[Federal Register Volume 62, Number 166 (Wednesday, August 27, 1997)]
[Rules and Regulations]
[Pages 45313-45326]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-22701]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 201
[Docket No. 89N-0474]
RIN 0910-AA25
Specific Requirements on Content and Format of Labeling for Human
Prescription Drugs; Addition of ``Geriatric Use'' Subsection in the
Labeling
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is amending its
regulations governing the content and format of labeling for human
prescription drug products, including biological products, to include
information pertinent to the appropriate use of drugs in the elderly
(persons aged 65 years and over) and to facilitate access to this
information by establishing a ``Geriatric use'' subsection in the
labeling. The final rule is one of several measures FDA has taken in
response to the special concerns associated with prescription drug use
in elderly patients. FDA believes that improving access to information
that is important to the elderly will facilitate the safe and effective
use of prescription drugs in older populations.
DATES: This final rule becomes effective on August 27, 1998. Submit
written comments on the collection of information provisions by October
27, 1997. See section IV of this document for the implementation dates
of this final rule for drug classes and drug products.
ADDRESSES: Submit written comments on the information collection
requirements to the Dockets Management Branch (HFA-305), Food and Drug
Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT: Thomas C. Kuchenberg, Center for Drug
Evaluation and Research (HFD-7), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-594-5621.
SUPPLEMENTARY INFORMATION:
I. Background
In the Federal Register of November 1, 1990 (55 FR 46134), FDA
proposed to amend its prescription drug labeling regulations
(Sec. 201.57) to establish in the ``Precautions'' section a subsection
on the use of drugs in elderly or geriatric patients (aged 65 years and
over). The final rule requires, in a new ``Geriatric use'' subsection
of prescription drug labeling, that sponsors describe available
information pertinent to the appropriate use of drugs in elderly
patients. In cases where none of the provisions of the ``Geriatric
use'' subsection are applicable, FDA may permit omission of the
subsection or approve an accurate and appropriate alternate statement.
The final rule recognizes the special concerns associated with the
geriatric use of prescription drugs and acknowledges the need to
communicate important information so that drugs can be used safely and
effectively in older patients. The medical community has become
increasingly aware that prescription drugs can produce effects in
elderly patients that are significantly different from those produced
in younger patients. Although both young and old patients can exhibit a
range of responses to drug therapy, factors contributing to different
responses are comparatively more common among the elderly. For example,
elderly patients are more likely to have impaired mechanisms of drug
excretion (e.g., decreased kidney function), to be on other medications
that can interact with a newly prescribed drug, or to have another
medical condition that can affect drug therapy.
Geriatric labeling information is of increasing importance because
of the growing proportion of the population that is over 65 years of
age, and the significant use of medications by this age group. People
over age 65 constitute only 12 percent of the U.S. population, but they
consume over 30 percent of the prescription drug products sold in this
country. The elderly are expected to constitute 22 percent of the U.S.
population by the year 2030.
The final rule is one of several actions taken by FDA to promote
safe and effective prescription drug use in the elderly. FDA has
encouraged sponsors to include more elderly subjects, especially those
over 75 years of age, in clinical studies. In the Federal Register of
March 5, 1990 (55 FR 7777), FDA announced the availability of a
guideline entitled ``Guideline for the Study of Drugs Likely to be Used
in the Elderly.'' The guideline emphasizes FDA's recommendation that
drugs should be studied in the full range of patients who will receive
them, including the elderly, and that efforts should be made to
discover differences in pharmacokinetics related to age, or to
conditions associated with age (e.g., decreased renal function,
concomitant drugs, concomitant illness), and that clinical data should
be analyzed to see whether the drug has different effects, favorable or
unfavorable, in the old and young. The guideline provides detailed
advice on how to evaluate new drugs in older patients and is intended
to encourage routine and thorough evaluation of the effects of drugs in
elderly populations so that sufficient information can be provided to
physicians. The guideline did not call for, or anticipate, an increase
in the number of patients or the number of clinical studies needed to
evaluate a new therapy. Patients over 65 years of age already
represented a significant portion of study subjects in most cases,
based on several FDA surveys. The principal new steps called for were
to not exclude the very old, to analyze the data already collected, and
to obtain modest additional pharmacokinetic data. Only in special cases
(e.g., drugs especially targeted for older patients or where age-
related differences or problems are anticipated) were separate studies
in the elderly recommended.
In the Federal Register of August 2, 1994 (59 FR 39398), FDA
published a guideline regarding the use of drugs in geriatric
populations entitled ``Studies in Support of Special Populations:
Geriatrics.'' The guideline was prepared by the Efficacy Expert Working
Group of the International Conference on Harmonisation (ICH) of
Technical Requirements for Registration of Pharmaceuticals for Human
Use, which is concerned with the harmonization of technical
requirements among the European Union, Japan, and the United States.
The guideline reflects sound scientific principles for testing drugs in
geriatric populations and for submitting
[[Page 45314]]
marketing applications to regulatory authorities worldwide. The
guideline is consistent with FDA's existing geriatric guideline
discussed previously.
II. Highlights of the Final Rule
This final rule furthers FDA efforts to promote safe and effective
prescription drug use in the elderly by requiring that information on
the safe and effective use of drugs in the elderly be included in
labeling, and by specifying a location and format for presenting this
information.
A. General Provisions
The final rule establishes, in new Sec. 201.57(f)(10), a
``Geriatric use'' subsection that provides information on the safe and
effective use of drugs in patients aged 65 and older. This subsection
of the ``Precautions'' section of the labeling describes what is known
about the effects of a drug in the elderly and lists any limitations,
hazards, or monitoring needs associated with geriatric use.
Although FDA encourages further study of drug effects in the
elderly, this labeling change is not intended to require additional
clinical studies. The ``Geriatric use'' subsection is intended to
establish a place in prescription drug labeling where practitioners can
find pertinent information that is already available from clinical
experience and investigations. FDA believes that providing this
information in a clear and accessible way should promote the safe and
effective use of prescription drugs in the elderly.
Section 201.57(f)(10) also states that specific geriatric
indications, if any, are to be described in the ``Indications and
Usage'' section, and specific geriatric dosing instructions are to be
described in the ``Dosage and Administration'' section. Additional
details about information summarized in the ``Geriatric use''
subsection may be found in other sections of the labeling, as
appropriate.
B. Sources of Information on Geriatric Use
Under Sec. 201.57(f)(10)(ii), the ``Geriatric use'' subsection is
based on all information available to sponsors that is relevant to the
use of the drug in elderly patients. The information includes results
from controlled studies, both those that are part of a marketing
application and those available to the sponsor but not submitted,
information gathered from other studies and experience (e.g., adverse
drug reaction reports), and pertinent information from well-documented
studies obtained from a literature search.
C. Statements on Geriatric Use
Section 201.57(f)(10)(ii) calls for appropriate labeling statements
that are based on the information available regarding use of the drug
in geriatric populations:
(1) If there have not been sufficient numbers of geriatric subjects
involved in clinical studies to determine whether those over age 65
differ from younger subjects in their responses to the drug, and other
reported clinical experience has not identified such differences,
Sec. 201.57(f)(10)(ii)(A) requires that the labeling state this fact
and note that generally the selection of dosage levels for the elderly
should proceed with caution, usually starting at the low end of the
dosing range.
(2) If sufficient numbers of geriatric subjects have been included
in studies (both those in marketing applications and other relevant
studies available to the sponsor) to make it likely that a difference
in safety and effectiveness between older and younger subjects would
have been detected, but no such differences in safety or effectiveness
were apparent and no other reported clinical experience identified such
differences, Sec. 201.57(f)(10)(ii)(B) requires that the labeling state
this fact. The statement must also indicate the percentage of the total
number of subjects, or the total number of subjects, in a defined group
of clinical studies who were 65 and over and 75 and over.
(3) If evidence from clinical studies and other reported clinical
experience available to the sponsor indicates that use of the drug in
elderly patients is associated with differences in safety or
effectiveness in the geriatric population, or if administration of the
drug to the elderly requires specific dosage adjustment or monitoring,
Sec. 201.57(f)(10)(ii)(C) requires that the labeling briefly describe
these special geriatric conditions and, when appropriate, refer to
other labeling sections for more detailed discussions.
D. ``Geriatric Use'' and Other Labeling Sections
Section 201.57(f)(10)(iii)(A) requires that if specific
pharmacokinetic or pharmacodynamic studies of the drug's action were
carried out in the elderly, they must be described briefly in the
``Geriatric use'' subsection and in detail in the ``Clinical
Pharmacology'' section.
The potential for problems stemming from the use of drugs in
patients with certain diseases or from interactions between drugs is
higher among the elderly because they are more likely to have multiple
illnesses requiring multiple drug treatments. Section
201.57(f)(10)(iii)(A) notes that the ``Clinical Pharmacology'' and
``Drug Interactions'' sections of the labeling ordinarily contain
information on drug-drug and drug-disease interactions. For example,
Sec. 201.57(b) requires, in part, that the Clinical Pharmacology
section of the labeling contain a concise factual summary of the
clinical pharmacology and actions of the drug in humans.
Section 201.57(f)(4)(i), the ``Drug Interactions'' subsection of
the ``Precautions'' section, includes a requirement that the labeling
shall contain specific practical guidance on preventing clinically
significant drug/drug and drug/food interactions that may occur in vivo
in patients taking the drug, including identification of specific drugs
or classes of drugs with which the drug may interact in vivo in
patients and a brief description of the mechanism(s) of the
interaction.
If the use of a drug in the elderly appears to cause a specific
hazard, the hazard must be described in the ``Geriatric use''
subsection as required under Sec. 201.57(f)(10)(iv), or information
about the hazard would be placed appropriately under the
``Contraindications,'' ``Warnings,'' or ``Precautions'' sections of the
labeling, and the ``Geriatric use'' subsection would refer to those
sections. Geriatric labeling, under Sec. 201.57(f)(10)(v), may also
include statements reflecting good clinical practice or experience with
a particular situation if they would be useful in enhancing the safe
use of the drug. As an example, the final rule provides a possible
statement for a sedating drug.
E. Renal Function
Geriatric patients are more likely than younger patients to have
impaired renal function. Therefore, when it is known that a drug is
substantially excreted by the kidney, Sec. 201.57(f)(10)(iii)(B)
requires a statement to that effect in the ``Geriatric use''
subsection, as well as a statement noting that care should be taken in
dose selection and that it may be useful to monitor renal function.
Renal function may be monitored by calculating creatinine clearance.
F. Alteration or Omission of Geriatric Statements
Although the geriatric statements provided in the final rule will
be appropriate for most drug products, there are certain drugs that are
not indicated for geriatric use or for which the specified geriatric
statements are not needed. In this situation, the sponsor, under
Sec. 201.57(f)(10)(vi), must provide reasons for omitting the specific
geriatric use information and statements
[[Page 45315]]
in Sec. 201.57 and, if appropriate, may propose alternative geriatric
language.
FDA may permit omission of a geriatric use statement and permit the
use of an alternate statement if FDA determines that the statements
described in Sec. 201.57(f)(10)(i) through (f)(10)(v) are inappropriate
or not relevant to the drug's labeling and that the alternate statement
is accurate and appropriate.
III. Comments on the Proposed Rule
The agency received approximately 60 comments on the proposed rule.
The comments came from Congress, prescription drug manufacturers,
physicians, professional societies, organizations with special
interests in the elderly, the lay public, and others. Most comments
agreed with the proposed labeling change, calling it ``long overdue,''
``timely and important,'' and a ``major step'' in promoting the safe
and effective use of prescription drugs in the elderly.
Many comments expressed the belief that a ``Geriatric use''
statement in the labeling would result in increased awareness among
practitioners and patients and thus enhance the physician's ability to
provide quality health care to older patients.
1. While expressing support, some comments reflected confusion
about the practical effect of the regulation, recommending such steps
as the use of large print, bright ink, and ``simple language'' to make
the labeling more easily read and understood by older patients.
The agency believes these comments misinterpret the intent of this
rulemaking. The regulation does not describe information that would be
distributed directly to the patient. Rather, the rule amends the
``professional'' labeling requirements for prescription drugs, commonly
referred to as the physician package insert, to require that a
``Geriatric use'' subsection appear in the ``Precautions'' section of
the package insert. Professional labeling is designed for and directed
to physicians and other health care professionals and is required to
provide information ``under which practitioners licensed by law to
administer the drug can use the drug safely and for the purposes for
which it is intended * * *'' (Sec. 201.100(c)(1) (21 CFR
201.100(c)(1)).
Although this final rule does not require that written information
on geriatric use be distributed directly to elderly patients or
establish any print size requirements, the agency expects that it will
result in more and better information reaching these patients. The
final rule amends the labeling requirements to give physicians and
other health care professionals easier access to more information about
geriatric use. A health care community so informed will be better able
to deliver superior care and to provide more information on the safe
and effective use of prescription drugs to elderly patients.
Because some confusion exists regarding the purpose of this
regulation, and as a result of the changes made in response to comments
received, FDA has reformatted and redesignated some provisions in
proposed Sec. 201.57(f)(10) for this final rule. These changes were
made to clarify obligations and options provided in the regulation.
Except where specific substantive changes or additions are indicated
and were made in response to comments, these changes do not involve
changes in the obligations imposed on sponsors by the regulation. FDA
has also replaced the word patient with the more appropriate
``subject'' when referring to individuals participating in clinical
studies.
2. Some comments opposed establishing a ``Geriatric use''
subsection in prescription drug labeling. The comments stated that in
communicating drug information to patients, the role of pharmacists and
other health care practitioners should be adequate to reduce problems
in the elderly, making this labeling change unnecessary.
The agency disagrees. FDA recognizes that pharmacists and other
health care practitioners play important roles in communicating
information about prescription drug use to elderly patients. However,
surveys show that a substantial number of elderly patients fail, in
some way, to comply with their prescription drug regimen; and the
elderly population is greatly in need of medication counseling and
information. Pharmacists and others cannot transmit information they do
not have, and information on how younger and older patients respond
differently to a drug is difficult to find.
The final rule does not diminish the role that health care
professionals play in communicating information to the elderly about
their prescription drugs. Rather, it facilitates that role by providing
health care professionals with more information about how drugs affect
older patients.
3. One comment claimed that the proposed ``Geriatric use''
subsection is redundant because existing FDA guidelines and labeling
regulations already provide that important information should be
included in the labeling.
FDA acknowledges that some prescription drug labeling consistent
with existing FDA guidelines and regulations contains information on
use in the elderly. This reflects growing recognition of the need to
provide patient information on individualizing drug therapy and,
specifically, of the need to provide information on use in the elderly.
The final rule is intended to make geriatric labeling format and
content more consistent by requiring that there be a ``Geriatric use''
statement in prescription drug labeling, that the statement reflect all
information available to the sponsor that is relevant to the
appropriate use of the drug in elderly patients, that the information,
or direct reference to it, be found in a particular location in the
labeling, and that the statement follow a standard format. The
``Geriatric use'' statement will give practitioners and others easier
access to more information about prescription drug use in elderly
patients.
4. Other comments objected to a ``Geriatric use'' subsection on
economic grounds, saying that the costs of producing and compiling the
information necessary to comply with this labeling change will be
significant, adding to the already high cost of drug development. The
comments were concerned that these costs would be passed along to the
elderly consumer, who may not be able to afford them.
The agency's review of the cost issues posed by the comments is
contained in section VI of this document. The agency agrees that
manufacturers will incur some costs as a result of this final rule. The
agency believes, however, that the costs associated with the final rule
will not be significant, especially in light of the potential benefits
of the labeling change. This rule does not require any new clinical
studies, but the preparation of the ``Geriatric use'' subsection should
include analyses of previously collected data and available literature.
The cost of preparing the ``Geriatric use'' subsection may be
offset by lower health care costs resulting from fewer adverse
reactions to prescription drugs. Because older people take about three
times as many prescription drugs as younger individuals and because
taking several drugs together substantially increases the risk of drug
interactions, unwanted effects, and adverse reactions (Ref. 1),
labeling addressing this information should result in fewer adverse
reactions. A number of studies have indicated that adverse drug
reactions and patient noncompliance contribute to costly emergency room
and hospital visits (Ref. 2). If the information required by the rule
prevents only a modest fraction of these
[[Page 45316]]
adverse reactions, the health care savings will be sizeable.
Costs will also be lessened by the manner in which the rule is to
be implemented. The extended period allotted for implementation is
designed to reduce burdens for both industry and the agency.
Implementation will take place over 6 years (in accordance with the
plan described in section IV of this document). The implementation
schedule divides drug products subject to this regulation into four
multiyear groups based on the date of approval of the products' new
molecular entities (NME's). FDA recognizes that it will be more
difficult to develop geriatric labeling for older NME's, due to the
probable need to manually examine data and the likelihood that a more
extensive literature search will be needed. In contrast, the
information available for recently approved drugs is more likely to be
readily available to sponsors and more likely to be computer
accessible. As a result, implementation will proceed in reverse
chronological order.
In addition, the agency will not require prior approval of labeling
changes for drug products under Sec. 201.57(f)(10)(ii)(A) (i.e., where
insufficient data exist to determine whether the responses of geriatric
patients to a drug are different from responses of younger patients).
5. Some comments found the proposed regulation ``confusing'' and
suggested that FDA provide ``model labeling'' for each drug or drug
class.
The regulation does provide specific ``model'' language for several
possible labeling statements. The agency has revised proposed
Sec. 201.57(f)(10) to make the ``Geriatric use'' labeling requirements
clearer and to make several organizational and other general changes.
The agency does not agree, however, that it should draft model
geriatric labeling for each drug or drug class. The agency does not
believe that a small number of ``models'' could be developed that would
be helpful in formulating the labeling of all drug products, nor does
the agency have the resources necessary to draft such labeling.
6. Several comments objected to the agency's designation of 65
years and older as the age range to which this rule would apply. Some
comments called the choice ``arbitrary,'' noting that, while 65 years
old has become widely used as a sociological marker of the beginning of
senior citizen status, there is no physiological basis for identifying
65 years old as the age at which differences in drug effects begin to
occur.
One comment suggested that the age be lowered to include persons in
their fifties; others suggested that the appropriate age should be 60
years old; another thought 80 years and older would be the most
meaningful age category with regard to differences in drug response.
Several comments complained that the proposed rule treated all persons
over 65 years old as a homogeneous group, and suggested that it be
changed to categorize 65 to 74, 75 to 84, and 85 years and older as
three distinct age categories for purposes of assessing drug response.
Other comments suggested that age not be used at all to define the
geriatric population, but that other factors, such as changes in body
composition or organ function, be used as criteria for categorizing
appropriate labeling statements.
The agency recognizes that attempts to define populations to which
clinical or regulatory requirements apply are subject to certain
limitations and are difficult to achieve. This is evidenced by the
number and variety of suggestions for alternative age designations
posed by the comments. Nonetheless, for ease of implementation, it is
necessary to specifically and simply define the population to which
this final rule applies.
Defining the geriatric population based on age (persons 65 years of
age and older) lends an important element of uniformity in the
development of the ``Geriatric use'' subsection and establishes
boundaries for the application of the final rule. These boundaries are
necessary to enable manufacturers to determine how to gather, evaluate,
and communicate geriatric use information. Defining the scope of the
final rule in this way also will aid practitioners who consult the
``Geriatric use'' subsection, allowing them to presume that, unless
otherwise stated, the population being addressed is 65 years of age and
older and that this standard remains constant in all prescription drug
labeling. The agency notes that age 65 is a widely used marker for the
beginning of elderly status and believes that 65 years of age is a
reasonable starting place for a discussion of differences in drug
response that are related to advancing age. However, the agency does
not consider 65 years of age to be an absolute boundary for this
rulemaking. For some drugs, it may be more appropriate for the labeling
to reflect evaluation of another elderly age group, or, where there are
important differences in response, to address specific subgroups within
the geriatric population. In some cases, changes might be expressed as
a continuous function of age. FDA would expect the manufacturer to
advise the agency of these cases, and to submit, as appropriate,
``Geriatric use'' labeling that reflects and communicates these special
concerns.
FDA agrees with the comments that note that the interaction of drug
responses and the aging process can vary widely among individuals. As
with labeling for any age group, ``Geriatric use'' labeling is no
substitute for the sound medical judgment of the prescriber, who must
keep in mind individual responses to drug therapy.
7. Several comments questioned the scope of the review a
manufacturer would have to undertake to obtain all ``available
information,'' as described in the preamble to the proposed rule. The
comments claimed that the required review would be too broad in scope,
impossible to complete, and would yield irrelevant or useless
information. In particular, the comments objected to the use of
information obtained from FDA's Spontaneous Reporting System (now the
Medical Products Reporting Program or MedWatch) for adverse drug events
as the basis of labeling statements, and suggested excluding it from
the scope of review. Specifically, these comments requested that the
evaluation reflect information from the following: (1) All controlled,
clinical trials contained in the new drug application; (2) other
controlled, clinical trials in the applicant's possession that are
reasonably relevant to the use of the drug in older patients; (3)
postmarketing studies or published literature that specifically concern
the use of the drug in older patients; and (4) pharmacokinetic and
pharmacodynamic studies that have been conducted in the elderly.
The agency has considered the scope of ``available information'' in
light of the recommendations made in these comments. Aside from the
suggestion that MedWatch information not be required, the comments
support the same review of information as set forth in the proposal. In
order for ``Geriatric use'' labeling to be a meaningful prescribing
tool, it must reflect a comprehensive review of a broad range of
information sources. The agency believes that the scope of the review
appropriately includes information both in the applicant's possession
and available through a search of professional literature or published
studies that are relevant to an evaluation of the geriatric use of the
drug.
Concerning the inclusion of MedWatch information, FDA regards a
[[Page 45317]]
review of information from this system or from the Vaccine Adverse
Events Reporting System (VAERS) for vaccines as potentially important
in developing comprehensive labeling for the safe and effective use of
the drug in the elderly. The agency fully appreciates the limitations
associated with MedWatch and VAERS data, but believes that this
information when placed in its proper context can in some cases yield
data on the age-relatedness of adverse effects that are interpretable
and valuable. In submitting ``Geriatric use'' information, a
manufacturer should evaluate the merit of particular MedWatch reports
and utilize them appropriately.
8. Several comments argued that the proposed ``Geriatric use''
labeling subsection does not adequately address problems that are
frequently associated with prescription drug use in the elderly. The
comments contended that the labeling statements should discuss the
issue of polypharmacy in the elderly and include specific information
on drug-drug interactions. Another comment asserted that the rule
overlooks the development of ``drug allergies'' and the ``psychological
effects'' of prescription drugs in older patients.
The agency believes that the final rule adequately addresses the
problems most commonly associated with prescription drug use in the
elderly, including those areas cited in the comments. Section
201.57(f)(10)(ii)(C) directs that differences in safety or
effectiveness of a drug in the elderly, or specific monitoring or
dosage adjustment requirements, shall be described briefly in the
``Geriatric use'' subsection and, as appropriate, be discussed in more
detail in the appropriate section of the labeling. In addition, as
stated in Sec. 201.57(f)(10)(iii)(A), data about drug-disease and drug-
drug interactions are ordinarily included in the ``Clinical
Pharmacology'' section (Sec. 201.57(b)) and ``Drug interactions''
subsection of the ``Precautions'' section (Sec. 201.57(f)(4)(i)), and
this information is often particularly relevant to the elderly.
9. Other comments expressed concern that the overall approach of
the prescribed ``Geriatric use'' statements is too general and overly
cautious. In particular, these comments objected to language in
proposed Sec. 201.57(f)(10)(ii)(A), advising that `` * * * [i]n
general, dose selection for an elderly patient should be cautious,
usually starting at the low end of the dosing range * * * '' and to the
caveat in proposed Sec. 201.57(f)(10)(ii)(B) that, although no
differences between older and younger patient responses had been
observed, `` * * * greater sensitivity of some older individuals cannot
be ruled out.'' The comments found these generalizations to be less
than helpful and were concerned that they might cause undue caution by
health professionals, possibly resulting in suboptimal or even
subtherapeutic dosing of elderly patients.
The final rule is intended to provide information to health
professionals about a subgroup of the population that may have a
different response to certain drug products than the population as a
whole. Section 201.57(f)(10)(ii)(A) and (f)(10)(ii)(B) include some
words of caution but are phrased carefully to avoid any implication of
universal application. FDA does not intend that ``Geriatric use''
statements substitute for medical judgment, but FDA intends that
geriatric labeling information be used, along with professional
judgment, as a tool for achieving optimum prescribing practices. The
information on prescription drug use in elderly patients required by
this final rule will assist health professionals in tailoring drug
therapy to the individual needs of patients.
The cautionary tone of Sec. 201.57(f)(10)(ii)(A) and (f)(10)(ii)(B)
reflects the agency's opinion that, in general, the greater likelihood
of impaired excretory function or impaired homeostatic mechanisms in
the elderly does suggest a cautious approach. That caution should not
result in a failure to attain therapeutic goals, even if a period of
adjustment is necessary to determine the optimum dose for individual
patients. If a sponsor believes that particular statements presented in
this provision are not appropriate or relevant, the sponsor, under
Sec. 201.57(f)(10)(vi), may seek permission to omit these statements or
propose an alternative statement.
10. Several comments questioned other specific aspects of the
proposed labeling statements and requirements. The comments questioned
the terms ``sufficient numbers of patients'' and ``enough elderly
patients'' as used in proposed Sec. 201.57(f)(10)(ii)(A) and
(f)(10)(ii)(B), respectively. The comments asked how many patients
would be ``sufficient'' or ``enough'' to determine if a particular
labeling statement applied. One comment asked if ``enough elderly
patients'' meant enough to reveal differences that are clinically
significant or statistically significant.
The question of a sufficient number of subjects arises when
analysis shows no difference between younger and older subjects but the
small number of subjects available for analysis precludes any real
conclusions about the population as a whole. In such cases, as stated
in Sec. 201.57(f)(10)(ii)(A), a labeling statement would, in part,
state that clinical studies did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently
from younger subjects. Adequacy of subject numbers depends on the
specific comparisons being made and the number of ``events''
(therapeutic effects, adverse events) observed, and there is no number
that will always constitute ``adequate.'' Thus, smaller numbers could
be informative about high-rate events when no difference is found, and
a positive finding (a difference) could arise in any size population
(and be described under Sec. 201.57(f)(10)(ii)(C)).
FDA advises that, with regard to the phrases ``sufficient numbers
of subjects aged 65 and over'' in Sec. 201.57(f)(10)(ii)(A) and
``enough elderly subjects'' in Sec. 201.57(f)(10)(ii)(B), participation
of at least 100 subjects age 65 and older in clinical studies would
allow detection of clinically important differences. This is the number
of elderly subjects recommended in the ICH guideline entitled ``Studies
in Support of Special Populations: Geriatrics.'' Results in elderly
subjects would be compared with those in the (usually) larger number of
younger subjects. The information gathered from available sources, as
described in Sec. 201.57(f)(10)(ii), would ordinarily be descriptive
and not necessarily subject to intense statistical analysis. The
primary purpose of examining the information is to detect substantial
and consistent (across studies) differences in drug response in the
elderly as compared to the overall population. There are problems in
interpretation wherever subsets of the overall trial population are
examined, but these difficulties do not mean the effort should not be
made. Within the limitations of these analyses, however, a finding of
``no difference'' in a population with less than 100 elderly usually
would lead to the statement described in Sec. 201.57(f)(10)(ii)(A),
while a finding of no difference in a larger population could lead to
the statement in Sec. 201.57(f)(10)(ii)(B). A finding of difference,
whatever the population, would lead to labeling as in
Sec. 201.57(f)(10)(ii)(C).
FDA's ``Guideline for the Format and Content of the Clinical and
Statistical Sections of New Drug Applications,`` which refers to subset
analyses, discusses the analysis and presentation of data regarding
drug response in different subsets of the population, and the agency's
``Guideline for the Study of
[[Page 45318]]
Drugs Likely to be Used in the Elderly'' specifically relates this
discussion to the geriatric population. The ICH guideline ``Studies in
Support of Special Populations: Geriatrics'' reflects sound scientific
principles for testing drugs in geriatric populations. FDA recommends
consulting these documents for guidance and encourages individuals to
contact the agency if questions arise on the sufficiency of data to
support ``Geriatric use'' statements not addressed by the guidelines.
11. One comment said that the use of numbers and percentages
required in proposed Sec. 201.57(f)(10)(ii)(B) would be impractical,
stating that a burdensome amount of updating and revision would be
necessary as new information becomes available. The comment suggested
that the statements should address whether ``certain thresholds have
been reached,'' with the agency verifying that the manufacturer has the
numbers to support the statements.
The agency disagrees with the comment. The expression of
percentages or actual numbers of older subjects involved in clinical
studies is an essential part of Sec. 201.57(f)(10)(ii)(B). The
percentage or total number of geriatric subjects precedes the statement
that ``No overall differences in safety or effectiveness were observed
between these subjects and younger subjects, * * * but greater
sensitivity of some older individuals cannot be ruled out.'' This
statement applies where sufficient numbers of elderly subjects have
taken part in studies to reveal a different response between age
groups, but where no differences were detected. The statement suggests
that adjusting dosage recommendations for geriatric patients generally
will not be necessary. To permit such an implication, it is important
to provide practitioners with numbers so that they can weigh the
evidence in relation to the needs of an individual patient.
FDA also does not believe that Sec. 201.57(f)(10)(ii)(B) will be
overly burdensome or require constant updating. This provision provides
for alternative labeling formats using either percentages or the total
number of subjects, age 65 and over and age 75 and over, included in
clinical studies. The comment may have misunderstood this provision
because the percentages refer to the number of subjects included in
clinical studies and, unless additional studies are performed, there is
no need to update or revise the percentages.
The revised implementation plan should permit ample time for
collection and evaluation of data. Manufacturers are urged to contact
the agency if they have questions as to the significance of geriatric
data related to this requirement.
12. Several comments addressed proposed Sec. 201.57(f)(10)(iii)(B),
which requires a statement in the ``Geriatric use'' subsection of the
labeling for drugs that are substantially excreted by the kidney. The
comments asked for more guidance to determine when a drug is
``substantially excreted'' by the kidney. Another comment suggested
that the proposed statement not apply to drugs that are substantially
excreted by the kidney but pose no greater risk to patients with renal
impairment.
Some drugs, such as phenobarbital, are primarily metabolized and
excreted by the liver, while a number of other drugs, such as
diuretics, are primarily excreted by the kidneys. The prescriber's
knowledge and experience with the individual patient will determine the
course of treatment, and FDA does not feel it would be useful at this
time to further quantify this phrase. This provision is intended to
alert practitioners to the fact that adequate kidney function is
important to the optimum safety and effectiveness of the drug product.
If a sponsor believes that none of the requirements described in
paragraphs Sec. 201.57(f)(10)(i) through (f)(10)(v) are appropriate or
relevant, the sponsor must provide reasons for the omission of a
labeling statement and may propose alternative statements as provided
under Sec. 201.57(f)(10)(vi).
13. Another comment recommended that, for drugs that are
substantially excreted by the kidney, FDA require pharmacokinetic and
pharmacodynamic studies in elderly persons.
As stated earlier in this preamble, although the agency encourages
further study of drug effects in the elderly, the rule is not intended
to require additional clinical studies. The ``Geriatric use''
subsection is intended to provide a place in prescription drug labeling
where practitioners can find pertinent information that is already
available from clinical experience and investigations. For example, in
the ``Guideline for the Study of Drugs Likely to be Used in the
Elderly,'' FDA has encouraged assessment of the pharmacokinetic effects
of age and of decreased excretory function.
This final rule does not add new requirements for conducting
geriatric studies. As stated in the preamble to the regulation on
pediatric labeling, various provisions of the Federal Food, Drug, and
Cosmetic Act (the act) and the Public Health Service Act (the PHS act),
and existing regulations authorize FDA to require such studies under
certain circumstances (see section III.C of the document published in
the Federal Register of December 13, 1994 (59 FR 64240 at 64242)).
14. A few comments objected to the use of the formula provided in
the proposed labeling section for calculating creatinine clearance from
a serum creatinine measurement. One comment criticized the specific
formula, Cockroft-Gault (Nephron 16:31-41, 1976), pointing out its
limitations when applied to older patients, and suggested that another
formula, Jelliffe (Lancet 1:975-976, 1971), might be more accurate and
appropriate for a ``Geriatric use'' dosage adjustment. Another comment
suggested that any formula can become obsolete, and proposed that the
regulation not include a formula. The comment said that the agency
should instead provide more general guidance for dosing in the presence
of kidney impairment that would allow for the use of state-of-the-art
assessment tools.
While a survey of available literature indicates that the Cockroft-
Gault formula provides a reasonably good estimate of renal function in
the elderly, the agency agrees with concerns that a specific formula
might be superseded either by a more precise formula or by a new method
for estimating creatinine clearance. Because codification of a specific
formula could result in less flexibility and to accommodate possible
changes in methods of estimating renal function, FDA has deleted the
actual formula from the final rule. The agency, however, wishes to
stress the importance of monitoring renal function by calculating
creatinine clearance. Creatinine clearance can be measured (often
difficult outside the metabolic unit) or can be estimated from a
creatinine clearance measurement using a formula.
IV. Implementation
15. Several comments addressed the proposed implementation plan for
the ``Geriatric use'' labeling requirement. Under the proposal,
manufacturers would have had 1 year from the date of publication of a
final rule to comply with the ``Geriatric use'' labeling requirements
for all products. FDA acknowledged that it may be unable to review all
supplements by this effective date, and stated that it would exercise
its enforcement discretion not to take action against any product that
lacks revised labeling, provided that the applicant has submitted its
proposed labeling changes in a timely manner and otherwise acted in
good faith to comply with the requirements of the final regulation.
[[Page 45319]]
The comments asserted that it would be impossible for companies to
comply with the proposed implementation scheme, and that the agency
would not have the resources to meet approval dates, thus creating new
backlogs in an already over-burdened system. Some comments suggested
other timeframes, such as a 2-year, 3-year, or 4-year effective date.
Other comments recommended that the agency employ a ``staggered
implementation scheme,'' similar to the one used for the implementation
of FDA's physician labeling regulations under 21 CFR 201.59.
FDA agrees that the proposed implementation could pose difficulties
and has revised the plan to reduce the burdens of compliance on both
manufacturers and the agency, while allowing for efficient
implementation of the ``Geriatric use'' labeling requirements. The
agency has considered the comments and has adopted a plan that will
stagger implementation dates. Because some drug classes and drug
products are more likely than others to have a significant impact on
geriatric patients, based on existing labeling, research, and reports
from health care professionals, FDA has provided for staggered
implementation of geriatric labeling requirements to expedite labeling
for certain drug products and drug classes. The implementation plan is
discussed in greater detail in sections IV.A and B of this document.
Certain changes to an approved application require prior FDA
approval of a supplemental application in accordance with
Sec. 314.70(b) (21 CFR 314.70(b)) or Sec. 601.12(b). For those products
not regulated under section 351 of the PHS act (42 U.S.C. 262), changes
to add or strengthen contraindications, warnings, precautions, or
adverse reactions or to add or strengthen dosage and administration
instructions to increase a product's safety (for products other than
biological products) may be put into effect at the time a supplement
covering the change is submitted to FDA in accordance with
Sec. 314.70(c). Labeling changes should be implemented immediately
under Sec. 314.70(c)(2)(i) where additional data or clinical trials
indicate a need to add or strengthen a contraindication, warning,
precaution, or adverse reaction.
Applicants may make some minor labeling changes to products, other
than biological products, without submitting a supplement in accordance
with Sec. 314.70(d). The applicant is to describe such changes in the
annual report.
Applicants need not obtain prior FDA approval of many supplements.
For instance, the statement in the ``Geriatric use'' subsection can
refer to a particular data base. Where the completion of additional
clinical trials and accumulation of data simply strengthen conclusions
reflected in existing statements in the geriatric labeling, revision of
labeling to incorporate these additional numbers may be regarded as
changes to strengthen instructions about dosage and administration.
Under Sec. 314.70(c)(2)(iii), these labeling changes may be implemented
at the time a supplement is submitted to FDA.
For those products regulated under section 351 of the PHS act,
labeling changes must be made in accordance with Sec. 601.12. In the
Federal Register of July 24, 1997 (62 FR 39890), FDA revised the
requirements in Sec. 601.12 for the reporting of changes, including the
reporting of changes in labeling, to an approved license application.
With the revision of Sec. 601.12, manufacturers will be required to
implement and report changes in labeling by the same procedures as
described above for other drugs.
As noted above, persons who have questions regarding such changes
for biological products should contact the appropriate division.
16. One comment argued that manufacturer and agency implementation
burdens would be lessened if the geriatric labeling change applied only
to those drugs approved in the last 3 to 5 years. The comment claimed
that drugs on the market for a longer time (older drugs) have been used
to a sufficient extent that practitioners can determine any unique
problems encountered by the elderly patient, making a ``Geriatric use''
subsection unnecessary.
FDA recognizes that while professional experience with older drugs
may decrease the need for geriatric labeling, there may be less
understanding of the pharmacokinetics of older drugs. Moreover,
previously unrecognized problems may be revealed through new research
or the circumstances under which drug products are used may change.
Such a situation could, for example, result from the discovery of an
adverse interaction in geriatric patients between an older drug product
and one that has recently been approved.
FDA further recognizes that ease of compliance with this final rule
may vary depending on the amount of, and the ability to access,
available information. The implementation plan for this final rule
takes these and other factors into account to minimize burdens for
manufacturers. For instance, the agency expects that the need for a
``Geriatric use'' subsection often may be greatest for recently
approved drugs where there is little collective professional experience
with the drug in older patients. In addition, this information is most
likely to be readily available to manufacturers from a current data
base. Likewise, the agency expects geriatric use information for drugs
that have been marketed for a longer period of time will be more
extensive and more diffuse, and thus more difficult to retrieve and
summarize. Printed reports and clinical data for these drugs may be
scattered and less likely to have been processed and stored in a
computer data base than would be the case for more recently approved
drugs. In these cases, a manual search to gather available information
may be necessary. The implementation plan for this final rule
recognizes that the necessity for such a search is likely to be
directly related to the date of an NME approval or biological product
license approval. Therefore, under the implementation scheme for the
final rule, sponsors will be required to submit geriatric labeling
supplements at an earlier date for more recently approved products than
for products that have been marketed for a longer time. The agency
believes that this implementation plan will allow manufacturers to work
within a reasonable timetable to craft meaningful and usable
``Geriatric use'' labeling.
As discussed in section IV, comment 15 of this document, the
implementation plan has been revised to reduce the burdens of
compliance for both the agency and manufacturers. In revising the
implementation plan, the agency specifically considered and addressed
the concerns associated with drugs that have been marketed for a number
of years. The revised plan gives manufacturers of these drugs longer
periods of time to submit geriatric labeling. At the same time, the
agency has determined that priority should be given to implementation
for certain categories of drugs that either alone or in combination
with other drug products may be more likely to cause problems in
geriatric patients.
Implementation of the ``Geriatric use'' subsection of prescription
drug labeling is as follows:
A. Priority Implementation
Geriatric patients are more likely to have more problems with
certain classes of drugs than with others because of the following:
Age-induced physiological changes in the patient, the narrow
therapeutic range of some drug
[[Page 45320]]
products, and the potential for drug-drug and drug-disease
interactions, as well as other factors. The revised labeling for drugs
subject to priority implementation must be submitted to FDA by August
27, 1998. FDA has therefore selected the following drug classes or drug
products for priority implementation:
1. Psychotropic Drugs:
a. Antidepressants,
b. Anxiolytics,
c. Hypnotics, and
d. Antipsychotics;
2. Nonsteroidal Anti-inflammatory Drugs (NSAID's);
3. Digoxin, Antiarrhythmics, and Calcium Channel Blockers;
4. Oral Hypoglycemics;
5. Anticoagulants; and
6. Quinolones.
B. Implementation Based on the NME or Biological Product License
Approval Date
All drug products not subject to priority implementation, must
comply with this regulation on the basis of the year in which the drug
product's NME (active moiety) or biological product license was first
approved. For combination products, application holders must determine
the approval date of the earliest NME or biological product license.
That earlier date will be the controlling date for implementation
purposes. The date of issuance of a biological product license should
be used for a combination biological product.
FDA is aware that, for a variety of reasons, drug products subject
to approved drug applications are not always marketed. An approved
product may, for example, be withheld from the marketplace for economic
reasons. Later, when conditions change, the drug may be manufactured
and actively marketed. To further lessen the burden of implementing
this rule, FDA will not require geriatric labeling for approved
products that are not currently marketed, including products selected
for priority implementation. If, however, an unmarketed approved drug
product is subsequently marketed, the product must include appropriate
geriatric labeling at the time it is marketed.
The implementation schedule is based on the NME or biological
product license approval date as follows:
1989 to present: Revised labeling due August 27, 1999,
1982 through 1988: Revised labeling due August 28, 2000,
1975 through 1981: Revised labeling due August 27, 2001,
1963 through 1974: Revised labeling due August 27, 2002, and
Prior to 1963: Revised labeling due August 27, 2003.
FDA will notify all holders of approved abbreviated applications of
the changes in the listed product's geriatric labeling and provide
directions on how to incorporate the new text in the labeling. All
holders of approved abbreviated applications for which there is no
reference listed new drug application (NDA) drug product in the
prescription drug product list section of the publication entitled
Approved Drug Products with Therapeutic Equivalence Evaluations are
expected to comply with the implementation plan described in sections
IV.A and B of this document by submitting geriatric labeling.
The agency encourages sponsors to voluntarily implement these
provisions prior to the scheduled implementation date, where feasible.
All supplements submitted under this rule should be noted as
``Geriatric Labeling Supplement'' in the ``Reason for Submission''
block.
V. Legal Authority
This final rule to revise prescription drug labeling regulations to
require a ``Geriatric use'' subsection is authorized by the act and by
the PHS act. Section 502(a) of the act (21 U.S.C. 352(a)) prohibits
false or misleading labeling of drugs, including, under section 201(n)
of the act, failure to reveal material facts relating to potential
consequences under customary conditions of use. Section 502(f) of the
act identifies as misbranded any drug whose labeling does not bear
adequate directions for use, as well as such adequate warnings against
unsafe dosage or methods or duration of administration as are necessary
to protect users. In addition, section 502(j) defines as misbranded
those drugs that are dangerous to health when used in the manner
prescribed, recommended, or suggested in their labeling.
In addition to the misbranding provisions, the premarketing
approval provisions of the act authorize FDA to require that
prescription drug labeling provide the practitioner with adequate
information to permit the safe and effective use of the drug product.
Under section 505 of the act (21 U.S.C. 355), FDA will approve an NDA
only if the drug is shown to be both safe and effective for its
intended use under the conditions set forth in the drug's labeling.
Section 701(a) (21 U.S.C. 371(a)) authorizes FDA to issue regulations
for the efficient enforcement of the act.
Under Sec. 201.100(d) of FDA's labeling regulations, prescription
drug products must bear labeling that contains adequate information
under which licensed practitioners can use the drug safely for its
intended purposes. Section 201.57 describes specific categories of
information, including information for drug use in selected subgroups
of the general population, which must be present to meet the
requirements of Sec. 201.100. In addition, under Sec. 314.125 (21 CFR
314.125), FDA will not approve an NDA unless, among other things, there
is adequate safety and effectiveness information for the labeled
indications.
Section 351 of the PHS act provides legal authority for the agency
to regulate biological products, including labeling. Licenses for
biological products are to be issued only upon a showing that they meet
standards ``designed to insure the continued safety, purity, and
potency of such products'' prescribed in regulations (42 U.S.C.
262(d)). The ``potency'' of a biological product includes its
effectiveness (21 CFR 600.3(s)). Section 351(b) of the PHS act
prohibits falsely labeling a biological product. FDA's regulations at
21 CFR part 201 apply to all prescription drug products, including
biological products.
A drug product not in compliance with Sec. 201.57(f)(10) of this
final rule would be considered to be misbranded and an unapproved new
drug under the act. A noncomplying product that is a biological product
would, in addition, be considered falsely labeled and an unlicensed
biological under the PHS act.
VI. Analysis of Impacts
A. Introduction
FDA has examined the impacts of the final rule under Executive
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612).
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). If a rule has a
significant impact on a substantial number of small entities, the
Regulatory Flexibility Act requires agencies to analyze regulatory
options that would minimize the impact of that rule on small entities.
The agency believes that this final rule is consistent with the
regulatory philosophy and principles
[[Page 45321]]
identified in Executive Order 12866 and the Regulatory Flexibility Act.
The Unfunded Mandates Reform Act (Pub. L. 104-4) requires that
agencies prepare an assessment of anticipated costs and benefits before
proposing any rule that may result in an annual expenditure by State,
local, and tribal governments, in the aggregate, or by the private
sector, of $100,000,000 or more (adjusted annually for inflation). The
rule does not impose any mandates on State, local, or tribal
governments, or the private sector that will result in an annual
expenditure of $100,000,000 or more.
The following discussion presents FDA's assessment of the direct
costs that the rule will impose on the prescription drug industry.
(Further background data are provided in the agency report entitled
``Threshold Assessment of Requirements for Geriatric Labeling'' on file
at the Dockets Management Branch (Ref 3.).)
Comments to the agency by an innovator trade group and one large
innovator firm ( a pharmaceutical firm that develops new drugs)
indicated that the proposed requirements would impose a severe economic
burden. However, these comments provided no written estimates of either
the expected costs or the extent of the research effort that would be
needed to comply with the new provisions. FDA's cost estimates,
therefore, are based on extrapolations from various agency data bases
and plausible assumptions of unit costs. The estimates took into
account the number of labels affected, the estimated availability of
data on the elderly, the estimated availability of computerized data
files, and the amount of existing geriatric labeling. Costs that are
not considered include possible industry efforts to conduct new
clinical trials to generate data on problems unique to the elderly,
possible market shifts among competing products due to changes in
labeling, possible displacement of industry workers due to the costs of
the regulatory requirements, or any other costs beyond direct effects.
Because part of this analysis was prepared in 1993, in support of this
final rule as then drafted, much of the underlying data are several
years old. As explained below, the use of more recent data would
probably project significantly lower costs.
B. Methodology
Estimating the costs to industry required several steps. Data on
numbers of marketed drugs, use by the elderly, the frequency of
labeling supplement approvals, and the existence of geriatric labeling
were available from FDA data files or from previously conducted
studies. Information on the effort required to determine appropriate
label changes and physically change labels was developed from industry
sources and drug reviewing officials within FDA.
1. Number and Age of Products Affected
Two separate analyses were conducted to estimate the number of
products affected by the rule. One analysis estimated the number of
innovator products, and the other, the number of generic products that
would be subject to the rule. An analysis of 1993 IMS America data on
marketed products (data derived from a proprietary data base in the
National Disease and Therapeutic Index maintained by IMS America;
Plymouth Meeting, PA) determined that about 1,578 innovator labels
would be subject to the rule. The actual number of innovator product
labels subject to the rule is probably slightly larger than this number
because the IMS data collection methodology most likely missed very
small volume products. However, because there is no easy way to
estimate the number of omitted products and the degree of error is
thought to be of little practical significance, the counted number of
products was used.
Conversations with industry representatives indicated that the
process of complying with the regulation would be much more difficult
for drugs that have been marketed for a longer time. Products approved
before 1975, and in some cases before 1980, lack computer readable
clinical trial data. Therefore, subgroup analysis of these early data
would require some data entry directly from data recording sheets or
individual patient records. Most clinical trial data used for products
approved since 1985 are already in an easily analyzable form. However,
some data for products approved between 1975 and 1985, although
computerized, would not be in a compatible format. This data would
require additional manipulation before subgroup analysis could be
performed.
Table 1 shows the distribution of the 1,578 innovator products by
year of FDA approval. Based on the trend of automation described
previously, geriatric labeling compliance will become progressively
less expensive with the more recent the date of drug product approval.
Compliance activities for products approved after 1985 will cost less
than for products approved between 1975 and 1984. Products approved
before 1975 will require the greatest expenditure.
Table 1--Number of Innovator Products by Year of FDA Approval
------------------------------------------------------------------------
Year Approvals
------------------------------------------------------------------------
Pre-1975 1,191
1975 to 1984 199
1985 to 1991 188
Total 1,578
------------------------------------------------------------------------
An analysis of abbreviated new drug application (ANDA) approvals
conducted in July 1996, found 2,417 generic products (excluding
different strengths and package sizes) approved for marketing at that
time. The estimated costs for labeling changes in section VI.C of this
document are based on all 2,417 generic products. Although not
insignificant, these costs will be considerably less than the costs for
innovator products.
2. Current Incidence of Geriatric Use
Ideally, the agency would like to have had access to data on
geriatric subjects included in clinical trials for all approved drugs
currently marketed. Such information would have helped determine the
cost and effort required to analyze the data and the likelihood that
the data would prove useful for labeling revisions. Although the
elderly are the largest consumers of certain drug products (e.g., for
the treatment of cancer and cardiovascular disease), in the past
elderly individuals were not commonly included in controlled clinical
trials. Therefore, clinical data on elderly patients for drugs that
have been marketed for many years will be sparse--even for drugs
commonly used by the elderly. Recently, elderly individuals have been
included and identified as a subgroup in clinical trials. Consequently,
more data will be
[[Page 45322]]
available for recently approved products.
Because comprehensive summary data on geriatric subjects in
clinical trials do not currently exist, insight on the incidence of
geriatric use was gained for this analysis from IMS America data on the
number of times a product was mentioned during a doctor/patient visit
or phone conversation. Specifically, annual statistics were generated
(as of the year ending September 30, 1991) on the number of product
mentions for all patients and for patients age 65 and older for all
prescription products. The term ``mention'' means that a specific drug
was recommended, prescribed, or handed to the patient by the physician.
Although the actual number of instances where the patient used the
product may be different than the number of mentions, this analysis
used only the ratio of elderly use to total use, which tended to cancel
out any significant bias.
The raw data on product mentions were summarized into
therapeutically equivalent product groups to account for the 1,578
innovator products marketed in 1991. Geriatric use ranged from nearly
zero to almost 100 percent depending on the product. The analysis
showed that fully half of the innovator products are infrequently used
by the elderly--that is, geriatric patients constitute less than 25
percent of the market share for 789 of the 1,578 products. By contrast,
the elderly constitute more than 50 percent of the market share for a
quarter of the innovator products. This information does not indicate
the percentage of elderly subjects participating in clinical trials. In
recent years, however, geriatric participation in clinical trials for
drug products frequently used by the elderly has increased, and it is
likely that less frequent use of a drug product by geriatric patients
is consistent with low participation by the elderly in clinical trials
for that product.
3. Current Incidence of Geriatric Labeling
In 1989, FDA's Division of Drug Advertising and Labeling conducted
a survey of geriatric labeling covering the top 25 drug products used
by the elderly and all products in the top 12 classes of drugs used by
the elderly. This survey included 425 products including 370 innovator
products and 55 generic products. Because the labeling survey did not
provide geriatric labeling information for all products, and the
geriatric labeling that was found on the surveyed labels did not
typically comply fully with the regulation, FDA has used the survey
results in this analysis as an indicator of potential data
availability, rather than an indicator of compliance with the
regulation.
A detailed comparison of the incidence of the geriatric labeling
data with the geriatric use data showed that products falling in the
middle range of geriatric use have a higher incidence of geriatric
labeling than those products with relatively low and relatively high
geriatric use. (See FDA's ``Threshold Assessment of Requirements for
Geriatric Labeling'' for a graphical illustration of these respective
distributions (Ref. 3).) This finding was unexpected. Particularly
curious was the low incidence of geriatric labeling among the high
geriatric use products. One possible explanation is that a high degree
of geriatric use was assumed, but discussions with industry
representatives could not confirm this hypothesis.
4. Products By Cost Category
As noted in section VI.B.2 of this document, the geriatric use of
75 percent of the products surveyed is less than 50 percent. FDA
assumed that the availability of geriatric data (at least some
analyzable data) would not exceed the incidence of geriatric labeling
found in the previously described labeling survey. For the 25 percent
of the surveyed products for which geriatric use constituted more than
50 percent of total use (high use), the agency assumed that analyzable
data exists for the proportion of products that currently have
geriatric labeling and that at least some data exist for the remaining
products. These distributions led to the construction of four distinct
groups of products based on the degree of geriatric use and the
availability of geriatric data, roughly defined as follows:
(1) Low geriatric use products with no data available (no
incidence of geriatric labeling)--about half of the low elderly use
products.
(2) Low geriatric use products with some data available (at least
some geriatric labeling)--about half of the low elderly use products.
(3) High geriatric use products with limited data available (no
incidence of geriatric labeling)--about half of the high elderly use
products.
(4) High geriatric use products with data available (at least some
geriatric labeling)--about half of the high elderly use products.
These four product label groups, combined with the distribution of
new drug approvals shown in Table 1, provide the basis for FDA's
estimated costs. Table 2 displays the estimated number of product
labels falling into each of 16 cost categories. The two low geriatric
use categories account for three-quarters (three-eights each) of the
products in each column and the high use categories account for one-
fourth (one-eighth each) of the products. The two columns under the
1975 to 1984 heading account for the differences in the way the data
are likely to be stored--half in a form readable by the computer
technology used today and half in a form that will require some effort
to reformat.
Table 2--Innovator Products per Cost Category
----------------------------------------------------------------------------------------------------------------
1975 to 1984
Geriatric Use and Data Pre-1975 ------------------------------------ 1985 to 1991 Totals
Availability Formatted Data Unformatted Data
----------------------------------------------------------------------------------------------------------------
Low Use/ No Data 447 38 37 71 592
Low Use/ Some Data 447 38 37 71 592
High Use/ Limited Data 149 13 12 24 197
High Use/ Some Data 149 13 12 24 197
Totals1 1,191 100 99 188 1,578
----------------------------------------------------------------------------------------------------------------
\1\ Column totals may not add due to rounding
Table 3 provides estimates of the average cost per product of
complying with the regulation for each geriatric use/geriatric data
category shown in Table 2. These values were arrived at after
discussing anticipated industry effort to comply with the regulation
with several industry officials, and after considering FDA's own
experience conducting short-term studies requiring data retrieval, data
formatting, and data analysis. The category costs, therefore, are based
on subjective, but reasonable, estimates of the levels of effort likely
to be involved.
[[Page 45323]]
The highest costs ($24,000) are for drug products approved before
1975 for which extensive geriatric data exist, but such data are not
available in a computer readable format. In this case, at a minimum,
the data would have to be extracted from subject records, entered into
a computer file, and analyzed. The results would be compared with
summary data on all remaining subjects included in the clinical trials
to detect any significant geriatric differences.
Calculations assume that this process, including a literature
search and label and supplement preparation, would take about three
person-months (the amount of time a person works in 3 months) at a
loaded cost of about $50 per person-hour. The least complicated case
($4,000), would be for drug products with no data available on
geriatric patients. A literature search would have to be conducted, the
label revised, and a supplement submitted to reflect the revision. This
process was estimated to take about two person-weeks at the same hourly
rate. The remaining cost categories fall between the two just described
with differing levels of effort requiring differing levels of costs.
Table 3--Innovator Costs Per Product by Product Category
--------------------------------------------------------------------------------------------------------------------------------------------------------
1975 to 1984
Geriatric Use and Data Availability Pre-1975 -------------------------------------------------------------- 1985 to 1991
Formatted Data Unformatted Data
--------------------------------------------------------------------------------------------------------------------------------------------------------
Low Use/ No Data $4,000 $4,000 $4,000 $4,000
Low Use/ Some Data $8,000 $6,000 $8,000 $6,000
High Use/ Limited Data $16,000 $6,000 $8,000 $6,000
High Use/ Some Data $24,000 $6,000 $8,000 $6,000
--------------------------------------------------------------------------------------------------------------------------------------------------------
C. Total Costs of Compliance
The category costs in Table 3 were multiplied by the numbers of
labels shown in Table 2 and summed over all categories to arrive at the
estimated total costs of compliance for the innovator products. These
results are shown in Table 4. Clearly, the greatest costs of the
regulation will be for products approved before 1975. These products
account for $11,314,500, or 84 percent of the total $13,470,000
estimated costs for innovators, as shown in Table 4.
Table 4--Total Innovator Compliance Costs by Category
----------------------------------------------------------------------------------------------------------------
1975 to 1984
Geriatric Use and Pre-1975 -------------------------------------- 1985 to 1991 Totals
Data Availability Formatted Data Unformatted Data
----------------------------------------------------------------------------------------------------------------
Low Use/ No Data $1,786,500 $150,000 $148,500 $282,000 $2,367,000
Low Use/ Some
Data $3,573,000 $225,000 $297,000 $423,000 $4,518,000
High Use/ Limited
Data $2,382,000 $75,000 $99,000 $141,000 $2,697,000
High Use/ Some
Data $3,573,000 $75,000 $99,000 $141,000 $3,888,000
Totals $11,314,500 $525,000 $643,500 $987,000 $13,470,000
----------------------------------------------------------------------------------------------------------------
FDA's estimates the cost of relabeling each generic product to be
$2,000, which accounts for the supplement preparation, the revision and
printing of labels based on changes made to innovator product labels,
and the destruction of small stocks of existing labels. Thus, the total
estimated cost of relabeling 2,417 generic products is $4,834,000,
bringing the total estimated cost of the regulation to $18,304,000.
Manufacturers of innovator products will incur about 74 percent and
manufacturers of generic products about 26 percent of this total.
Although these projections are the best available to the agency,
FDA notes that there are reasons to believe that they overstate the
likely consequences of the rule. For example:
(1) Part of the analysis is based on data that are several years
old, and a greater percentage of products now on the market are thought
to be close to compliance with the final rule. Many recently approved
NME's (those approved since 1991) contain a geriatric labeling section
and already comply with the rule. Moreover, several of the older drug
products that would not comply with the rule have been removed from the
market since 1991.
(2) The rule applies only to approved products that are actually
marketed. This cost analysis, however, assumes that all approved NME's
would be subject to the provisions of the rule. Adjusting for these
differences would substantially reduce the estimated costs to industry.
D. Effects on Small Entities
The affected pharmaceutical companies can be classified into three
industry sectors: Large innovator firms (more than 750 employees),
small innovator firms (fewer than 750 employees), and independent
generic firms (fewer than 750 employees). Within the two innovator
sectors, almost all of the costs will be borne by the large innovators
because large firms sponsor almost all innovator product applications.
Although the occasional product sponsored by a small innovator firm may
require additional research and analysis to support geriatric labeling,
it is unlikely that any one small firm would have more than one or two
such products or that any one of these products would be marketed if it
could not generate over several hundred thousand dollars of revenue per
year. As firms have up to 6 years to comply with the rule for all
products, the estimated one-time cost per product of $6,000 to $24,000
would be extremely low relative to the income generated from such
product(s) during this period.
Most of the small firms affected by the rule will be independent
manufacturers of generic drugs. These firms will incur the cost of
changing the labels of numerous drug products. The following example
illustrates that even the largest of these small firms would not likely
incur significant costs in comparison to company revenues. For example,
one of the largest independent generic manufacturers (350 employees)
held ANDA's in 1995 for approximately 250
[[Page 45324]]
products containing 95 chemical entities. According to their 10-k
filing with the Securities and Exchange Commission, the company
marketed only 37 drug products containing 21 chemical entities in mid-
1995. Therefore, the firm would need to make about 21 label changes at
a total cost of about $42,000. Not all of these costs would be incurred
during the same year, however, because the regulation will be phased in
over a 6-year period. Considering these circumstances, the $42,000 cost
to this small entity would not be a significant fraction of the
company's $200 million in annual sales.
Although the previous example applies to just one firm, given the
estimated $2,000 compliance cost for each marketed generic drug, it is
difficult to construct a scenario in which the cost of the required
label changes could constitute a significant portion of a company's 6-
year revenue stream. As a result, although most manufacturers of
generic drugs will be affected, very few, if any, will incur costs that
are significant in comparison with company revenues. FDA therefore
certifies that this rule will not have a significant effect on a
substantial number of small entities.
VII. Environmental Impact
The agency has determined under 21 CFR 25.24(a)(11) 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.
VIII. 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
following title, description, and respondent description of the
information collection provisions are shown with an estimate of the
annual reporting burden. This estimate includes the time needed for
reviewing instructions, gathering and maintaining the data needed, and
completing and reviewing the collection of information.
Most of the paperwork burden imposed by this final rule will be a
one-time reporting burden associated with gathering data and designing
and manufacturing new labeling that includes a geriatric use subsection
in the ``Precautions'' section of the labeling. The paperwork burden
will vary widely, with the most significant burden, up to 480 hours,
estimated for some innovator drug products approved before 1975. By
contrast, the burden for most generic drug products is estimated at 80
hours or less.
In response to comments and on its own initiative, FDA has made a
number of changes in the final rule to ease the paperwork burden.
First, for the great majority of products affected by this regulation,
the revised implementation dates will permit manufacturers sufficient
time to design and print new labeling and deplete existing stocks of
old labeling before the geriatric subsection is required for the
product. Second, FDA will not require geriatric labeling to be
submitted for approved products that are not currently marketed. Third,
all of the labeling language under Sec. 201.57(f)(10)(ii)(A), and much
of the labeling language under Sec. 201.57(f)(10)(ii)(B) and
(f)(10)(ii)(C) are provided in the regulation. Fourth, as discussed in
section IV of this document, many NME's approved since 1991 contain a
geriatric labeling section and are already in compliance, and the
labeling of a substantial number of drug products approved before 1991
contains some geriatric information.
Title: Geriatric Use Labeling for Human Prescription Drugs.
Description: FDA is amending its regulations governing the content
and format of labeling for human prescription drug products, including
biological products, to include information on the appropriate use of
drugs for persons 65 and older.
Description of Respondents: Business and other for-profit
organizations, including small businesses and manufacturers.
Because labeling was not considered collection of information under
the Paperwork Reduction Act of 1980, the agency did not provide a
paperwork comment period for the proposed rule. However, the agency is
providing an opportunity for public comment under the Paperwork
Reduction Act of 1995, which was enacted after the publication of the
proposed rule and applies to this final rule. 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
October 27, 1997. 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 and approval.
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.
Table 5--Estimated Annual Reporting Burden
----------------------------------------------------------------------------------------------------------------
21 CFR Section Annual no. of respondents Hours per response Total burden hours
----------------------------------------------------------------------------------------------------------------
201.57(f)(10) 290 120 34,800
----------------------------------------------------------------------------------------------------------------
IX. References
The following references have been placed on display in 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. Rochon, P. A., and J. H. Gurwitz, ``Drug Therapy,'' Lancet
346(8966):32-36, 1995.
2. Schneider, J. K., L. C. Mion, and J. D. Frengley, ``Adverse
Drug Reactions in an Elderly Outpatient Population,'' American
Journal of Hospital Pharmacy, 49(1):90-96, 1992.
[[Page 45325]]
3. Food and Drug Administration, ``Threshold Assessment of
Requirements for Geriatric Labeling,'' June 30, 1997.
List of Subjects in 21 CFR Part 201
Drugs, Labeling, Reporting and recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act, the
Public Health Service Act, and under authority delegated to the
Commissioner of Food and Drugs, 21 CFR part 201 is amended as follows:
PART 201--LABELING
1. The authority citation for 21 CFR part 201 continues to read as
follows:
Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 508,
510, 512, 530-542, 701, 704, 721 of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357, 358,
360, 360b, 360gg-360ss, 371, 374, 379e); secs. 215, 301, 351, 361 of
the Public Health Service Act (42 U.S.C. 216, 241, 262, 264).
2. Section 201.57 is amended by adding new paragraph (f)(10) to
read as follows:
Sec. 201.57 Specific requirements on content and format of labeling
for human prescription drugs.
* * * * *
(f) * * *
(10) Geriatric use. (i) A specific geriatric indication, if any,
that is supported by adequate and well-controlled studies in the
geriatric population shall be described under the ``Indications and
Usage'' section of the labeling, and appropriate geriatric dosage shall
be stated under the ``Dosage and Administration'' section of the
labeling. The ``Geriatric use'' subsection shall cite any limitations
on the geriatric indication, need for specific monitoring, specific
hazards associated with the geriatric indication, and other information
related to the safe and effective use of the drug in the geriatric
population. Unless otherwise noted, information contained in the
``Geriatric use'' subsection of the labeling shall pertain to use of
the drug in persons 65 years of age and older. Data summarized in this
subsection of the labeling shall be discussed in more detail, if
appropriate, under ``Clinical Pharmacology'' or the ``Clinical
Studies'' section. As appropriate, this information shall also be
contained in ``Contraindications,'' ``Warnings,'' and elsewhere in
``Precautions.''
(ii) Specific statements on geriatric use of the drug for an
indication approved for adults generally, as distinguished from a
specific geriatric indication, shall be contained in the ``Geriatric
use'' subsection and shall reflect all information available to the
sponsor that is relevant to the appropriate use of the drug in elderly
patients. This information includes detailed results from controlled
studies that are available to the sponsor and pertinent information
from well-documented studies obtained from a literature search.
Controlled studies include those that are part of the marketing
application and other relevant studies available to the sponsor that
have not been previously submitted in the investigational new drug
application, new drug application, biological license application, or a
supplement or amendment to one of these applications (e.g.,
postmarketing studies or adverse drug reaction reports). The
``Geriatric use'' subsection shall contain the following statement(s)
or reasonable alternative, as applicable, taking into account available
information:
(A) If clinical studies did not include sufficient numbers of
subjects aged 65 and over to determine whether elderly subjects respond
differently from younger subjects, and other reported clinical
experience has not identified such differences, the ``Geriatric use''
subsection shall include the following statement:
``Clinical studies of (name of drug) did not include sufficient
numbers of subjects aged 65 and over to determine whether they
respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the
elderly and younger patients. In general, dose selection for an
elderly patient should be cautious, usually starting at the low end
of the dosing range, reflecting the greater frequency of decreased
hepatic, renal, or cardiac function, and of concomitant disease or
other drug therapy.''
(B) If clinical studies (including studies that are part of
marketing applications and other relevant studies available to the
sponsor that have not been submitted in the sponsor's applications)
included enough elderly subjects to make it likely that differences in
safety or effectiveness between elderly and younger subjects would have
been detected, but no such differences (in safety or effectiveness)
were observed, and other reported clinical experience has not
identified such differences, the ``Geriatric use'' subsection shall
contain the following statement:
Of the total number of subjects in clinical studies of (name of
drug), -- percent were 65 and over, while -- percent were 75 and
over. (Alternatively, the labeling may state the total number of
subjects included in the studies who were 65 and over and 75 and
over.) No overall differences in safety or effectiveness were
observed between these subjects and younger subjects, and other
reported clinical experience has not identified differences in
responses between the elderly and younger patients, but greater
sensitivity of some older individuals cannot be ruled out.
(C) If evidence from clinical studies and other reported clinical
experience available to the sponsor indicates that use of the drug in
elderly patients is associated with differences in safety or
effectiveness, or requires specific monitoring or dosage adjustment,
the ``Geriatric use'' subsection of the labeling shall contain a brief
description of observed differences or specific monitoring or dosage
requirements and, as appropriate, shall refer to more detailed
discussions in the ``Contraindications,'' ``Warnings,'' ``Dosage and
Administration,'' or other sections of the labeling.
(iii)(A) If specific pharmacokinetic or pharmacodynamic studies
have been carried out in the elderly, they shall be described briefly
in the ``Geriatric use'' subsection of the labeling and in detail under
the ``Clinical Pharmacology'' section. The ``Clinical Pharmacology''
section and ``Drug interactions'' subsection of the ``Precautions''
section ordinarily contain information on drug-disease and drug-drug
interactions that is particularly relevant to the elderly, who are more
likely to have concomitant illness and to utilize concomitant drugs.
(B) If a drug is known to be substantially excreted by the kidney,
the ``Geriatric use'' subsection shall include the statement:
``This drug is known to be substantially excreted by the kidney,
and the risk of toxic reactions to this drug may be greater in
patients with impaired renal function. Because elderly patients are
more likely to have decreased renal function, care should be taken
in dose selection, and it may be useful to monitor renal function.''
(iv) If use of the drug in the elderly appears to cause a specific
hazard, the hazard shall be described in the ``Geriatric use''
subsection of the labeling, or, if appropriate, the hazard shall be
stated in the ``Contraindications,'' ``Warnings,'' or ``Precautions''
section of the labeling, and the ``Geriatric use'' subsection shall
refer to those sections.
(v) Labeling under paragraphs (f)(10)(i) through (f)(10)(iii) of
this section may include statements, if they would be useful in
enhancing safe use of the drug, that reflect good clinical practice or
past experience in a particular situation, e.g., for a sedating drug,
it could be stated that:
``Sedating drugs may cause confusion and over-sedation in the
elderly; elderly patients generally should be started on low doses
of (name of drug) and observed closely.''
(vi) If the sponsor believes that none of the requirements
described in
[[Page 45326]]
paragraphs (f)(10)(i) through (f)(10)(v) of this section is appropriate
or relevant to the labeling of a particular drug, the sponsor shall
provide reasons for omission of the statements and may propose an
alternative statement. FDA may permit omission of the statements if FDA
determines that no statement described in those paragraphs is
appropriate or relevant to the drug's labeling. FDA may permit use of
an alternative statement if the agency determines that such statement
is accurate and appropriate.
* * * * *
Dated: July 31, 1997.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 97-22701 Filed 8-26-97; 8:45 am]
BILLING CODE 4160-01-F