Prescription Drug Product Labeling; Medication Guide Requirements
Federal RegisterDec 1, 1998
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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
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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
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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
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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
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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 5
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