Guides at convenient 
locations so that interested patients have access to them. However, 
where the agency determines that the circumstances or characteristics 
of a particular drug make it necessary, FDA will require the 
distribution of a Medication Guide to institutionalized patients.
    FDA believes that distribution requirements should be sufficiently 
flexible to permit licensed practitioners to instruct that a Medication 
Guide be withheld when the information is deemed inappropriate for an 
individual patient. However, FDA emphasizes that Medication Guides 
cannot be withheld from patients who request them.

C. Economic/Environmental Issues

    44. Several comments stated that FDA's estimated cost for 
developing patient information was flawed. One comment stated that a 
particular drug manufacturer took 16 person-months of effort (eight 
professionals, full-time for 2 months) to develop the patient 
information for Proscar and that FDA should rely on this 
estimate for the effort needed to produce a new Medication Guide.
    FDA agrees that drug manufacturers' recent experiences provide the 
best source of information for estimating the average cost of 
developing a new Medication Guide. Indeed, FDA used this sort of 
information in its Regulatory Impact Assessment, which relied on the 
July 1993 issue of Pharmaceutical Executive (Ref. 21), in which Merck 
Pharmaceuticals' manager of information services states that 
``[d]evelopment of the PPI was a 6-month process, including initial 
drafting, research to ensure that potential users of 
Proscar understood the important information about the 
medicine contained in the PPI, and revision and refinement based on the 
results of our research.'' The article further explains that Merck 
elected to conduct readability and comprehensibility studies during the 
development phase.
    FDA would not require manufacturers to conduct this level of 
evaluation prior to issuing a new Medication Guide. Medication Guides 
are designed to draw upon readily available professional labeling. Even 
patient labeling drafted at the time of initial drug approval would be 
based upon the professional labeling, often, FDA assumes, utilizing the 
same staff that developed the professional label. FDA believes that 
minimal additional staff, such as a medical writer skilled in writing 
for laypersons, would be needed; therefore, most of the staff who would 
work on Medication Guides would be extremely familiar with the 
medication and its professional labeling. FDA considers 6 months to be 
an upper bound estimate for developing an original Medication Guide 
because Merck conducted testing beyond that required to develop the 
patient information for Proscar.
    45. Several industry comments claimed that FDA underestimated, 
perhaps by as much as 30 percent, the annual compensation for 
nonproduction staff.
    FDA believes that the estimated $70,000 salary used in its analysis 
is a fair estimation and may even overstate the average salary. 
According to the Bureau of Labor Statistics Monthly Report of Earnings, 
nonproduction workers in the Pharmaceutical Preparations Industry (SIC 
2834) earned an average of $49,579 in 1992. The U.S. Bureau of Economic 
Analysis (BEA), National Income and Product Reports, reported that the 
ratio of total compensation to wages within this industry is 1.249, 
resulting in total average 1992 compensation for a nonproduction 
employee in the pharmaceutical industry of $61,924. The BEA also 
reported that the average increase in compensation between 1992 and 
1994 was 6.3 percent. Thus, the average total compensation for a 
nonproduction employee in the pharmaceutical industry in 1994 was 
$65,825. FDA has used $70,000 as a reasonable estimate of this 
compensation.
    46. Several comments stated that FDA should prepare and publish an 
environmental impact statement (EIS) regarding the effects of the 
proposed rule, given the agency estimate that the average pharmacy will 
use 28,600 pages of computer paper and 23 dot matrix printer ribbons 
annually, and that the agency assumes a total of 71,386 pharmacy 
outlets use 2,041,688,200 pages of computer paper and discarded 
1,641,901 printer ribbons annually.

[[Page 66393]]

    FDA does not agree that it should develop either an environmental 
assessment (EA) or an EIS for this rule. This comment relied on 
environmental impact figures that were based on the effects of a 
voluntary program of disseminating written patient information 
concerning all prescription drugs from the proposed rule. The final 
rule has a much narrower focus because it applies only to a small 
number of products of ``serious and significant concern'' and therefore 
is not dependant on the outcomes achieved by a voluntary program. Thus, 
these figures are not accurate for this program. Further, 21 CFR 
25.24(a)(11) provides a categorical exclusion from the preparation of 
an EA for actions that establish by regulation labeling requirements 
for marketing articles if there is no increase in the existing levels 
of use or change in the intended uses of the product or its 
substitutes. The requirement for mandatory Medication Guides for 
medications of ``serious and significant concern'' will not produce 
such change because about as many products (on average no more than 5 
to 10 per year) will be affected as are currently affected by agency 
requests that their manufacturers voluntarily produce patient labeling 
for the products to ensure safe and effective use.
    47. One comment noted that the proposal's analysis under the 
Paperwork Reduction Act demonstrates the large amount of paperwork to 
implement this program but does not count the cost to produce this 
paperwork.
    FDA did include such costs in its economic evaluation. The 
Paperwork Reduction Act requires FDA to estimate the costs, in terms of 
hours, of reporting and recordkeeping resulting from Government 
regulations. This estimate was included in the proposal in a table 
included in section XIV (60 FR 44182 at 44233). The analysis of impacts 
in the proposal (60 FR 44182 at 44210 through 44213) presented monetary 
costs of implementing a comprehensive mandatory program, if it were to 
be instituted. This estimate included a variety of recordkeeping 
functions, e.g., cost of printing and dispensing Medication Guides and 
development costs incurred by manufacturers. Further, given the 
narrowed focus of the final rule, the costs of the paperwork burden, as 
well as other costs, will be low because only a small number of 
Medication Guides will be required. However, in recalculating these 
costs for consistency with the final rule, FDA included manufacturers' 
resources needed to produce and obtain approval for Medication Guide 
revisions.

IV. Analysis of Impacts

    FDA has examined the impact of the final rule under Executive Order 
12866, under the Regulatory Flexibility Act (5 U.S.C. 601-612) and 
under the Unfunded Mandates Reform Act (Pub. L. 104-4). Executive Order 
12866 directs 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).
    Under the Regulatory Flexibility Act, unless an agency certifies 
that a rule will not have a significant economic impact on a 
substantial number of small entities, the agency must analyze 
regulatory options that would minimize any significant impact of the 
rule on small entities. The Unfunded Mandates Reform Act requires (in 
section 202) that agencies prepare an assessment of anticipated costs 
and benefits before proposing any expenditure by State, local, and 
tribal governments, in the aggregate, or by the private sector, of $100 
million in any one year (adjusted annually for inflation).
    The agency has reviewed this final rule and has determined that the 
rule is consistent with the principles set forth in the Executive Order 
and in these two statutes. Further, the agency finds that the rule will 
not have a significant effect on a substantial number of small 
entities, and that it imposes no unfunded mandates to State, local or 
tribal governments. Indeed, as explained below, the expected annual 
incremental costs of this rule will not require expenditures 
significantly above what would be likely to occur in the absence of 
regulation.
    The final rule articulates the agency's decision to require 
mandatory Medication Guides for those prescription drug products 
identified as posing a ``serious and significant concern.'' Only when 
information is critical to patients'' safety will a manufacturer be 
required to distribute this information. In its absence, patients would 
be more likely to fail to adhere to therapeutically critical directions 
or to recognize signs and symptoms of both preventable and 
unpreventable adverse reactions. Such improper use of prescription 
medications can increase morbidity and mortality by contributing to 
additional or prolonged illness. As current estimates of the annual 
direct medical costs related to the improper use of prescribed 
medications exceed $20 billion, even small reductions in the incidence 
of such events would yield significant savings.
    Currently, patient labeling for most high risk products is 
developed voluntarily by manufacturers on a case-by-case basis. No 
formal mechanism exists, however, to ensure that all exposed patients 
receive concise, understandable information, or that the information 
they do receive is best for consumer protection.
    As described previously, FDA currently works with industry on a 
product-by-product basis to develop patient information sheets for the 
small number of products that pose the most serious public health 
risks. The agency does not expect this rule to significantly increase 
the frequency of this practice, nor will any additional information 
typically be required because the determining criteria will not change. 
Nevertheless, the voluntary nature of the current process may result in 
occasional disagreements between the agency and manufacturers of drug 
products with ``serious and significant concerns.'' These disagreements 
and negotiations would delay or preclude patients receiving necessary 
information. On average, therefore, based on past practice, FDA 
estimates that, each year, no more than 5 to 10 products with ``serious 
and significant concerns'' would develop patient information sheets. 
Only one of these products, however, would not have developed these 
sheets voluntarily. Thus only one additional product with a ``serious 
and significant concern'' may have to develop a Medication Guide as a 
result of this rule. In FDA's view, the nature and magnitude of the 
adverse outcomes that may result from the misuse of even this one 
additional product of ``serious and significant concern'' warrants the 
implementation of a limited, clearly articulated regulation.
    The existence of regulations that mandate the inclusion of critical 
patient information in a standardized format will ensure that all 
patients who use drug products with ``serious and significant 
concerns'' receive adequate information on their medication. For 
example, the identification of certain products with ``Medication 
Guide'' information will increase patients'' ability to recognize 
products of ``serious and significant concern'' that require their 
thorough and careful monitoring. Further, the communication of critical 
information concerning serious risks and directions for use will 
improve consumers' ability to identify and to learn essential 
prescription drug information. In addition, while approximately 70 
percent of all patients

[[Page 66394]]

have reported receiving patient information, this rule will ensure that 
all affected patients receive these Medication Guides.
    Second, by identifying the criteria, format, contents, and other 
requirements of patient information, manufacturers will be aware of the 
need for Medication Guides for products under development. Thus, this 
rule will increase the sponsors' ability to work in conjunction with 
FDA to develop this information as part of the traditional review 
package, facilitating FDA's timely review of the information and 
helping to assure that drug approvals are not delayed. In the absence 
of this rule, the ad hoc practice of developing patient information 
would continue in its currently less efficient and more burdensome 
form.
    Because FDA and industry currently work to assure the development 
and distribution of this patient information, and because these 
activities would continue even in the absence of this rule, the rule 
will impose minimal incremental costs on the industry. Almost every 
year, several firms are asked by FDA to develop patient information 
leaflets, and there is no reason to believe that this total number 
would change substantially. Consequently, as noted above, the agency 
estimates that one additional product each year will be required to 
develop information as a direct result of this rule. FDA has estimated 
a cost of under $12,000 (or 2-resource months) to develop a patient 
information sheet for a new drug product. Thus, this incremental 
compliance cost to manufacturers would be about $12,000 per year.
    Similarly, the distribution of information for the affected 
products will continue in the same manner. About half of these products 
(such as oral contraceptives) may be distributed in unit-of-use 
packaging that contains patient information sheets. These information 
sheets may cost manufacturers about an additional 2 cents per package 
for printing and paper. Alternatively, patient information for those 
products designated as posing a ``serious and significant concern,'' 
but not marketed in unit-of-use packaging, are distributed through a 
variety of information channels, including individual leaflets that 
circulate with the products, or automated systems that print individual 
leaflets from larger data bases. Most retail pharmacies, regardless of 
size, already distribute this information to consumers. FDA anticipates 
that these activities will continue, as the rule does not dictate any 
particular distribution approach, but places the ultimate 
responsibility for ensuring the content and availability of patient 
information with the manufacturer of the drug product. Moreover, the 
issuance of this rule will encourage third-party electronic information 
vendors to incorporate this mandatory patient information into their 
systems.
    According to FDA estimates, approximately 70 percent of all 
pharmacies supply patient information with prescriptions. The remaining 
30 percent will be required to provide medication guides for all drug 
products with ``serious and significant concerns.'' No more than 5 to 
10 such products are expected each year. FDA estimates that each 
affected drug product may account for 100,000 annual prescriptions, 
each Medication Guide will consist of one printed page, 50 percent of 
the affected products are manufactured in unit-of-use packages, and 5 
seconds of pharmacist time is necessary to dispense each guide. Based 
on these assumptions, within 10 years, the total cost for all 
pharmacies to include Medication Guides for the 50 to 100 identified 
drugs equals $434,000 to $868,000 (about 9 cents per prescription 
dispensed). The incremental cost of providing these Medication Guides 
(accounting for the 70 percent current compliance) would be about 30 
percent of this amount, or $130,000 to $260,000 per year.
    In sum, the actions described in this regulation will formalize the 
agency's current policy and impose few incremental costs on the 
affected industry sectors. Public health will be enhanced by ensuring 
the wider availability of consistent and understandable patient 
information for products of ``serious and significant concern.''
    With respect to the Regulatory Flexibility Act, even if a few 
additional products would require patient information sheets, the costs 
described above would not impose a significant effect on any entity. 
Thus, the agency certifies that the rule will not have a significant 
economic impact on a substantial number of small entities.

V. Environmental Impact

    The agency has determined under 21 CFR 25.30(a) 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.

VI. Paperwork Reduction Act of 1995

    This final rule contains information collection provisions that are 
subject to review by the Office of Management and Budget (OMB) under 
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The title, 
description, and respondent description of the collection of 
information are shown below 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.
    Title: Prescription Drug Product Labeling; Medication Guide 
Requirements
    Description: This final rule imposes reporting requirements on 
manufacturers of drug products that pose a serious and significant 
public health concern. These manufacturers will be required to develop 
Medication Guides for such products and submit them to FDA for 
approval.
    FDA estimates that on average no more than 5 to 10 products 
annually would fall under the ``serious and significant concern'' 
classification and thus require mandatory Medication Guides. FDA 
believes that four of these products (estimating conservatively) would 
be newly approved. One already-marketed product would require a 
Medication Guide, with two ``supplementary'' Medication Guides needed 
for products in the same narrow therapeutic class, and one Medication 
Guide needed for a generic product in this class. FDA's regulatory 
impact analysis estimated that applicants would need approximately 2 
months of full-time effort (320 hours) to develop for submission to FDA 
a ``model'' Medication Guide that would be consistent with the 
requirements in Sec. 208.20. (A ``model'' Medication Guide is for a 
medication in a class that has no previous Medication Guide.) 
``Supplementary'' Medication Guides would require approximately half 
that time (160 hours), and generic Medication Guides would require 1/
20th of the time (16 hours). FDA also estimates that one ``serious and 
significant'' Medication Guide sponsor annually may wish to request an 
exemption or deferral from specific Medication Guide requirements and 
that this would take approximately 4 hours.
    In addition, FDA estimates that two existing Medication Guides 
annually might require minor changes under Sec. 314.70(b)(3)(ii) or 
Sec. 601.12(f), necessitating 3 days (24 hours) of full-time effort.

[[Page 66395]]

    Under Sec. 208.24(e), authorized dispensers are required to provide 
a Medication Guide directly to the patient (or the patient's agent) 
upon dispensing a product for which a Medication Guide is required. 
Thus, the final rule imposes a third-party reporting burden on 
authorized dispensers, who, for the most part, will be pharmacists. FDA 
estimates that, over the next 3 years, assuming that 5 Medication 
Guides are required annually, an average of 10 Medication Guides 
annually would be available for prescribing and dispensing. Assuming a 
base of approximately 100,000 prescriptions dispensed for each of these 
products annually, and subtracting from this base the approximately 50 
percent of products with Medication Guides that are dispensed in unit-
of-use packages, results in a total of 500,000 prescriptions annually 
for products that pose a ``serious and significant public health 
concern.'' Based on data collected in 1996, the agency estimates that 
at least 70 percent of patients are already receiving some kind of 
patient medication information voluntarily provided by pharmacists when 
they dispense prescriptions. Therefore, this final rule would represent 
an incremental burden, in terms of third party reporting, for only 30 
percent, or about 150,000, of these prescriptions. Given 60,574 
pharmacies, including chains, independents, and food/drug combinations, 
this represents an average of 2.5 prescriptions per store, per year. 
Because FDA estimates that, on average, it would take a pharmacist 
approximately 5 seconds (.0014 hour) to provide a Medication Guide to a 
patient, the overall annual third party reporting burden for this final 
rule is approximately 212 hours.
    No estimate for recordkeeping burden is necessary because the 
recordkeeping provision in the proposed rule (proposed Sec. 208.26(c)) 
has been eliminated and this final rule contains no other recordkeeping 
provisions.
    Description of Respondents: Businesses or other for-profit 
organizations.
    Although the August 24, 1995, proposed rule (60 FR 44182) provided 
a 90-day comment period under the Paperwork Reduction Act of 1980, and 
this final rule incorporates the comments received, as required by 44 
U.S.C. section 3507(d), FDA is providing an additional opportunity for 
public comment under the Paperwork Reduction Act of 1995, which applies 
to this final rule and became effective after the expiration of the 
comment period. Therefore, FDA now invites comments on: (1) Whether the 
proposed collection of information is necessary for the proper 
performance of FDA's functions, including whether the information will 
have practical utility; (2) the accuracy of FDA's estimate of the 
burden of the proposed collection of information, including the 
validity of the methodology and assumptions used; (3) ways to enhance 
the quality, utility, and clarity of the information to be collected; 
and (4) ways to minimize the burden of the collection of information on 
respondents, including through the use of automated collection 
techniques, when appropriate, and other forms of information 
technology. Individuals and organizations may submit comments on the 
information collection provisions of this final rule by February 1, 
1999. Comments should be directed to the Dockets Management Branch 
(address above).
    At the close of the 60-day comment period, FDA will review the 
comments received, revise the information collection provisions as 
necessary, and submit these provisions to OMB for review. FDA will 
publish a notice in the Federal Register when the information 
collection provisions are submitted to OMB, and an opportunity for 
public comment to OMB will be provided at that time. Prior to the 
effective date of this final rule, FDA will publish a notice in the 
Federal Register of OMB's decision to approve, modify, or disapprove 
the information collection provisions. An agency may not conduct or 
sponsor, and a person is not required to respond to, a collection of 
information unless it displays a currently valid OMB control number.

                                       Estimated Annual Reporting Burden 1
----------------------------------------------------------------------------------------------------------------
                                                               Annual        Total
                21 CFR section                    No. of      frequency      annual      Hours per   Total hours
                                               respondents  per response   responses     response
----------------------------------------------------------------------------------------------------------------
208.20.......................................            8           1              8      242             1,936
314.70(b)(3)(ii) or 601.12(f)................            2           1              2       24                48
208.24(e)....................................       60,574           2.5      150,000         .0014          212
208.26(a)....................................            1           1              1        4                 4
                                              ------------------------------------------------------------------
      Total..................................  ...........  ............  ...........  ............       2,200
----------------------------------------------------------------------------------------------------------------
1There are no capital costs or operating and maintenance costs associated with this information collection.

VII. References

    The following references have been placed on display at the Dockets 
Management Branch (address above) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.

    1. Mullen, P. D., and L. W. Green, ``Measuring Patient Drug 
Information Transfer: An Assessment of the Literature,'' 
Pharmaceutical Manufacturers Association, Washington, DC, 1983.
    2. Kanouse, D. E. et al., ``Informing Patients About Drugs: 
Summary Report on Alternative Designs for Prescription Drug 
Leaflets,'' Rand Corp., Santa Monica, CA, 1981.
    3. Morris, L. A., M. Mazis, and E. Gordon, ``A Survey of the 
Effects of Oral Contraceptive Patient Information, Journal of the 
American Medical Association, 238(23), 2504-2508, 1977.
    4. Gibbs, S., W. E. Waters, and C. F. George, ``The Benefits of 
Prescription Information Leaflets (2),'' British Journal of Clinical 
Pharmacology, 28:345-351, 1989.
    5. Guarino, R., ``PPI: The Proper Prescription?'' Food Drug and 
Cosmetic Law Journal, 34:116, 1979.
    6. Howland, S., M. G. Baker, and T. Poe, ``Does Patient 
Education Cause Side Effects? A Controlled Trial,'' The Journal of 
Family Practice, 31:62-64, 1990.
    7. Lamb, G. C., S. S. Green, and J. Heron, ``Can Physicians Warn 
Patients of Potential Side Effects Without Fear of Causing Those 
Side Effects?'' Archives of Internal Medicine, 154:2753-2756, 1994.
    8. Morris, L. A., and D. E. Kanouse, ``Informing Patients About 
Drug Side Effects,'' Journal of Behavioral Medicine, 5:363-373, 
1982.
    9. Docket No. 93N-0371.
    10. Morris, L. A. et al., ``Patient Receipt of Prescription Drug 
Information,'' National Technical Information Service, No. PB84-
100031, 1984, Springfield, VA.
    11. Morris, L. A. et al., ``A National Survey of Prescription 
Drug Information Provided to Patients,'' National Technical 
Information Service, No. PB86-186947/XAB, 1986, Springfield, VA.
    12. Morris, L. A., A. M. Myers, and D. G. Thilman, ``Application 
of the Readability Concept to Patient-oriented Drug Information,'' 
American Journal of Hospital Pharmacy, 37:1504-1509, 1980.

[[Page 66396]]

    13. Morris, L. A., and D. Kanouse, ``Consumer Reactions to the 
Tone of Written Drug Information,'' American Journal of Hospital 
Pharmacy, 38:667-671, 1981.
    14. Morris, L. A., M. Hastak, and M. Mazis, ``Consumer 
Comprehension of Environmental Advertising and Labeling Claims,'' 
Journal of Consumer Affairs, 29: 328-350, 1995.
    15. Morris, L. A., and D. Kanouse, ``Consumer Reactions to 
Differing Amounts of Written Drug Information,'' Drug Intelligence 
and Clinical Pharmacy, 14:531-536, 1980.
    16. Backinger, C. L., and P. A. Kingsley, ``Write It Right: 
Recommendations for Developing User Instructions for Medical Devices 
Used in Home Health Care,'' Department of Health and Human Services, 
Publication No. FDA 93-4258, 1993.
    17. Doak, C. C., L. G. Doak, and J. H. Root, ``Teaching Patients 
with Low Literacy Skills,'' Philadelphia, J. B. Lippincott Co., 
1985.
    18. Felker, D. B. et al., ``Guidelines for Document Designers,'' 
Washington, DC, American Institutes for Research, 1981.
    19. Mettger, W., and J. Mara, ``Clear and Simple: Developing 
Print Materials for Low-Literacy Readers,'' Bethesda, MD, National 
Cancer Institute, 1992.
    20. Nonprescription Drug Manufacturers Association, ``Label 
Readability Guidelines,'' Washington, DC.
    21. Koberstein, W., ``Reach the People: The Progress of Direct-
to-Consumer Communications,'' Pharmaceutical Executive, 7: 36-58, 
July 1993.

List of Subjects

21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.

21 CFR Part 208

    Drugs, Patient labeling, Reporting and recordkeeping requirements.

21 CFR Part 314

    Administrative practice and procedure, Confidential business 
information, Drugs, Reporting and recordkeeping requirements.

21 CFR Part 601

    Administrative practice and procedure, Biologics, Confidential 
business information.

21 CFR Part 610

    Biologics, Labeling, Reporting and recordkeeping requirements.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, Chapter I of 
Title 21 of the Code of Federal Regulations is amended to read 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. Section 201.57 is amended by revising paragraph (f)(2) to read 
as follows:


Sec. 201.57  Specific requirements on content and format of labeling 
for human prescription drugs.

* * * * *
    (f) * * *
    (2) Information for patients: This subsection of the labeling shall 
contain information to be given to patients for safe and effective use 
of the drug, e.g., precautions concerning driving or the concomitant 
use of other substances that may have harmful additive effects. Any 
printed patient information or Medication Guide required under this 
chapter to be distributed to the patient shall be referred to under the 
``Precautions'' section of the labeling and the full text of such 
patient information or Medication Guide shall be reprinted at the end 
of the labeling. The print size requirements for the Medication Guide 
set forth in Sec. 208.20 of this chapter, however, do not apply to the 
Medication Guide that is reprinted in the professional labeling.
* * * * *
    3. Part 208 is added to read as follows:

PART 208--MEDICATION GUIDES FOR PRESCRIPTION DRUG PRODUCTS

Subpart A--General Provisions

Sec.
208.1  Scope and purpose.
208.3  Definitions.

Subpart B--General Requirements for a Medication Guide

208.20  Content and format of a Medication Guide.
208.24  Distributing and dispensing a Medication Guide.
208.26  Exemptions and deferrals.

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357, 
360, 371, 374; 42 U.S.C. 262.

Subpart A--General Provisions


Sec. 208.1  Scope and purpose.

    (a) This part sets forth requirements for patient labeling for 
human prescription drug products, including biological products, that 
the Food and Drug Administration (FDA) determines pose a serious and 
significant public health concern requiring distribution of FDA-
approved patient information. It applies primarily to human 
prescription drug products used on an outpatient basis without direct 
supervision by a health professional. This part shall apply to new 
prescriptions and refill prescriptions.
    (b) The purpose of patient labeling for human prescription drug 
products required under this part is to provide information when the 
FDA determines in writing that it is necessary to patients' safe and 
effective use of drug products.
    (c) Patient labeling will be required if the FDA determines that 
one or more of the following circumstances exists:
    (1) The drug product is one for which patient labeling could help 
prevent serious adverse effects.
    (2) The drug product is one that has serious risk(s) (relative to 
benefits) of which patients should be made aware because information 
concerning the risk(s) could affect patients' decision to use, or to 
continue to use, the product.
    (3) The drug product is important to health and patient adherence 
to directions for use is crucial to the drug's effectiveness.


Sec. 208.3  Definitions.

    For the purposes of this part, the following definitions shall 
apply:
    (a) Authorized dispenser means an individual licensed, registered, 
or otherwise permitted by the jurisdiction in which the individual 
practices to provide drug products on prescription in the course of 
professional practice.
    (b) Dispense to patients means the act of delivering a prescription 
drug product to a patient or an agent of the patient either:
    (1) By a licensed practitioner or an agent of a licensed 
practitioner, either directly or indirectly, for self-administration by 
the patient, or the patient's agent, or outside the licensed 
practitioner's direct supervision; or
    (2) By an authorized dispenser or an agent of an authorized 
dispenser under a lawful prescription of a licensed practitioner.
    (c) Distribute means the act of delivering, other than by 
dispensing, a drug product to any person.
    (d) Distributor means a person who distributes a drug product.
    (e) Drug product means a finished dosage form, e.g., tablet, 
capsule, or solution, that contains an active drug ingredient, 
generally, but not necessarily, in association with inactive 
ingredients. For purposes of this part, drug product also means 
biological product within the meaning of section 351(a) of the Public 
Health Service Act.
    (f) Licensed practitioner means an individual licensed, registered, 
or otherwise permitted by the jurisdiction

[[Page 66397]]

in which the individual practices to prescribe drug products in the 
course of professional practice.
    (g) Manufacturer means for a drug product that is not also a 
biological product, both the manufacturer as described in Sec. 201.1 
and the applicant as described in Sec. 314.3(b) of this chapter, and 
for a drug product that is also a biological product, the manufacturer 
as described in Sec. 600.3(t) of this chapter.
    (h) Medication Guide means FDA-approved patient labeling conforming 
to the specifications set forth in this part and other applicable 
regulations.
    (i) Packer means a person who packages a drug product.
    (j) Patient means any individual, with respect to whom a drug 
product is intended to be, or has been, used.
    (k) Serious risk or serious adverse effect means an adverse drug 
experience, or the risk of such an experience, as that term is defined 
in Secs. 310.305, 312.32, 314.80, and 600.80 of this chapter.

Subpart B--General Requirements for a Medication Guide


Sec. 208.20  Content and format of a Medication Guide.

    (a) A Medication Guide shall meet all of the following conditions:
    (1) The Medication Guide shall be written in English, in 
nontechnical, understandable language, and shall not be promotional in 
tone or content.
    (2) The Medication Guide shall be scientifically accurate and shall 
be based on, and shall not conflict with, the approved professional 
labeling for the drug product under Sec. 201.57 of this chapter, but 
the language of the Medication Guide need not be identical to the 
sections of approved labeling to which it corresponds.
    (3) The Medication Guide shall be specific and comprehensive.
    (4) The letter height or type size shall be no smaller than 10 
points (1 point = 0.0138 inches) for all sections of the Medication 
Guide, except the manufacturer's name and address and the revision 
date.
    (5) The Medication Guide shall be legible and clearly presented. 
Where appropriate, the Medication Guide shall also use boxes, bold or 
underlined print, or other highlighting techniques to emphasize 
specific portions of the text.
    (6) The words ``Medication Guide'' shall appear prominently at the 
top of the first page of a Medication Guide. The verbatim statement 
``This Medication Guide has been approved by the U.S. Food and Drug 
Administration'' shall appear at the bottom of a Medication Guide.
    (7) The brand and established or proper name of the drug product 
shall appear immediately below the words ``Medication Guide.'' The 
established or proper name shall be no less than one-half the height of 
the brand name.
    (b) A Medication Guide shall contain those of the following 
headings relevant to the drug product and to the need for the 
Medication Guide in the specified order. Each heading shall contain the 
specific information as follows:
    (1) The brand name (e.g., the trademark or proprietary name), if 
any, and established or proper name. Those products not having an 
established or proper name shall be designated by their active 
ingredients. The Medication Guide shall include the phonetic spelling 
of either the brand name or the established name, whichever is used 
throughout the Medication Guide.
    (2) The heading, ``What is the most important information I should 
know about (name of drug)?'' followed by a statement describing the 
particular serious and significant public health concern that has 
created the need for the Medication Guide. The statement should 
describe specifically what the patient should do or consider because of 
that concern, such as, weighing particular risks against the benefits 
of the drug, avoiding particular behaviors (e.g., activities, drugs), 
observing certain events (e.g., symptoms, signs) that could prevent or 
mitigate a serious adverse effect, or engaging in particular behaviors 
(e.g., adhering to the dosing regimen).
    (3) The heading, ``What is (name of drug)?'' followed by a section 
that identifies a drug product's indications for use. The Medication 
Guide may not identify an indication unless the indication is 
identified in the indications and usage section of the professional 
labeling for the product required under Sec. 201.57 of this chapter. In 
appropriate circumstances, this section may also explain the nature of 
the disease or condition the drug product is intended to treat, as well 
as the benefit(s) of treating the condition.
    (4) The heading, ``Who should not take (name of drug)?'' followed 
by information on circumstances under which the drug product should not 
be used for its labeled indication (its contraindications). The 
Medication Guide shall contain directions regarding what to do if any 
of the contraindications apply to a patient, such as contacting the 
licensed practitioner or discontinuing use of the drug product.
    (5) The heading, ``How should I take (name of drug)?'' followed by 
information on the proper use of the drug product, such as:
    (i) A statement stressing the importance of adhering to the dosing 
instructions, if this is particularly important;
    (ii) A statement describing any special instructions on how to 
administer the drug product, if they are important to the drug's safety 
or effectiveness;
    (iii) A statement of what patients should do in case of overdose of 
the drug product; and
    (iv) A statement of what patients should do if they miss taking a 
scheduled dose(s) of the drug product, where there are data to support 
the advice, and where the wrong behavior could cause harm or lack of 
effect.
    (6) The heading ``What should I avoid while taking (name of 
drug)?'' followed by a statement or statements of specific, important 
precautions patients should take to ensure proper use of the drug, 
including:
    (i) A statement that identifies activities (such as driving or 
sunbathing), and drugs, foods, or other substances (such as tobacco or 
alcohol) that patients should avoid when using the medication;
    (ii) A statement of the risks to mothers and fetuses from the use 
of the drug during pregnancy, if specific, important risks are known;
    (iii) A statement of the risks of the drug product to nursing 
infants, if specific, important risks are known;
    (iv) A statement about pediatric risks, if the drug product has 
specific hazards associated with its use in pediatric patients;
    (v) A statement about geriatric risks, if the drug product has 
specific hazards associated with its use in geriatric patients; and
    (vi) A statement of special precautions, if any, that apply to the 
safe and effective use of the drug product in other identifiable 
patient populations.
    (7) The heading, ``What are the possible or reasonably likely side 
effects of (name of drug)?'' followed by:
    (i) A statement of the adverse reactions reasonably likely to be 
caused by the drug product that are serious or occur frequently.
    (ii) A statement of the risk, if there is one, of patients' 
developing dependence on the drug product.
    (8) General information about the safe and effective use of 
prescription drug products, including:
    (i) The verbatim statement that ``Medicines are sometimes 
prescribed for purposes other than those listed in a Medication Guide'' 
followed by a statement that patients should ask

[[Page 66398]]

health professionals about any concerns, and a reference to the 
availability of professional labeling;
    (ii) A statement that the drug product should not be used for a 
condition other than that for which it is prescribed, or given to other 
persons;
    (iii) The name and place of business of the manufacturer, packer, 
or distributor of a drug product that is not also a biological product, 
or the name and place of business of the manufacturer or distributor of 
a drug product that is also a biological product, and in any case the 
name and place of business of the dispenser of the product may also be 
included; and
    (iv) The date, identified as such, of the most recent revision of 
the Medication Guide placed immediately after the last section.
    (9) Additional headings and subheadings may be interspersed 
throughout the Medication Guide, if appropriate.


Sec. 208.24  Distributing and dispensing a Medication Guide.

    (a) The manufacturer of a drug product for which a Medication Guide 
is required under this part shall obtain FDA approval of the Medication 
Guide before the Medication Guide may be distributed.
    (b) Each manufacturer who ships a container of drug product for 
which a Medication Guide is required under this part is responsible for 
ensuring that Medication Guides are available for distribution to 
patients by either:
    (1) Providing Medication Guides in sufficient numbers to 
distributors, packers, or authorized dispensers to permit the 
authorized dispenser to provide a Medication Guide to each patient 
receiving a prescription for the drug product; or
    (2) Providing the means to produce Medication Guides in sufficient 
numbers to distributors, packers, or authorized dispensers to permit 
the authorized dispenser to provide a Medication Guide to each patient 
receiving a prescription for the drug product.
    (c) Each distributor or packer that receives Medication Guides, or 
the means to produce Medication Guides, from a manufacturer under 
paragraph (b) of this section shall provide those Medication Guides, or 
the means to produce Medication Guides, to each authorized dispenser to 
whom it ships a container of drug product.
    (d) The label of each container or package, where the container 
label is too small, of drug product for which a Medication Guide is 
required under this part shall instruct the authorized dispenser to 
provide a Medication Guide to each patient to whom the drug product is 
dispensed, and shall state how the Medication Guide is provided. These 
statements shall appear on the label in a prominent and conspicuous 
manner.
    (e) Each authorized dispenser of a prescription drug product for 
which a Medication Guide is required under this part shall, when the 
product is dispensed to a patient (or to a patient's agent), provide a 
Medication Guide directly to each patient (or to the patient's agent) 
unless an exemption applies under Sec. 208.26.
    (f) An authorized dispenser or wholesaler is not subject to section 
510 of the Federal Food, Drug, and Cosmetic Act, which requires the 
registration of producers of drugs and the listing of drugs in 
commercial distribution, solely because of an act performed by the 
authorized dispenser or wholesaler under this part.


Sec. 208.26  Exemptions and deferrals.

    (a) FDA on its own initiative, or in response to a written request 
from an applicant, may exempt or defer any Medication Guide content or 
format requirement, except those requirements in Sec. 208.20 (a)(2) and 
(a)(6), on the basis that the requirement is inapplicable, unnecessary, 
or contrary to patients' best interests. Requests from applicants 
should be submitted to the director of the FDA division responsible for 
reviewing the marketing application for the drug product, or for a 
biological product, to the application division in the office with 
product responsibility.
    (b) If the licensed practitioner who prescribes a drug product 
subject to this part determines that it is not in a particular 
patient's best interest to receive a Medication Guide because of 
significant concerns about the effect of a Medication Guide, the 
licensed practitioner may direct that the Medication Guide not be 
provided to the particular patient. However, the authorized dispenser 
of a prescription drug product subject to this part shall provide a 
Medication Guide to any patient who requests information when the drug 
product is dispensed regardless of any such direction by the licensed 
practitioner.

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG OR AN 
ANTIBIOTIC DRUG

    4. The authority citation for 21 CFR part 314 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 357, 371, 
374, 379e.

    5. Section 314.50 is amended by revising the first and third 
sentences of the introductory text, paragraph (c)(2)(i), the first 
sentence of paragraph (d)(5)(vi)(b), paragraph (e)(2)(ii), and the 
fourth sentence in paragraph (l)(1) to read as follows:


Sec. 314.50  Content and format of an application.

    Applications and supplements to approved applications are required 
to be submitted in the form and contain the information, as appropriate 
for the particular submission, required under this section. * * * An 
application for a new chemical entity will generally contain an 
application form, an index, a summary, five or six technical sections, 
case report tabulations of patient data, case report forms, drug 
samples, and labeling, including, if applicable, any Medication Guide 
required under part 208 of this chapter. * * *
* * * * *
    (c) * * *
    (2) * * *
    (i) The proposed text of the labeling, including, if applicable, 
any Medication Guide required under part 208 of this chapter, for the 
drug, with annotations to the information in the summary and technical 
sections of the application that support the inclusion of each 
statement in the labeling, and, if the application is for a 
prescription drug, statements describing the reasons for omitting a 
section or subsection of the labeling format in Sec. 201.57 of this 
chapter.
* * * * *
    (d) * * *
    (5) * * *
    (vi) * * *
    (b) The applicant shall, under section 505(i) of the act, update 
periodically its pending application with new safety information 
learned about the drug that may reasonably affect the statement of 
contraindications, warnings, precautions, and adverse reactions in the 
draft labeling and, if applicable, any Medication Guide required under 
part 208 of this chapter. * * *
* * * * *
    (e) * * *
    (2) * * *
    (ii) Copies of the label and all labeling for the drug product 
(including, if applicable, any Medication Guide required under part 208 
of this chapter) for the drug product (4 copies of draft labeling or 12 
copies of final printed labeling).
* * * * *
    (l) * * *
    (1) * * * Information relating to samples and labeling (including, 
if

[[Page 66399]]

applicable, any Medication Guide required under part 208 of this 
chapter), described in paragraph (e) of this section, is required to be 
submitted in hard copy. * * *
* * * * *
    6. Section 314.70 is amended by revising paragraph (b)(3) to read 
as follows:


Sec. 314.70  Supplements and other changes to an approved application.

* * * * *
    (b) * * *
    (3) Labeling. (i) Any change in labeling, except one described in 
paragraphs (c)(2) or (d) of this section.
    (ii) If applicable, any change to a Medication Guide required under 
part 208 of this chapter, except for changes in the information 
specified in Sec. 208.20(b)(8)(iii) and (b)(8)(iv).
* * * * *
    7. Section 314.94 is amended by revising paragraph (a)(8) to read 
as follows:


Sec. 314.94  Content and format of an abbreviated application.

* * * * *
    (a) * * *
    (8) Labeling--(i) Listed drug labeling. A copy of the currently 
approved labeling (including, if applicable, any Medication Guide 
required under part 208 of this chapter) for the listed drug referred 
to in the abbreviated new drug application, if the abbreviated new drug 
application relies on a reference listed drug.
    (ii) Copies of proposed labeling. Copies of the label and all 
labeling for the drug product including, if applicable, any Medication 
Guide required under part 208 of this chapter (4 copies of draft 
labeling or 12 copies of final printed labeling).
    (iii) Statement on proposed labeling. A statement that the 
applicant's proposed labeling including, if applicable, any Medication 
Guide required under part 208 of this chapter is the same as the 
labeling of the reference listed drug except for differences annotated 
and explained under paragraph (a)(8)(iv) of this section.
    (iv) Comparison of approved and proposed labeling. A side-by-side 
comparison of the applicant's proposed labeling including, if 
applicable, any Medication Guide required under part 208 of this 
chapter with the approved labeling for the reference listed drug with 
all differences annotated and explained. Labeling (including the 
container label, package insert, and, if applicable, Medication Guide) 
proposed for the drug product must be the same as the labeling approved 
for the reference listed drug, except for changes required because of 
differences approved under a petition filed under Sec. 314.93 or 
because the drug product and the reference listed drug are produced or 
distributed by different manufacturers. Such differences between the 
applicant's proposed labeling and labeling approved for the reference 
listed drug may include differences in expiration date, formulation, 
bioavailability, or pharmacokinetics, labeling revisions made to comply 
with current FDA labeling guidelines or other guidance, or omission of 
an indication or other aspect of labeling protected by patent or 
accorded exclusivity under section 505(j)(4)(D) of the act.
* * * * *

PART 601--LICENSING

    8. The authority citation for 21 CFR part 601 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 360c-360f, 
360h-360j, 371, 374, 379e, 381; 42 U.S.C. 216, 241, 262, 263; 15 
U.S.C. 1451-1561.

    9. Section 601.2 is amended by revising the first sentence in the 
introductory text of paragraph (a) and paragraph (c)(1)(viii) to read 
as follows:


Sec. 601.2  Applications for establishment and product licenses; 
procedures for filing.

    (a) To obtain a license for any establishment or product, the 
manufacturer shall make application to the Director, Center for 
Biologics Evaluation and Research, on forms prescribed for such 
purposes, and in the case of an application for a product license, 
shall submit data derived from nonclinical laboratory and clinical 
studies which demonstrate that the manufactured product meets 
prescribed standards of safety, purity, and potency; with respect to 
each nonclinical laboratory study, either a statement that the study 
was conducted in compliance with the requirements set forth in part 58 
of this chapter, or, if the study was not conducted in compliance with 
such regulations, a brief statement of the reason for the 
noncompliance; statements regarding each clinical investigation 
involving human subjects contained in the application, that it either 
was conducted in compliance with the requirements for institutional 
review set forth in part 56 of this chapter or was not subject to such 
requirements in accordance with Sec. 56.104 or Sec. 56.105 of this 
chapter, and was conducted in compliance with requirements for informed 
consent set forth in part 50 of this chapter; a full description of 
manufacturing methods; data establishing stability of the product 
through the dating period; sample(s) representative of the product to 
be sold, bartered, or exchanged or offered, sent, carried, or brought 
for sale, barter, or exchange; summaries of results of tests performed 
on the lot(s) represented by the submitted sample(s); and specimens of 
the labels, enclosures, containers, and, if applicable, any Medication 
Guide required under part 208 of this chapter proposed to be used for 
the product. * * *
* * * * *
    (c)(1) * * *
    (viii) Specimens of the labels, enclosures, containers, and, if 
applicable, any Medication Guide required under part 208 of this 
chapter proposed to be used for the product.
* * * * *
    10. Section 601.12 is amended by revising the second sentence of 
paragraph (f)(1), and paragraph (f)(3)(i) to read as follows:


Sec. 601.12  Changes to an approved application.

* * * * *
    (f) * * *
    (1) * * * Except as described in paragraphs (f)(2) and (f)(3) of 
this section, an applicant shall submit a supplement describing a 
proposed change in the package insert, package label, container label, 
or, if applicable, a Medication Guide required under part 208 of this 
chapter, and include the information necessary to support the proposed 
change. * * *
* * * * *
    (3) * * *
    (i) An applicant shall submit any final printed package insert, 
package label, container label, or Medication Guide required under part 
208 of this chapter incorporating the following changes in an annual 
report submitted to FDA each year as provided in paragraph (d)(1) of 
this section:
    (A) Editorial or similar minor changes;
    (B) A change in the information on how the product is supplied that 
does not involve a change in the dosage strength or dosage form; and
    (C) A change in the information specified in Sec. 208.20(b)(8)(iii) 
and (b)(8)(iv) of this chapter for a Medication Guide.
* * * * *

PART 610--GENERAL BIOLOGICAL PRODUCTS STANDARDS

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


[[Page 66400]]


    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42 
U.S.C. 216, 262, 263, 263a, 264.

    12. Section 610.60 is amended by adding paragraph (a)(7) to read as 
follows:


Sec. 610.60  Container label.

    (a) * * *
    (7) If a Medication Guide is required under part 208 of this 
chapter, the statement required under Sec. 208.24(d) of this chapter 
instructing the authorized dispenser to provide a Medication Guide to 
each patient to whom the drug is dispensed and stating how the 
Medication Guide is provided, except where the container label is too 
small, the required statement may be placed on the package label.
* * * * *
    Dated: April 21, 1998.
Michael A. Friedman,
Lead Deputy Commissioner for the Food and Drug Administration.
Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 98-31627 Filed 11-25-98; 11:08 am]
BILLING CODE 4160-01-P