[Federal Register Volume 60, Number 164 (Thursday, August 24, 1995)]
[Proposed Rules]
[Pages 44182-44252]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-21020]
[[Page 44181]]
_______________________________________________________________________
Part VII
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
21 CFR Part 201, et al.
Prescription Drug Product Labeling; Medication Guide Requirements;
Proposed Rule
Federal Register / Vol. 60, No. 164 / Thursday, August 24, 1995 /
Proposed Rules
[[Page 44182]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 201, 208, 314, and 601
[Docket No. 93N-0371]
RIN 0910-AA37
Prescription Drug Product Labeling; Medication Guide Requirements
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: Inadequate access to appropriate patient information is a
major cause of inappropriate use of prescription medications, resulting
in serious personal injury and related costs to the health care system.
The Food and Drug Administration (FDA) believes that it is essential
that patients receive information accompanying dispensed prescription
drugs. This information must be widely distributed and be of sufficient
quality to promote the proper use of prescription drugs. Therefore, FDA
is proposing performance standards that would define acceptable levels
of information distribution and quality, and to assess supplied
information according to these standards. Preliminary evidence suggests
recent increases in the distribution of privately-produced patient
medication information with dispensed prescriptions. Unfortunately,
estimated distribution rates indicate that significant portions of
patients do not receive information with their medications. FDA
analyses also indicate that there is a high variability in the quality
of this information. FDA believes that, with greater encouragement and
clear objectives, the private sector will substantially improve the
quality and distribution of patient information. Therefore, in concert
with Healthy People 2000, FDA is proposing that private sector
initiatives meet the goal of distributing useful patient information to
75 percent of individuals receiving new prescriptions by the year 2000
and 95 percent of individuals receiving new prescriptions by the year
2006. FDA is proposing two alternative approaches to help ensure that
these goals (performance standards) are achieved. FDA would
periodically evaluate and report on achievement of these goals. If the
goals are not met in the specified timeframes, FDA would either (1)
Implement a mandatory comprehensive Medication Guide program, or (2)
seek public comment on whether the comprehensive program should be
implemented or whether, and what, other steps should be taken to meet
patient information goals. Regardless of the approach chosen, a
mandatory Medication Guide program limited to instances where a product
poses a serious and significant public health concern requiring
immediate distribution of FDA-approved patient information would be
implemented within 30 days of publication of a final rule based on this
proposal. FDA believes that substantial health care cost savings can be
realized by ensuring that consumers obtain the inherent benefits of
proper use of prescription drugs, and by reducing the potential for
harm caused by inappropriate drug use by the patient.
DATES: Comments by November 22, 1995.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr.,
Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT: Louis A. Morris, Center for Drug
Evaluation and Research (HFD-240), Food and Drug Administration, 5600
Fishers Lane Rockville, MD 20857, 301-594-6828.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Introduction
II. Regulatory Background
A. Brief History of Patient Labeling Initiatives and the 1980
Final Rule on Patient Package Inserts
B. The Stay of Effectiveness for the 1980 Final Rule and Its
Subsequent Revocation
III. The Continuing Need for Prescription Drug Information
A. Continuing Problems of Lack of Adherence and Preventable
Adverse Drug Reactions
B. The Benefits of Patient Information
IV. Patient Education Programs Instituted Since 1982
A. NCPIE's Coordinating Function
B. Pharmaceutical Industry Programs
C. Patient Information Supplier Programs
D. Continuing FDA Encouragement
V. Evaluation of Progress
A. FDA Surveys of Oral and Written Patient Information
B. Other Literature About Oral and Written Patient Information
C. The Adequacy of Currently Available Written Information
D. Recent Changes in Pharmacy Provision of Patient Information
VI. Relationship to International Activities
VII. Options Considered
A. Continuation of the Status Quo
B. No Prior FDA Review
C. FDA-Approved Patient Information
D. Distribution-Focused Approaches
VIII. Proposed Options and Implementation
A. Alternative Approaches
B. Performance Standards
C. Evaluation
D. Feedback and Application of Standards
E. Medication Guide Program
IX. Conclusion
X. Description of the Proposed Rule
A. Scope and Implementation
B. Definitions
C. Content of a Medication Guide
D. Format for a Medication Guide
E. Distributing and Dispensing of a Medication Guide
F. Exemptions and Deferrals
G. Miscellaneous Amendments
XI. Legal Authority
XII. Analysis of Impacts
A. Affected Sectors
B. Gross Costs of Compliance
C. Incremental Compliance Costs
D. Small Pharmacy Exemption
E. Regulatory Options
F. Benefits
G. Preliminary Conclusion
XIII. Environmental Impact
XIV. Paperwork Reduction Act of 1980
XV. Federalism
XVI. References
I. Introduction
As the Federal agency responsible for the proper labeling of
prescription drug and biological products, FDA believes that patient
information accompanying these products is essential. It is paradoxical
that products as potentially hazardous as prescription medications are
often dispensed with little more than a ``use as directed'' statement
printed on the container label. Considerably less dangerous products,
such as foods and over-the-counter (OTC) drugs, contain extensive usage
labeling. Many OTC drugs also contain detailed warning labeling.
Further, food labeling serves to warn at-risk individuals of
potentially harmful ingredients. For example, people with
phenylketonuria need to know what foods contain phenylalanine.
Similarly, people with diabetes need to know about sugar content and
people with high blood pressure need to know about sodium content.
FDA believes that improved dissemination of accurate, thorough and
understandable information about prescription drug products is
necessary to fulfill patients' need and right to be informed.
Regardless of any other effects of such information, FDA believes that
the direct educational benefits are sufficient to justify a requirement
that such information be disseminated.
The use of drug and biological products often entails complex risk-
benefit deliberations by prescribers. Yet, there is often little or no
information shared with patients about the treatment's potential
outcomes (i.e., its risks and benefits). In contrast, even simple
surgical procedures, often posing
[[Page 44183]]
less severe risks to the patient, routinely require detailed patient
consent prior to instituting the procedure. Improved education will
enhance patients' ability to understand the benefits and risks of
treatment. This will help patients interact more fully with health care
professionals, thereby enabling patients to take a more active role in
their own health care.
FDA also believes that improved patient education will improve
adherence with prescribed regimens, decreasing unnecessary physician
visits and hospitalizations, and will give patients the information
they need to make truly informed decisions about the drugs they take.
Demographics suggest an increasing need for better information and
counseling about drugs. As the population ages, a greater proportion
will rely heavily on prescription drugs.
It has been over a decade since FDA withdrew regulations mandating
patient package inserts (PPI's) for prescription drugs. (PPI's are
leaflets containing information about a drug product's benefits, risks,
and directions for use.) At that time, the agency stated that mandatory
requirements were unnecessary because the goal of improved patient
education could be achieved through private sector initiatives. During
this period, numerous voluntary programs designed to improve patient
knowledge were launched, many with direct support from FDA and
virtually all with FDA encouragement. In addition, FDA has asked
certain manufacturers to include patient labeling for a few
prescription drugs, where FDA believed that it was essential that
patients were directly informed about the products' risks and
limitations.
In the decade following withdrawal of the PPI regulations, FDA
conducted research to evaluate the progress made by the voluntary
programs. This research has shown minimal progress in improving the
distribution of prescription drug information to patients.
However, very recently there have been new and encouraging signs
that a greater percentage of patients are now receiving written
information with their prescriptions. Many State Boards of Pharmacy
expanded the offer to counsel requirement of the Omnibus Budget
Reconciliation Act of 1990 (OBRA '90) to include all patients, instead
of only Medicaid recipients. Developments in computer technology have
permitted pharmacies more effectively to store and generate written
documents for patients. As a result, there appears to be a sharp
increase in the number of patients receiving computer-generated
information along with their medication.
FDA is encouraged by this recent trend and hopes that: (1) It
continues so that eventually the vast majority of Americans will
receive this vital information, and (2) the information dispensed will
be sufficiently accurate, thorough, and understandable for patients to
properly use and monitor their treatment.
Therefore, in concert with goals established by the Public Health
Service's Healthy People 2000, FDA is proposing performance standards
for the distribution and quality of voluntary written prescription drug
information dispensed to patients. Achievement of these performance
standards would indicate that there is no need for Federal regulations
for a comprehensive mandatory patient information program. Failure to
achieve these performance standards would indicate that a federally-
mandated comprehensive patient information program is necessary to meet
patients' prescription drug information needs. In this document, FDA is
proposing for public comment two alternative approaches that could be
used to encourage achievement of performance standards for quality and
distribution of patient prescription drug information, and to ensure
that those products that pose a serious and significant public health
concern include FDA-approved patient labeling. If the private sector
fails to attain the performance standards in the specified timeframes,
both alternatives would ultimately result in a regulation that would
require that FDA-approved patient labeling be prepared and dispensed to
patients, along with new prescriptions, for most prescription drug
products used primarily on an outpatient basis. The alternatives are
described in detail in section VIII. of this document.
FDA will continue to monitor and evaluate progress toward the
standards for a 5- to 11-year period. During this time, FDA will
continue to work with and encourage private sector efforts to educate
patients. It is FDA's hope and belief that a renewed partnership to
encourage voluntary distribution of prescription drug information,
coupled with feedback and accountability, is the best mechanism for
achieving the goal of improved patient information.
Currently, although numerous sources of prescription drug
information suitable for distribution to patients have been developed,
sizeable proportions of patients have not received adequate written
information. With the advent of patient information software and
installation of computer systems in pharmacy outlets, FDA believes that
acceptable levels of patient information can result from voluntary
efforts if three important conditions are instituted. First, there must
be clearly established and attainable goals. Second, there must be
sufficient incentives to achieve these goals. Third, for selected
products, which cannot be marketed for safe and effective use unless
patients receive clear warnings and directions, patient labeling
(Medication Guides) must be required.
To promote responsibility and accountability, FDA is proposing
performance standards for both the distribution and quality of written
information. Performance standards would permit the flexibility
demanded by an ever-changing, complex, and diverse distribution system
for product information, while ensuring consistency in the application
of standards.
Performance standards would result in less burdensome requirements
on drug manufacturers and dispensers, the flexible adaptation of
product information requirements into broader patient education
programs, and increased utilization of technology to improve storage
and distribution of information. They would further encourage a
partnership approach so that health care providers, drug manufacturers,
patient/consumer groups, and the public sector can work cooperatively
to provide essential information to patients. If these standards are
met, a comprehensive program of FDA-approved patient labeling would not
be required. If these clearly defined and achievable performance
standards are not met within a reasonable time period, FDA will
institute steps to help ensure that the standards will be achieved.
During the hearings that led to the withdrawal of the 1980 PPI
regulations, promises were made by representatives of the
pharmaceutical, medical, and pharmacy communities that if FDA withdrew
the PPI regulations, the private sector would develop a variety of
systems that would meet the goals of the proposed PPI program. These
promises have not yet been fulfilled. In the withdrawal notice, FDA
promised to monitor periodically and evaluate progress made in
providing patients with necessary prescription drug information.
However, the withdrawal notice did not contain specified goals or a
time frame for evaluating progress toward these goals.
While FDA understands and accepts that the development of
grassroots programs will necessarily take longer than a mandatory
program, FDA
[[Page 44184]]
believes that the continuation of an open-ended promise without a clear
time frame for judging success is unacceptable. Therefore, FDA intends
to articulate clear distribution and quality goals and maintain a
specific timetable for judging success. During this time, FDA will only
require FDA-approved patient labeling for certain drugs for which
patient information will greatly facilitate safe and effective product
use.
FDA has found that there are certain prescription drugs for which
patient information is integral to the very marketing of the products.
For these products, patient information is essential to assure that the
drug can be used with acceptable levels of risk. Historically, PPI's
have been instituted by independent regulations (e.g., estrogen
products, oral contraceptives) or on a voluntary basis by the
manufacturer (e.g., Accutane, Halcion, Proscar, Metformin). FDA has
concluded that PPI's were essential for specific drug products based
upon the existence of significant and possibly life-threatening drug
effects about which patients must be warned in order to understand the
risks they are undertaking by using the product or how to minimize
those risks (e.g., by carefully monitoring their response to treatment
for signs of adverse drug effects). These considerations are based upon
a broad safety analysis that includes the indication for the product,
the existence of alternative treatments, and the potential for patient
information to increase the margin of safety in using the product.
While FDA has usually successfully relied upon the good will and
voluntarism of prescription drug manufacturers to institute PPI's when
needed, there have been occasions where manufacturers have refused to
include such information. For example, although one manufacturer of a
particular drug agreed to include a PPI when new information was
uncovered about the possibly fatal interaction of this product with
certain other products, the manufacturer of a similar product in the
same therapeutic class, for which the same drug-interaction warning
applied, did not agree to provide patients with a PPI.
As the agency has done with estrogens and oral contraceptive drug
products, FDA could rely on notice and comment rulemaking to require
patient labeling when necessary. However, it takes a significant amount
of time to propose and finalize such regulations. Therefore, FDA is
proposing rules that would require patient labeling (Medication Guides)
for certain products that pose a serious and significant public health
concern requiring immediate distribution of FDA-approved patient
information.
II. Regulatory Background
A. Brief History of Patient Labeling Initiatives and the 1980 Final
Rule on Patient Package Inserts
Since 1968, FDA has occasionally required that labeling written in
nontechnical language be distributed to patients whenever certain
prescription drugs were dispensed. Generally, FDA required distribution
of such patient information to alert patients of adverse reactions
associated with the drug product or to provide information about the
product's use, contraindications, precautions, and effectiveness.
Examples of such patient-oriented labeling include patient warnings on
isoproterenol inhalation drug products (see 33 FR 8812, June 18, 1968),
oral contraceptive drug products (see 35 FR 9001, June 11, 1970, and 43
FR 4212, January 31, 1978), estrogenic drug products (see 42 FR 37636,
July 22, 1977), and patient labeling requirements for progestational
drug products (see 43 FR 47198, October 13, 1978). (FDA has also
approved patient labeling as part of the labeling requirements for
certain individual drug products. These products include Roferon,
Introna, Nicoderm, Nicorette, Rogaine, Halcion, Norplant System,
Proscar, Accutane, and others.)
During the 1970's, FDA also began evaluating the usefulness of
patient labeling for prescription drug products generally, and studied
ways to present the information to patients. FDA discussed patient
labeling issues with interested and potentially affected persons,
reviewed scientific literature about patients' needs and desires for
patient labeling, conducted research projects to evaluate existing and
model patient labeling pieces, and reviewed existing methods for
communicating drug information to patients (44 FR 40016 at 40018-40025,
July 6, 1979, and 45 FR 60754 at 60755-60758, September 12, 1980). FDA
also published a notice in the Federal Register of November 7, 1975 (40
FR 52075), soliciting public comments to assist the agency in
formulating a policy on patient labeling.
As a result of these initiatives, in the Federal Register of July
6, 1979 (44 FR 40016), FDA issued a proposed rule to require PPI's for
prescription drug products. The proposal would have required
manufacturers or distributors to prepare PPI's for their drug products.
Persons dispensing the drug products would be required to distribute
the PPI's to patients. The PPI would be in nontechnical language, would
not be promotional in tone or content, would be based primarily on the
approved professional labeling, and:
* * * would contain both a summary of the information about the
product and more detailed information that identifies the product
and the person responsible for the labeling, the proper uses of the
product, circumstances under which it should not be used, serious
adverse reactions, precautions the patient should take when using
the product, information about side effects, and other general
information about the proper uses of prescription drug products.
(44 FR 40016 at 40025).
The 1979 proposed rule would have required PPI's to be distributed
to the patient with the drug product except in limited situations, such
as those where the patient was legally incompetent or when
institutionalized.
The 1979 proposal generated approximately 1,500 comments.
Generally, consumers favored the proposed PPI program, but many
licensed practitioners, pharmacists, and drug manufacturers opposed it.
Those in favor of a mandatory PPI program contended that it would: (1)
Promote patient understanding of and adherence to drug therapy; (2)
permit the patient to avoid interactions with other drugs or foods; (3)
prepare the patient for possible side effects; (4) inform the patient
of positive and negative effects from the use of the drug product; (5)
permit the patient to share in the decision to use the drug product;
(6) enhance the patient/licensed practitioner relationship; and (7)
provide the pharmacist and licensed practitioner with a basis for
discussing the use of a prescription drug product with the patient.
Those opposed to the program contended that it would: (1) Encourage
self-diagnosis and the transfer of prescription drug products between
patients; (2) produce adverse reactions in patients through suggestion;
(3) affect adversely the liability of drug manufacturers, licensed
practitioners, and pharmacists; (4) interfere with the patient/licensed
practitioner relationship; (5) impose unnecessary burdens on
manufacturers and pharmacists; and (6) increase the cost of
prescription drug products and health care in general.
After considering the comments, in the Federal Register of
September 12, 1980 (45 FR 60754), FDA published a final rule that
established requirements and procedures for the preparation and
distribution of PPI's. FDA concluded that there was ample evidence that
PPI's can significantly improve the quality of health care obtainable
from using prescription drugs. The agency
[[Page 44185]]
explained that PPI's can reduce the potential for harm to patients
resulting from prescription drug use by enhancing patient compliance
with prescribed regimens and by decreasing inappropriate drug use. In
addition, PPI's can increase patient knowledge about prescription
drugs, thereby promoting their optimal use.
The 1980 final rule required PPI's for human prescription drug
products, and, as in the 1979 proposed rule, required manufacturers and
distributors of prescription drug products to prepare PPI's for their
drug products. The 1980 final rule required distributors and dispensers
to distribute the PPI's to patients receiving a new prescription, but
did not require PPI distribution for prescription drug refills or where
the patient's licensed practitioner specifically directed that the PPI
not be given to the patient (unless the patient specifically requested
it). The 1980 final rule required a PPI to be written in nontechnical
language, be based primarily on the approved professional labeling for
the drug product, and contain: (1) The drug product's established name
or, for a licensed biological product, proper name; (2) a summary of
the information about the drug product; (3) a statement about the
proper use of the drug product, identifying its indications for use;
(4) information which the patient should provide the health
practitioner before taking the drug, including the circumstances under
which the drug product should not be used; (5) a statement of serious
adverse reactions and potential safety hazards; (6) caution
statement(s) that patients should observe, including statements about
risks to pregnant women, nursing mothers, and pediatric patients; (7) a
statement of the risks, if any, to the patient of developing a
tolerance to or dependence on the drug; (8) a statement of what the
patient should do in case of overdose or missed doses; (9) a statement
of clinically significant, frequently recurring, possible side effects;
(10) information about the safe and effective use of prescription drug
products; and (11) information about the drug product's manufacturer,
packer, or distributor, special storage instructions, and the PPI's
date (45 FR 60754 at 60781-60782).
Under the 1980 final rule, manufacturers, distributors, or
dispensers would provide PPI's to ``practitioners, pharmacists, other
dispensers and consumers'' in ``sufficient numbers'' to permit a party
to provide a PPI to each patient receiving a drug product. However, the
1980 final rule also permitted distributors and dispensers to prepare
and use their own PPI's. The 1980 final rule also contained provisions
that would require health care institutions to make PPI's available to
patients upon the patient's request, after notification of
availability. It would not have required PPI's for patients receiving
emergency treatment.
The 1980 final rule provided printing specifications, and stated
that FDA might prepare and make guideline PPI's available for specific
drugs or drug classes. In the Federal Register of September 12, 1980
(45 FR 60785), FDA issued draft guideline PPI's for 10 drugs or drug
classes. The 10 drugs or drug classes were: Ampicillin,
benzodiazepines, cimetidine, clofibrate, digoxin, methoxsalen,
propoxyphene, phenytoin, thiazide, and warfarin. FDA intended to
implement PPI's for these 10 drugs or drug classes over a 3-year
period, after which the agency would evaluate the program's results
before applying the requirements to additional drugs. FDA stated that,
although there was ample evidence of the value of PPI's in helping
patients use drug products safely and effectively, additional studies
were needed to confirm the costs of a mandatory, nationwide PPI
program, to determine whether those costs were reasonable in terms of
the benefits the program provides, and also to verify the best way to
convey to consumers information about prescription drug products. In
the Federal Register of November 25, 1980 (45 FR 78516), FDA announced
that the PPI requirements would be effective on May 25, 1981, for
cimetidine, clofibrate, and propoxyphene. In the Federal Register of
January 2, 1981 (46 FR 160), the agency announced that the requirements
for ampicillin and phenytoin would be effective on July 1, 1981. FDA
issued final PPI's for these five drugs. The agency did not establish
an effective date for the remaining five drugs.
B. The Stay of Effectiveness for the 1980 Final Rule and Its Subsequent
Revocation
On February 17, 1981, the President issued Executive Order 12291
(see 46 FR 13193, February 19, 1981). Section 2 of the Order required
each Federal agency to adhere to certain principles in promulgating new
regulations and reviewing existing regulations. Given this Executive
order, the Department of Health and Human Services and FDA decided to
review the 1980 final rule. In the Federal Register of April 28, 1981
(46 FR 23739), the agency stayed the effective date for the 1980 final
rule because it had received numerous comments stating that PPI's would
be unnecessarily burdensome, costly, and inconsistent with Executive
Order 12291. In the same issue of the Federal Register, FDA stayed the
effective date of the PPI's. FDA indicated that further review of the
PPI program was necessary. On September 30 and October 1, 1981, the
agency held public meetings on the PPI program. The meetings reviewed
FDA's administrative record of the PPI program and the results of a 3-
year study conducted for FDA by the Rand Corp. on PPI's of various
styles and formats.
On the basis of its review, in the Federal Register of February 17,
1982 (47 FR 7200), FDA proposed to revoke the 1980 final rule. The
agency stated that:
The goals of providing patients with information about
prescription drugs can be reached more effectively and efficiently
by cooperating with health professionals and others in both the
public and private sector to expand upon current initiatives in
patient education.
FDA reiterated its belief that informing patients about their
prescription drug products would significantly improve the quality of
their health care, and established a Committee on Patient Education to
coordinate efforts to educate consumers about prescription drugs and to
help private sector initiatives. However, the agency believed that
private sector initiatives would be more effective than a mandatory PPI
program and should be encouraged (see 47 FR 7200 at 7201).
In the Federal Register of September 7, 1982 (47 FR 39147), the
agency issued a final rule that revoked the PPI regulations. The
revocation was based, for the most part, on a decision to permit
voluntary private sector initiatives for distributing patient
information to proceed before a determination was made whether to
impose a mandatory program. The preamble to the final rule listed
several private sector programs underway at that time: (1) The National
Council on Patient Information and Education (NCPIE)--a national
consortium of health professionals, trade representatives, consumer
groups, and Government agencies formed to encourage, coordinate, and
promote private patient education efforts; (2) the American Medical
Association (AMA) distributed Patient Medication Instruction (PMI)
sheets--drug information leaflets to be handed out by licensed
practitioners at the time of prescribing; (3) the American Society of
Hospital Pharmacists, now known as the American Society of Health-
Systems Pharmacists (ASHP), designed publications and audiovisual
[[Page 44186]]
presentations to assist hospital and retail pharmacists in providing
drug information to patients; (4) the United States Pharmacopeial
Convention, Inc. (USP), published several consumer guides to
prescription drugs; (5) the American Association of Retired Persons
(AARP) provided package inserts with prescriptions filled by its mail-
order pharmacy service; (6) Doubleday, Inc., published a consumer's
compendium of drug therapy, which included tear-out sheets about
specific diseases; and (7) many retail pharmacies provided pamphlets,
posters, and books on prescription drugs to pharmacy customers (47 FR
39147 at 39151). Some of these programs and others are discussed in
detail below.
In the preamble to the final rule FDA stated:
*** Although the agency realizes that consumer groups generally
supported the PPI pilot program, it believes that as the voluntary
systems emerge, consumers will receive not only an adequate supply
of prescription drug information from a variety of sources, but
should receive more information about more drugs than would have
resulted from a mandatory system. FDA also believes that the current
regulatory environment demands that these various private sector
efforts be given the opportunity to demonstrate that they can meet
consumers' needs as well, if not better than, a government program.
(47 FR 39147 at 39153).
FDA indicated that, although it was revoking the 1980 regulation,
it intended to work closely with the private sector and with other
public sector agencies to identify and implement methods of providing
information about prescription drugs to consumers, to promote patient
education, to monitor changes in patient awareness of drug information,
and to develop and evaluate the effectiveness of information
dissemination activities. As mentioned above, FDA announced that it was
forming a Committee on Patient Education to coordinate efforts to
educate consumers about prescription drugs and to serve as a catalyst
for private sector initiatives. Specifically, the committee was
established to: (1) Evaluate existing patient information systems as
well as new ones; (2) encourage the formation of, and serve as a
liaison for, outside organizations that are or want to become active in
patient information systems; (3) provide guidance and serve as a
clearinghouse for firms that want to draft prescription drug
information; (4) alert consumers and health professionals to the
usefulness and availability of prescription drug information; and (5)
identify the need for patient information in the use of other FDA-
regulated products. FDA also indicated that it would be conducting
surveys of consumers and health care professionals to evaluate the
availability of adequate patient information on a nationwide basis. FDA
stated that it will assess this information ``over the next several
years.'' FDA also noted: ``The agency believes it would be
counterproductive to the development of private initiatives for it to
develop and publicly announce a course of action it might take should
these private initiatives not materialize'' (47 FR 39147 at 39152).
III. The Continuing Need for Prescription Drug Information
A. Continuing Problems of Lack of Adherence and Preventable Adverse
Drug Reactions
FDA's proposal and final rule extensively reviewed the literature
relating to patient adherence (also known as compliance) with
medication regimens. FDA cited two literature reviews, and completed
its own review of 50 studies, and concluded that noncompliance rates
averaged from 30 percent to 50 percent. FDA also concluded that
improved communication could contribute to improving compliance rates.
Written information was necessary not only to improve adherence rates,
but to inform patients about precautions, contraindications, and
adverse drug reactions, leading to better knowledge about: (1) Using
drugs properly, (2) monitoring reactions to medications for signs of
possible problems, and (3) raising issues with licensed practitioners
and other health professionals to improve communications about
medication. (The term ``licensed practitioner'' in this document refers
to individuals licensed, registered, or otherwise permitted to
prescribe drug products in the course of their professional practice.)
The literature published since 1982 continues to support the
conclusion that patient education can contribute to the prevention of
disease, successful results in treatment, and reduction in medical
costs. However, the need for drug information, education, and
counseling exceeds the current supply, both in quantity and quality,
and much of the available information fails to reach patients who need
it, when they need it, and in the form they need it (Ref. 1). Although
there is a wide variety of sources, the information that actually
reaches most patients is focused primarily on how to use the
medication, with little precautionary or adverse drug information
obtained by most patients (Ref. 2). FDA believes that standard drug
information, when combined with counseling from a prescribing
practitioner, pharmacist, or other health professional should
significantly increase patients' knowledge about the prescription drugs
they are taking, and thereby make prescription drugs safer and more
effective for consumer use.
The literature on patient compliance since 1982 continues to
demonstrate a significant lack of medication adherence. For example, a
1990 report by NCPIE found that about one-third of patients fail to
take their prescribed medications (Ref. 3). An overview of patient
compliance studies reveals that about one-half of prescribed
medications fail to produce the intended therapeutic effect because of
improper use (Ref. 4). Studies examining compliance rates in specific
patient populations suggest that parental noncompliance with drug
therapy prescribed for their children exceeds 50 percent (Ref. 5) and
noncompliance in the elderly ranges from 26 percent to 59 percent (Ref.
8).
Patient noncompliance with prescribed drug regimens can be directly
related to therapeutic failure. For example, missed doses of
antiglaucoma medications may lead to optic nerve damage and blindness.
Missed doses of antiarrhythmic medications may lead to arrhythmia and
cardiac arrest. Missed doses of antihypertensive drug products may lead
to rebound hypertension that is sometimes worse than if no medication
was taken at all. Missed doses of antibiotics may lead to recurrent
infection and also may contribute to the emergence of antibiotic-
resistant microorganisms (Ref. 9).
In addition to addressing problems of adherence, patient
information is also necessary to improve drug use by forewarning
patients about precautions to take to avoid adverse drug reactions.
Further, forewarning is necessary to improve the patient's ability to
monitor reactions to treatment to ensure both that the drug is working
and that it is not causing adverse reactions.
A 1990 report by the Office of the Inspector General found that the
process of patient education can save time by reducing calls or visits
to the licensed practitioner or pharmacist and reducing the number of
hospitalizations that are due to a patient's failure to follow his or
her prescribed drug regimen (Ref. 17). For example, increased visits to
the licensed practitioner may be required if the patient's condition
does not improve because of noncompliance with his or her drug regimen.
If the licensed practitioner is unaware of the
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noncompliance, he or she may increase the patient's dosage or prescribe
additional medicine that may be unnecessary and possibly dangerous. Or
if the patient's condition fails to improve, the licensed practitioner
may order additional diagnostic tests or unnecessary treatments.
Adverse drug reactions also are a continuing problem for the health
care system. Adverse drug reactions occur in 20 percent of ambulatory
patients (Ref. 10), and 2 percent to 5 percent of hospital admissions
are attributed to drug-related illness (Ref. 10). The case/fatality
rate from drug-induced disease in hospitalized patients is 2 percent to
12 percent (Ref. 10). Iatrogenic admissions to medical wards continue
to be a costly result of improper use of prescription drugs.
At a psychiatric service of a Veterans' Administration hospital, 41
admissions over a 4-month period were reviewed for drug-related
problems (Ref. 12). Two percent of admissions were determined to be due
to drug side effects.
Charts of 293 patients admitted over the course of 1 year to a
family medicine inpatient service were reviewed, showing 15.4 percent
of admissions to be drug related (Ref. 13). Six percent of admissions
for the most frequent type of drug-related admissions were for adverse
drug reactions.
Adverse drug reactions among older Americans are even more
frequent. In one study, researchers analyzed 463 charts of geriatric
outpatients (Ref. 14), revealing 107 notations of adverse drug
reactions in the charts of 97 patients (21 percent). Twelve patients
were hospitalized as a direct result of an adverse drug reaction. In
another study (Ref. 8) of 315 geriatric hospitalizations, 16.8 percent
of admissions were determined to be related to adverse drug reactions.
The hospital charge for these admissions was $224,542.
Some proportion of adverse drug reactions will occur regardless of
how carefully patients follow their therapeutic regimens. Although it
is difficult to estimate the proportion of adverse drug reactions and
associated health care costs that can be attributed to nonoptimal
patient adherence, there are some data relevant to this issue. In one
study, 834 admissions to a hospital medical service were reviewed for
iatrogenic disease, and 4 percent were determined to be drug-related
(Ref. 11). Of these, 54 percent were classified as potentially
avoidable, including, for example, overdoses and adverse reactions that
evolved slowly enough that had the problems been reported earlier,
treatment alterations could have been made in ambulatory care settings.
In an earlier study of a sample of 1,000 patients in a community
practice, it was determined that 55 percent of the adverse drug
reactions experienced were unnecessary and potentially preventable
(Ref. 84).
In addition, a 1990 meta-analysis of seven studies that looked at
the association between hospital costs and admissions for problems
specifically caused by noncompliance (strictly defined as overuse,
underuse, or erratic use) indicates that adverse drug reactions caused
by noncompliance constitute costly consequences for the health care
system. This analysis estimated that 5.3 percent of annual hospital
admissions, costing $8.5 billion in 1986, were a direct result of drug
treatment noncompliance (Ref. 15).
B. The Benefits of Patient Information
1. Written Information Increases Patient Knowledge and Satisfaction
Patients who receive written information about their medications
derive increased personal benefits from the information. The most
widely documented of these is increased knowledge.
Industry experts, practitioners, and consumers agree that patients
must have some basic information about prescription drugs to adhere
successfully to their prescribed drug therapy. Many studies have tested
whether the dissemination of written material increases patient
knowledge and understanding. For example, a 1983 study of FDA's PPI for
benzodiazepines concluded that the PPI effectively conveyed written
drug information to patients, and that knowledge and comprehension
varies according to the patient's age, years of education, and reading
environment (Ref. 58). In this study, patients who received written
patient information scored higher on a knowledge and comprehension test
than those who received no written information, and those who completed
the test at home scored higher than those who completed it at the
pharmacy.
It is clear that patients who receive written materials about
medications have increased knowledge about the use and effects of the
medications (Refs. 38, 42, 44, 47, 48, 52, 53, and 59 through 61). In
particular, patients who receive written information show more
knowledge about side effects (Refs. 46, 47, 48, 52, and 58), and are
better able to attribute adverse reactions to the medications they are
taking (Ref. 62). They can more easily discriminate adverse reactions
attributable to the medication from other clinical events (Ref. 63).
Patients who receive written information about their medications
are more likely to make healthy lifestyle changes (Ref. 60). They are
also more satisfied with their treatment (Refs. 33, 42, 47, and 53). In
a review of the literature, one author suggests that provision of
written materials may help patients cope with illnesses over time, as
their modes of coping evolve and the corresponding need for information
changes (Ref. 38).
When presented with written information about their medications,
the vast majority of patients read it, particularly if it is the
initial prescription (Refs. 38, 40, and 44). Reading may be thorough or
superficial (Ref. 45). Patients report reading the printed information
when receiving the first prescription and refills (Ref. 40), and they
may read the materials more than once (Ref. 46).
2. Written Materials About Medications Can Increase Patient Compliance
Even more critical to the health care system, studies of the
effects of providing written medication information to patients
demonstrate that the result can be increased compliance with the
treatment regimen (Refs. 38, 47, and 48). For example, in one study,
outpatients who received a patient information leaflet along with their
penicillin prescription were tested against patients who received no
information at all. Researchers found that a significantly lower
proportion of patients who received the patient information omitted
doses than those who did not receive the information (Ref. 47).
Similarly, researchers concluded that providing written information to
patients with antibiotic prescriptions resulted in significant
improvement in drug taking behavior and in knowledge about the therapy
prescribed (Ref. 48). In a study of psychiatric patients, those
receiving written information were more compliant in their medication
regimens than those not receiving it, and patients receiving both
written and oral information were the most compliant (Ref. 7). In
another study, patients receiving both written and oral information
about their medications were more compliant than those given no
information (Ref. 49). Providing written information has also resulted
in fewer patients stopping treatment (Ref. 50). The results of
increased compliance may be fewer deaths and lower overall costs of
treatment, due to fewer requirements for hospitalizations and
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nursing home admissions (Refs. 4 and 57).
In a broad review of the effects of written information, Ley (Ref.
36) concluded that most of the studies examined found positive effects
resulting from the provision of written information to patients. Out of
32 studies examining effects on knowledge, 97 percent found increases;
of the 25 studies examining compliance, 60 percent found increases; and
in 7 studies examining therapeutic benefit, 57 percent found increases.
It should be noted that ``compliance'' represents a broad range of
behaviors that are difficult to measure (Ref. 51). Several studies that
have sought to measure the effects of written information have failed
to find compliance improved by written information (Ref. 44, 52 through
55). However, in a critical review of the methodologically rigorous
studies of interventions to improve compliance, Haynes et al. (Ref. 56)
concluded that compliance with short-term treatments can be improved by
clear instructions, including written information, as well as by other
interventions. Compliance with long-term treatments is more difficult
to achieve; no single intervention has been shown to be effective on
its own. Rather, improved compliance with long-term regimens requires a
combination of interventions, including clear instructions enhanced by
written information.
3. Written Patient Information Does Not Have Negative Consequences
There has been speculation about the potential adverse effects of
providing information about medications to patients. However, the
studies suggest that written information does not increase reports of
adverse events (Refs. 38, 42, 44, 45, 48, 52, 53, 62 and 91), nor does
oral information (Ref. 65). Two studies that appear to indicate the
opposite are flawed. In one case, the authors admit that the written
information given to patients was inadequate (Ref. 52) and, in the
other, statistical analyses were performed by combining control and
experimental groups inappropriately (Ref. 50). A study of psychiatric
patients was inconclusive on this point (Ref. 66).
Studies do not show evidence of decreased compliance as a result of
written information (Refs. 52 and 66) or evidence of increased anxiety
levels (Ref. 60).
4. Relative Effectiveness of Oral and Written Patient Information
Studies examining the relative effectiveness of printed and oral
medication information are scarce. However, one study shows that
provision of printed information is more effective in increasing
patients' knowledge than oral information, and that a combination of
the two is best. The authors believe that written materials,
particularly those containing information about side effects, may be
more effective and timely and less alarming to patients than oral
information because most side effects do not occur until after the
medication has been taken for a while (Ref. 67). One author suggests
that written information should be used to supplement oral instructions
that should be tailored to meet the particular beliefs, concerns, and
expectations of the individual patient (Ref. 38).
One meta-analysis of the literature, published in 1983 by the
Pharmaceutical Manufacturers Association (PMA) (Ref. 68), merits
special attention because it purports to demonstrate that PPI's about
drugs have almost no effect in improving knowledge or compliance. After
careful review of this analysis, FDA has concluded that the methodology
was flawed and should not be relied upon with regard to the effects of
written drug information on compliance. The details of the study and
FDA's analysis of its methodology follow.
In 1983, PMA funded a grant to assess the literature regarding
mechanisms for improving patients' knowledge and use of prescription
drugs. The authors performed a meta-analysis of studies selected from
the patient education/compliance literature. They examined eight
different strategies to improve patient knowledge and use of
prescription drugs: Counseling, group education, behavior modification,
counseling plus materials, materials alone, memory aids, counseling
plus memory aids, and PPI's. The authors concluded that seven of the
strategies improved patient knowledge and use by 24 percent to 72
percent; however, PPI's had practically no effect in improving patient
knowledge or compliance. They concluded that PPI's were an ineffective
tool to improve patients' knowledge about or use of medication.
FDA staff reviewed the meta-analysis and found its conclusions to
be unsupported by the analysis performed by its authors. There are
major definitional and methodological problems with the authors'
analysis.
First, the inclusion criteria used were not rigorously followed.
Following Kanouse, et al. (Ref. 69), the authors of the meta-analysis
defined PPI's as ``standardized leaflets which accompany a prescription
drug as it is dispensed to the patient and which are designed to inform
patients about a drug's actions, indications, and proper use, and to
alert them about risks, necessary precautions, and possible side
effects.'' However, as a practical matter, the authors sorted studies
meeting this definition into two analytical groups (``materials'' and
``PPI's''). They placed studies in the PPI category if the authors of
that study called the leaflets ``PPI's'' as opposed to ``written''
information. The ``materials'' group included studies that did not
designate the written materials as PPI's.
Second, the PMA authors used a different analytical procedure for
the PPI section of their analysis than for the remaining sections.
Selecting test and control groups for the meta-analysis is a vital
aspect of this type of analysis because it seeks to estimate the effect
size of the difference between these groups. For all but a few studies
examined in the meta-analysis, a group of subjects that received an
intervention (e.g., counseling) was compared to a group that did not
receive the intervention (e.g., no counseling). However, for the PPI
analysis in 27 of the 28 studies examined, the test group was compared
to a group that received an alternative version of that PPI. Thus, for
PPI's, the authors compared intervention to intervention rather than
intervention to control.
The 27 PPI studies included in the meta-analysis were from FDA-
funded studies that had been conducted by the Rand Corp. These Rand
studies examined 12 different formats for communicating information to
patients for each of three drugs: erythromycin (an antibiotic),
flurazepam (a sleeping pill), and estrogens (for postmenopausal
symptoms). The Rand studies included no-intervention control groups for
erythromycin and flurazepam. For estrogens, the Rand study included a
control group composed of patients receiving the FDA-approved PPI for
estrogens. Citing incompatibility of the data offered by Rand with
meta-analytical procedures, the authors of the PMA-funded study
selected the intervention group that they believed should have
performed worst (i.e., was less sound educationally) to serve as the
control group.
The authors of the Rand studies concluded that PPI's lead to
reliable gains in drug knowledge. This conclusion directly contradicts
the PMA meta-analysis conclusion that was based primarily on Rand study
results. The Rand studies were designed only to compare the effects of
variations in style of information presentation within PPI's. Each of
the PPI's studied by Rand
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was highly similar in content and varied only in format or style.
Therefore, the selection of one of the intervention groups to serve as
a control by PMA researchers was inappropriate and obfuscated
differences Rand researchers observed and reported.
IV. Patient Education Programs Instituted Since 1982
A. NCPIE's Coordinating Function
As described in FDA's final rule that revoked mandated PPI's (47 FR
39147), the major coordinating body for private sector organizations
has been NCPIE. NCPIE is a voluntary organization comprised of
approximately 370 member organizations representing health care
professionals, consumer groups, voluntary health organizations,
pharmaceutical manufacturers, Government agencies, and other health-
related groups. Since its inception in 1982, NCPIE has engaged in
numerous activities to improve the delivery of communication of
prescription drug information to patients and consumers. For example,
NCPIE has coordinated broad scale public service advertising campaigns
targeted at improving medication use among older Americans and
children, sponsors an annual national conference on prescription
medicine information and education, has targeted reports on drug use in
population segments (elderly, pediatric, women), sponsors ``Talk About
Prescriptions Month'' every October, and creates and distributes
educational materials such as the ``Brown Bag Review Kit,'' in support
of the National Brown Bag Medicine Review Program, which NCPIE
developed with support from the Administration on Aging. NCPIE has also
compiled a directory of drug information, citing numerous patient
education resources. These include drug leaflet programs; specialized
pamphlets, newsletters, etc., which are directed to improving use of
specific drugs; books for patients and health professionals; high-tech
or other automated videos, telephone, and computer software;
interactive-computer kiosks, and other audiovisual instructional aids;
compliance reminder systems, aids, and devices; program guides to set
up educational systems; and other patient information and education
systems.
B. Pharmaceutical Industry Programs
In the past decade, the pharmaceutical industry has developed and
distributed drug information to consumers, both directly and through
health professionals.
In the early 1980's, these programs provided health professionals
with leaflets or booklets describing various disease processes and
medications that might be used to treat these conditions (Ref. 20). In
recent years, the industry has begun to prepare numerous additional
materials, ranging from simple brochures to elaborate patient education
kits and programs. Currently, the great majority of pharmaceutical
products prescribed to patients have some patient materials developed
as well.
Recently, pharmaceutical companies have begun the development of
relatively comprehensive patient support programs. Several such
programs have been developed, including the following: Alliance
Program, Good Start Program, Patient Support Program, Wellspring
Service, Partners Program, Growing with Humatrope, The Patient at
Heart, Stay in Control, HealthQuest, Unique Patient Support Program,
Clinical Experience Program, CardiSense, Hands on Health, Seasons, Care
Kits, Asthma Management Program, Total Lifestyle Connection, and
Dialogue. These programs provide a consistent flow of information to
patients initiated on therapy for the target drugs. They provide
information about the product as well as information about the disease
and lifestyle modifications necessary for treatment. As promotional
labeling or advertising, these materials necessitate the inclusion of
labeling information and must meet other regulatory standards.
In the mid-1980's, the pharmaceutical industry began to direct
advertisements to the consumer to promote certain prescription drugs.
These advertisements have taken many different forms. ``Help-seeking''
advertisements encourage consumers to seek professional assistance for
certain conditions, but do not promote a particular product. Reminder
advertisements merely mention a product and its dosage form but give no
other suggestions or representations of how the product is to be used
or its benefits. Institutional advertisements describe the
pharmaceutical company and the work it is doing.
There has also been a significant increase in consumer-directed
advertisements that directly promote a prescription drug product or
group of products and discuss in detail product risks and benefits.
Direct-to-consumer advertising (DTCA) has been placed in consumer
magazines or newspapers for several products, including Actigall,
Cardizem CD, Claritin, Cognex, Estraderm, Felbatol, Habitrol, Hismanal,
Mevacor, Minitran, N.E.E. 1/35, Neurontin, Nicoderm, Nicorette,
Nicotrol, Norplant System, Ortho Novum 777, Premarin, Proscar, Prostep,
Rogaine, Seldane and Seldane-D, and Transderm Scop. FDA reviews DTCA
for these products to ensure that they are not false or misleading and
are in fair balance. However, FDA acknowledges that the rules that
govern the regulation of advertising focus primarily on advertising
geared towards health professionals.
Although individual advertising materials disseminated to consumers
may meet regulatory standards in that they are in fair balance and are
not false or misleading, FDA remains concerned that the overall
practice of DTCA will have cumulative effects of providing patients
with information based primarily on promotional materials furnished by
the pharmaceutical industry, and that this promotional focus will
result in problematic overall perceptions of prescription drugs. For
example, it would not benefit the public health for consumers to
perceive prescription drugs--i.e., potentially dangerous medicines--as
relatively nonserious, or for consumers to believe that
nonprofessionals are competent to make skilled therapeutic decisions.
FDA believes that the availability of quality patient information will
help to counter any unbalanced perceptions of prescription drugs
promoted to the consumer.
C. Patient Information Supplier Programs
During the past 10 years, numerous health professional and consumer
associations and private sector organizations have initiated programs
to educate drug consumers about their prescriptions. FDA has worked to
support these programs through staff support, expert review, and
evaluating research.
1. Major Associn Programs
a. AMA. In 1982, the AMA initiated a program to encourage licensed
practitioner distribution of written patient medication information
(PMI's). AMA's PMI sheets were designed to provide licensed
practitioners with written drug information they could give to a
patient at the time a medication is prescribed. Each PMI consists of a
single sheet of paper, printed on both sides, containing information
about the specific drug or drug class. The instructions are designed to
improve the effectiveness of drug therapy, to reduce the risk of
adverse drug reactions, and to reinforce communication between patient
and licensed practitioner. Specific PMI's are
[[Page 44190]]
based on the drug information leaflets produced by the USP, which are
revised to conform to the PMI format and are then subjected to
additional review by the AMA and other medical consultants. Currently,
there are 101 drug titles, including classes and individual drugs,
offered through the PMI program. This provides coverage of over 1,700
of the most widely prescribed drugs.
Available sales data indicated a recent downturn in the use of
PMI's. While over 84,000 pads (each consisting of 50 sheets) were sold
between July 1, 1987, and June 30, 1988, a steady annual decline in
unit sales resulted in a sales figure of approximately 47,500 the 1993
fiscal year.
b. AARP pharmacy service. The AARP Pharmacy Service program,
Medication Information Leaflets for Seniors (MILS), addresses the
special drug information needs of the elderly. AARP requires its
pharmacies to include the drug information leaflets with the original
and first refill mail-order prescription for each patient. AARP
designed the leaflets in consultation with FDA and geriatric experts.
The leaflets cover between 80 percent and 85 percent of all drugs
dispensed by AARP pharmacies.
In addition to its printed materials, AARP also conducts seminars
concerning the safe and effective use of prescription and over-the-
counter drugs, and the special health care needs of the elderly. For
example, AARP advises its members how to prepare for an office visit,
what information to share with the licensed practitioner and
pharmacist, what information to get about each drug prescribed, and how
to organize a system for taking medicines.
c. Other association programs. Several other voluntary health
organizations have been involved in the development and delivery of
health information to patients. These programs are described in the
NCPIE Directory (Ref. 18). Some of the organizations that have
developed programs include:
(1) American Association of Family Physicians (AAFP): the DUET
program (recently discontinued program providing abstracts for
photocopying and distribution);
(2) American Dental Association: DDIS (Dental Drug Information
Series)--distribute leaflets;
(3) American Academy of Pediatrics: Patient Medication Instruction
Sheets--distribute leaflets;
(4) American Society of Health-Systems Pharmacists: Several
programs, such as MEDTEACH--software program, Medication Teaching
Manual--book, Drug Information Service--health professional reference
book.
2. Selected Private Sector Programs
In addition to these associations, several private sector
information suppliers have developed programs to communicate drug
information to the patient, including the following.
a. USP. USP has developed a drug information data base and prepares
written information. Both the data base and prepared medication
leaflets are used in many patient information programs. For example,
USP distributes drug information leaflets, which can be personalized
for the organization, to State pharmaceutical associations, chain and
independent pharmacies, and large institutions.
USP also produces the ``USP Dispensing Information, Advice for the
Patient'' publication as part of its 3-volume ``USP Dispensing
Information'' (USP DI) series. The ``Advice for the Patient''
publication contains monographs that provide general information (such
as information that the patient should tell his or her licensed
practitioner, nurse, or pharmacist before using the drug product,
proper use of the drug product, storage conditions, precautions, and
adverse reactions) about drug products. These monographs form the basis
of the USP's Patient Drug Education Leaflet program and other programs,
such as the National Association of Retail Druggists' (NARD) Patient
Information Leaflet program. USP DI Patient Education Leaflets are
currently available from USP as preprinted, English-language leaflets
for the 88 drugs or families of drugs most frequently used in
ambulatory care. USP also publishes full text, easy-to-read leaflets.
In addition, abstracts from the USP DI are available to health care
providers who wish to institute their own patient education leaflet
programs. These abstracts are stored on a data base, may be
personalized for the health care provider, and are available in both
English and Spanish.
b. Medi-Span, Inc. Medi-Span, Inc., has developed a drug education
data base consisting of patient-oriented information about prescription
and OTC medications. Drug information is both product and dosage form
specific. Programming by the user or computer software vendor and
integration into the pharmacy, medical records or patient care software
package allows health professionals to print a customized counseling
sheet for the particular drug product.
Medi-Span, Inc., also produces a stand-alone MS-DOS software
version of their patient drug information which allows printing of a
customized patient counseling message for prescription and OTC
medications. This software does not require programming by a software
vendor and is marketed to home health care agencies, retail pharmacies,
consultant pharmacists, physician offices, drug information centers,
and small hospital pharmacies. The software allows for selected
sections of the product information to be printed.
D. Continuing FDA Encouragement
Since the withdrawal of the PPI regulations, every FDA Commissioner
and HHS Secretary has urged private sector health professionals to be
more active in counseling patients about their medications. In 1992,
Commissioner Kessler and several other senior FDA staff renewed this
call for private sector health professional medication counseling,
reinforced by the provision of written information. Professional
journals published several articles publicizing FDA's renewed interest
in increasing the provision of written information to patients (Refs.
92 and 93). In addition, several speeches were delivered to communicate
similar messages. For example:
(1) On March 16, 1992, at the Opening General Session of the Annual
Meeting of the American Pharmaceutical Association (APhA), the
Commissioner challenged pharmacists to renew their commitment to
patient education. After taking note of the House of Delegates' newly
adopted position that ``makes pharmacists responsible for initiating
pharmacist-patient dialogue,'' the Commissioner reviewed the benefits
of patient information and the key role pharmacists play as
gatekeepers.
(2) In his address in June of 1992 at the Biannual Meeting of the
American Nurses Association, the Commissioner asserted that patients
are eager to learn more about medications they are taking and that
nurses should step up their efforts to instruct patients on how to take
their medications properly.
(3) At the National Association of Chain Drug Stores (NACDS)
Pharmacy Conference in the summer of 1992, the Commissioner emphasized
that pharmacists are ideally suited to take the lead in the patient
education effort because of their training and unique position in the
health care system. He also stated that it is inconceivable that a
patient could leave the pharmacy with a new prescription medication and
not have written advice about how to get the maximum benefit from their
medication.
(4) At the USP Open Conference on Patient Education in September
1992,
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the Deputy Commissioner for External Affairs stated that in order to
make patient education more effective, all health professionals need to
become more involved and invested in the process. She stated that the
question should no longer be ``Should I counsel?'' but ``What should I
say?''
(5) In May 1993, at the NCPIE Annual Conference, the Deputy
Commissioner for External Affairs once again challenged health
professionals to do a better job of communicating with patients. She
also predicted that the patient education message would become more
critical as we approve drugs with much more complex risk/benefit
profiles. Further, she stated that patients must understand the risks
and limitations of the products so that they can use the drugs
properly.
In addition, professional staff from FDA's Office of Health
Affairs, Office of Consumer Affairs, Office of Policy, and the Center
for Drug Evaluation and Research have researched and analyzed patient
information and challenged pharmacists, physicians, and nurses to renew
their commitment to patient education. At the same time, through
speeches, participation at professional meetings, site visits, and
articles in professional journals, these agency staff have renewed and
amplified the agency effort to promote communication to patients about
their medications.
V. Evaluation of Progress
As mentioned earlier, in the revocation of the 1980 mandatory PPI
regulation, FDA indicated that it would be conducting surveys to
evaluate the availability of adequate patient information. This section
discusses FDA surveys and other available data that assess the
effectiveness of the private sector initiatives in providing patient
medication information.
A. FDA Surveys of Oral and Written Patient Information
FDA sponsored national telephone surveys of patient receipt of
information about new prescriptions in 1982, 1984, and 1992 (Refs. 22,
23, and 24, respectively). In each survey year, researchers collected
data from approximately 1,000 patients who had received a new
prescription for either themselves or a family member during the 4
weeks before the interview. Researchers asked respondents about their
experiences at the licensed practitioner's office and the pharmacy, and
whether they had gained any drug knowledge independent of those
experiences. In an effort to establish patient drug education trends,
the latter report (Ref. 24) compares data collected from the surveys
over the past 10 years.
1. Experiences at the Licensed Practitioner's Office
a. Oral counseling. When asked whether they received any
prescription drug counseling at the licensed practitioner's office,
approximately 66 percent of patients in each year answered
affirmatively. The surveys asked patients about five specific drug
counseling topics: (1) Directions regarding how much medication to
take, (2) directions regarding how often to take the medication, (3)
information about refills, (4) precautions, and (5) adverse reaction
information. Researchers found no meaningful change in the percentage
of patients whose licensed practitioner voluntarily instructed them how
much or how often to take their medication. Slightly over half of the
respondents in each year received instructions without questioning
their licensed practitioner. Researchers discovered a small gain in
counseling about precautionary information, from 26 percent in 1982 to
33 percent in 1984; the level remained at 33 percent with no increase
experienced between 1984 and 1992. For counseling about adverse
reactions, the rate measured increased from 23 percent (in 1982 and
1984) to 29 percent in 1992. Less than 5 percent of respondents, in
each of the three surveys, received any additional counseling other
than directions for use, refills, precautionary and adverse reaction
information.
The rate at which patients question their licensed practitioners
about their prescriptions has also remained low over the past 10 years;
only between 2 percent and 3 percent ask for directions regarding the
correct use of their prescriptions and 4 percent to 6 percent ask for
refill, precaution, and adverse reaction information. When researchers
examined both spontaneous counseling and spontaneous questioning, the
only meaningful gain in licensed practitioner-patient communication was
in the area of adverse drug reaction counseling. However, even though
this rate increased from 27 percent to 35 percent, only slightly more
than one-third of patients receive any counseling regarding possible
adverse drug reactions.
b. Written information. A comparison of the three surveys reveals
an increase in licensed practitioner dissemination of written drug
information, from 5 percent in 1982, to 9 percent in 1984, to 14
percent in 1992. Seventy-five percent of the 1992 respondents who
received written information said that they received an instruction
sheet, 55 percent of which were preprinted, and 39 percent of which
were printed at the licensed practitioner's office. Overall,
approximately 5 percent of all participants in the 1992 survey received
a personalized, computer-generated brochure or sheet to instruct them
about their prescription medications.
2. Experiences at the Pharmacy
a. Oral counseling. During the past 10 years, fewer pharmacists,
and more pharmacy clerks or cashiers, are distributing prescriptions to
patients at the pharmacy counter. In 1992, 43 percent of consumers
received their prescription from the pharmacist, and 41 percent
received their prescription from a clerk. However, even though the
number of pharmacists distributing drugs to consumers has decreased,
the amount of counseling has increased.
Respondents were questioned about the same five areas of counseling
at the licensed practitioners' office. There has been an increase in
pharmacist counseling in four out of the five prescription education
areas that were tested. In 1992, 32 percent of the patients said that
their pharmacist instructed them about how much or how often to take
their medicine, as compared to between 20 percent and 23 percent in
1982 and 1984. Similarly, there was an increase in refill and
precautionary counseling. The rate for refills increased from 12
percent in 1982 to 18 percent in 1992, and for precautions from 8
percent in 1982 to 21 percent in 1992. Adverse drug reaction counseling
decreased in 1984 to 9 percent, from 16 percent in 1982. It has
increased since 1984, to 13 percent, but remains below the 1982 level.
Although research indicated gains in pharmacist counseling in four
of five areas covered, analysis of the percentage of patients who
obtain counseling about any of the topics covered indicates that this
percentage has remained stable over the years. This suggests that
patients obtaining counseling at the pharmacy are more likely to obtain
a broader overview of topic coverage.
The percentage of patients who question their pharmacists has
increased from 2 percent in 1982 to 5 percent in 1984 to the 7 percent
to 9 percent range in 1992. The largest gain was made in the area of
patients questioning their pharmacists about adverse drug reactions.
Data indicate that the type of verbal information that pharmacists
are most likely to give reinforces the licensed practitioner's
instructions on how often and how much medicine to take. In other
words, although the data indicate
[[Page 44192]]
an increase in pharmacist counseling, patients are receiving redundant
information. On the other hand, the increase in patient-initiated
questioning resulted in patients receiving information at the pharmacy
that they had not received at the licensed practitioner's office.
b. Written information. Respondents were asked if they received any
written information furnished with the medicines aside from the label
information on the medication container. The percentage of respondents
answering affirmatively has increased over the three surveys.
Specifically, 32 percent of patients reported receiving written drug
information in 1992 as compared to 26 percent in 1984 and 16 percent in
1982. The type of additional information ranged from sticker labels
affixed to the container to brochures and information sheets. Examining
the particular form of information provided in the 1992 survey
indicated that, overall, 23 percent of subjects reported receiving
informational brochures or instructions (more than brief sticker
labels).
FDA's 1992 survey also revealed changes in how written material is
prepared. Technological advances, most notably in the use of personal
computers, led to an increase in the dissemination of computer-
generated information. Overall, 12 percent of patients in the 1992
survey received a computer-generated information sheet at the pharmacy.
3. Ten-Year Trends in Information Distribution
The data from these surveys do not indicate any sweeping changes in
the nature or frequency of information disseminated either by licensed
practitioner or pharmacist. However, the data do indicate some
discernible trends.
Consumers are more likely to receive oral instructions for use and
information about precautions and adverse reactions related to their
medicines today than they were 10 years ago. In addition, patients are
more likely to receive some form of written prescription information
today, especially at the pharmacy, than they were 10 years ago. There
have been some gains in all categories of information disseminated at
the pharmacy, except adverse reaction information. However, a broader
analysis indicates that the gains made in patient counseling are
attributable to an increase in the number of categories of information
disseminated, not to an increase in the number of patients who receive
counseling. Finally, despite overall gains in health professionals'
counseling and disseminating written information, over three-fourths of
all patients in the 1992 survey received no substantial written
prescription information. Further, data from the 1992 survey indicate
that when a drug is initially prescribed and dispensed, approximately
half of all patients receive no forewarning of possible adverse
reactions that they may experience from their medications.
B. Other Literature About Oral and Written Patient Information
1. Patients Continue to Want Written Information
In the 1979 PPI proposal, FDA reviewed five studies in which
consumers were asked about their desire to obtain additional
information about their prescriptions. Three of the studies
specifically addressed patients' desire to obtain printed information
about their medication. The studies indicated that the majority of
patients who were provided written information with their medication
(oral contraceptive users or those in an experimental test of a PPI for
Thiazide drugs) wanted to obtain written information for additional
drugs (86 percent to 97 percent wanted this additional information).
The third study simply asked consumers if they thought it was important
for printed patient information to be provided with prescription drugs.
Sixty-four percent responded affirmatively.
Studies completed after 1979 continue to support the previous
trends that indicate that patients want to know more about their
medications, especially the risks, and that people would like to
receive written information with their prescriptions. A 1982 AARP
survey of people over age 45 indicated that 60 percent of respondents
would like to receive written information with their medication. The
majority of respondents indicated that their licensed practitioner or
pharmacist did not provide written information.
A national survey conducted in 1984 by the Columbia Broadcasting
System also indicated that labels on medication and inserts would be
useful for obtaining information about safety and potential adverse
reactions (83 percent and 74 percent) as well as effectiveness (60
percent and 64 percent) (Ref. 25). Subjects in the survey were asked to
rate 27 categories of information about medication in terms of their
perceived knowledge about that category and how important it would be
to know about that aspect of information. The perceived knowledge gap
(i.e., the difference between ratings of knowledge and perceived
importance) for safety and efficacy of medication was 50 percent (i.e.,
27 percent of the sample believed that they were well-informed about
the safety and efficacy of medications and 77 percent believed that it
was important to be well-informed about this aspect of medication
information).
Another study, conducted by the President's Commission for the
Study of Ethics in Medicine and Biomedical and Behavioral Research
(Ref. 26), found that both licensed practitioners and members of the
public believed that patients should be informed about the potential
adverse reactions of medical treatment. The survey also indicated that
patients and licensed practitioners alike believed that this
information should be delivered spontaneously, without patients having
to ask for the information. The majority of the general population
surveyed (64 percent) also asserted that they should be informed of
serious risks regardless of how likely the risk was to occur.
Other studies, both in this country and abroad, consistently show
that patients want more information about their drugs (Refs. 29, 38,
42, and 43), including information about precautions and interactions
(Ref. 33). In one study, when asked whether they want information
orally, in writing, or both, more patients preferred to have both (45
percent) than preferred only written information (21 percent) or only
oral information (30 percent) (Ref. 43).
2. Limitations of Current Patient Counseling Efforts
The literature since 1982 demonstrates that patients need and want
additional information about their medications. Studies have shown that
licensed practitioners and pharmacists often do not provide information
about drugs to patients (Refs. 27, 28, and 29), including information
about side effects (Refs. 29 through 32), precautions, and interactions
(Ref. 33).
A study published in 1987 revealed that, while over 90 percent of
the patients interviewed had received some information about their drug
treatment from licensed practitioners, nurses, or pharmacists, only 32
percent received counseling regarding adverse reactions (Ref. 29), even
though another study showed that patients rate information about
precautions, drug interactions, and adverse reactions as most important
(Ref. 33). Only 14 percent of patients in the 1987 study received
written information, despite the fact that 74 percent said that written
instructions would be valuable. Despite the great demand for
information, however, only one-third of the patients in this study
[[Page 44193]]
questioned their licensed practitioners about their treatment (Ref.
29).
Two FDA-sponsored studies, one of consumers and one of physicians
and pharmacists, reveal that the professional and consumer groups have
substantially different perceptions of the type and amount of
information provided by licensed practitioners, as well as the
intensity of patients' demand for drug information. Eighty-eight
percent of licensed practitioners surveyed believed their patients were
well or adequately informed about the purpose and use of their
prescriptions. However, patients revealed that only 26 percent received
oral information about side effects from licensed practitioners'
offices (11 percent from pharmacies) and only 32 percent of patients
reported receiving oral precaution information from licensed
practitioners' offices (16 percent from pharmacies). Approximately 60
percent received information about how and when to take the medications
from licensed practitioners and about 25 percent from pharmacists (Ref.
34).
Licensed practitioners may find it difficult to counsel patients
because they are not comfortable in the role of counselor (Ref. 32) or
because medical records do not always contain the information necessary
for them to provide appropriate counseling for individual patients
(Ref. 35). For example, a study that monitored charts of patients who
had been prescribed amiodarone found that only 14 percent of the charts
documented patient education concerning photosensitivity which can be
controlled, at least partially, with a sunscreen (Ref. 31). In another
study, researchers reviewed the charts of hospital patients who had
been prescribed benzodiazepines. Fifty-seven percent of the charts
failed to show whether the patient used alcohol, even though the
introduction of alcohol could result in a life-threatening interaction
(Ref. 35).
When licensed practitioners do provide counseling, information on
side effects is often omitted (Ref. 29), and side effect information,
if given, usually relates to the most frequent, rather than the most
serious, side effects (Ref. 30).
Even if counseling is provided, patients may not remember the
information that is given. In a review of primarily pre-1983 research
on this issue, one author notes that it is well established that
patients forget much of what they are told during medical consultations
(Ref. 36).
Pharmacists, as well as licensed practitioners, often fail to
provide information about medications. In a 1993 nationwide survey of
2,000 consumers, a substantial proportion of respondents stated that
their pharmacists did not regularly tell them how to take their
medications or advise them of possible adverse reactions (Ref. 37).
Almost half of the consumers said they were not told how to take their
medicine. Almost 30 percent reported that their pharmacist never warns
them of common adverse reactions that are bothersome although not
necessarily serious. Nearly half of the consumers responded that their
pharmacist never told them about serious adverse reactions for which
they should contact their licensed practitioner. The author of this
study notes that these results conflict with a survey of pharmacists,
conducted by two pharmacist associations, in which 89 to 98 percent of
pharmacists reported that they orally counsel their patients (Ref. 37).
The disparity between these two surveys may suggest that pharmacists
and consumers have different perceptions about the quality and quantity
of counseling provided by pharmacists. The results of a 1992 Wisconsin
Statewide survey of pharmacy patients are consistent with the
nationwide consumer survey. In this study of persons who recalled the
time their last new prescription was filled, 53 percent had not
received any oral consultation from their pharmacists, and 23 percent
had not received consultation from their prescribers. Nineteen percent
received no consultation from either pharmacists or prescribers. For
new and refill prescriptions combined, 60 percent reported receiving no
oral information from pharmacists and 26 percent reported none from
prescribers. The authors cited comparable findings in other studies
(Ref. 27).
These results are similar to responses given in a 1985 survey, in
which pharmacists reported having provided oral counseling for 52
percent of patients with new prescriptions and for 18 percent of those
with refill prescriptions. The authors concluded that pharmacists
provide oral and written information selectively to patients and this
information is usually not complete. They suggest increased counseling
and the provision of comprehensive leaflets about the medication (Ref.
28).
3. Elderly Patients Have Special Information Needs
In a review of the literature, one author demonstrates that elderly
patients, who are prone to forget or to be confused, and who may be
taking several medications, require special attention when drug
information is given (Ref. 38). Research indicates that 23 percent of
nursing home admissions are attributable to noncompliance with drug
therapy, in part because a gap exists in elderly patients'
understanding of proper medication use (Ref. 4). They frequently do not
remember to take their medications and report receiving little
information about their medications (Ref. 41). One study concluded
that, because almost 75 percent of elderly patients could not remember
receiving oral instructions regarding potential adverse reactions, and
only 14 percent claimed to have received any written information, the
elderly require special medication education that includes both oral
counseling and written reinforcement (Ref. 52).
C. The Adequacy of Currently Available Written Information
Patients report reading written information when they receive it
(Ref. 38). However, currently available written material often is
inadequate. Even when written information is provided to patients, the
material may not be expressed appropriately to communicate the
important information (Ref. 39), and patients often fail to understand
the written materials (Refs. 38 and 40). In addition, written materials
often take the form of auxiliary labels (Ref. 28) that offer a few
directives with no explanation or background information to improve
comprehension and retrieval of the message.
However, with the trend in pharmacy toward computer automation of
label-making and record keeping, there has also been an increase in
electronically-available patient drug information designed to be given
out with dispensed prescriptions. FDA reviewed patient drug information
from eight independent sources that provide information on electronic
media designed to be used by retail pharmacists as an aid to patient
counseling at the time of drug dispensing. These sources were the
American Society of Health-Systems Pharmacists, Clinical Reference
Systems, Ltd., Facts and Comparisons, First Data Bank, Medi-Span, Inc.,
Medi*CHEX, Inc., Pharmex, and the U.S. Pharmacopeia. The accuracy and
comprehensiveness of the patient information for three drugs was
determined by an assessment of consistency with the approved labeling.
The specificity of the information communicated was judged on the basis
of whether the directions for use were clear and whether the risk
information conveyed the significance of the risk, how to recognize
negative
[[Page 44194]]
consequences, and the proper response to take should they occur.
Patient information was gathered from each source for three drugs:
Oral alprazolam (a benzodiazepine), oral amoxicillin (a penicillin),
and oral enalapril (an angiotensin converting enzyme (ACE) inhibitor).
Only four of the eight sources produced drug-specific information for
the three drugs chosen; the other four sources produced therapeutic
class information.
FDA's review found substantial differences between sources in the
quality of information provided. One source included no mention of
indication for any of the three drugs studied. Only two of the eight
sources mentioned both of alprazolam's approved indications (i.e.,
anxiety disorder and panic disorder). On the other hand, the sources
that provided general benzodiazepine information mentioned uses that
are not approved for alprazolam, including the treatment of insomnia,
muscle spasm, convulsive disorders, and symptoms of alcohol withdrawal.
Only two of eight sources mentioned either of alprazolam's
contraindications (i.e., known sensitivity to a benzodiazepine or acute
narrow angle glaucoma). Side effect/risk information tended to be
highly general and nonspecific; the significance of the risks was often
minimized and the serious, but rare risks were often missing. For
alprazolam, all information providers included the common side effects
of drowsiness and dizziness, but four failed to mention any risk
incurred when alprazolam is taken during pregnancy and none of them
described the risk itself (either a birth defect when taken during the
first trimester or withdrawal symptoms in the child at birth).
Unlabeled side effect information (``wormlike movements, tongue
protrusions, chewing motions, and lip smacking'') were reported for
alprazolam by some sources; none of these effects appear in its label.
Only two of the eight sources mentioned amoxicillin's only
contraindication (previous allergic reaction to any of the
penicillins). Only two of the eight warned the patient to be aware of
symptoms that may signal a superinfection with mycotic or bacterial
pathogens.
None of the eight sources mentioned the contraindications for the
use of enalapril, i.e., allergic reactions or swelling (angioedema) on
previous treatment with similar drugs. Two of the sources failed to
warn the patient about symptoms of angioedema, a potentially deadly
allergic reaction. Of the six including such symptoms (i.e., swelling
of face, extremities, eyes, lips, tongue or difficulty in swallowing or
breathing), only one advised the patient experiencing such symptoms to
take no more drug and to seek medical attention immediately.
The analysis did not assess the accuracy of important and relevant
information not derived from the approved labeling. The most common
types of such information were: (1) Directions for what to do in case
of a missed dose, (2) proper storage conditions, (3) directions for
what to do in case of accidental ingestion or overdose, (4) directions
for when to take the drug with respect to meal times. However, there
was little consistency between sources in inclusion of this
information. For example, different sources gave opposing directions
for handling missed doses and for when to take the product in relation
to mealtimes.
The lack of specificity and contextual information found in
information from some of these systems is of special concern. Research
examining the effectiveness of warning labels points to the need for
warning messages to include sufficient context to explain to users why
they should take certain actions or precautions or pay attention to
certain aspects of the product. Standards for warning labels indicate
that, in addition to being conspicuous and understandable to the
targeted population, labels need to get the reader's attention (e.g.,
by use of a signal word), and disclose the potential danger, why it is
important to avoid the danger, and specific instructions regarding how
to avoid it.
Research on warnings provided in consumer-directed advertisements
for prescription drugs indicate that general warnings (e.g., see your
doctor) do not give consumers a sufficient understanding of the risks
inherent in product use. Consumers interpret advice to consult a health
care professional as ``general reassurance'' that the condition is
under sufficient treatment, rather than that ``specific vigilance'' is
needed to protect the consumer from product risks (Ref. 94). Therefore,
nonspecific advice to consult with the health care professional may be
insufficient as a means of communicating risk information.
Searches through a frequently-used patient medication information
data base for products with boxed warnings in the approved labeling
(generally indicating an extremely serious warning) revealed a general
lack of the kind of information that would allow the reader to
understand the reason for or significance of the warning. For example,
despite Hismanal's boxed warning concerning life-threatening heart
arrhythmias that may occur on use with common prescription antibiotics
and antifungals, the advice given was simply to check with the doctor
or pharmacist before taking any new medicine, either prescription or
over-the-counter. The information for Seldane-D, which has the same
boxed warning, added the names of the drugs that cause the
interactions. Neither specified that a potential outcome of mixing
these drugs is a fatal heart attack.
D. Recent Changes in Pharmacy Provision of Patient Information
The most recently analyzed FDA survey of patient receipt of
medication information was conducted at the end of 1992, immediately
prior to the implementation date of the 1990 Omnibus Budget
Reconciliation Act (OBRA '90) (Ref. 70). OBRA '90 requires pharmacists
to offer to counsel Medicaid recipients. Guidelines and requirements
for how to implement this statute have been issued by individual
states. Many states expanded the covered population to include all
patients. In addition, several pharmacy organizations, individual
pharmacies, and drug store chains have been implementing their own
policy regarding prescription drug counseling.
In recent meetings, FDA staff informally discussed the issue of
patient education with representatives from consumer, medical
professional, pharmacy, pharmaceutical industry, and patient
information provider groups, including the National Consumer League,
AARP, NCPIE, AMA, AAFP, ASHP, APhA, NARD, NACDS, Pharmaceutical
Research and Manufacturers Association (PhRMA), USP, and Medi-Span. In
many of these discussions, representatives suggested that the
implementation of OBRA '90, although focused on oral counseling, had
also significantly affected the distribution of written information.
Several of these groups also recently conducted surveys to describe
pharmacist behavior and perceptions concerning printed patient
information. According to a 1993 NARD survey of its members, 92 percent
of independent retail pharmacists responding to the survey reported
that they provide printed patient drug information. NACDS determined
that 95 percent of responding drug store chains reported having a
printed patient information program in place in 1994.
However, these estimates do not allow specification of the type of
printed patient information available.
[[Page 44195]]
Manufacturer-supplied promotional brochures, as well as leaflets that
accompany drug products in unit-of-use packaging (e.g., oral
contraceptive patient labeling) and short labels designed to stick onto
prescription vials would be included in the broad definition of printed
patient information. These surveys were not designed to examine these
distinctions.
The Research Institute of Pharmaceutical Sciences of the University
of Mississippi School of Pharmacy conducted surveys of chain and
independent drug stores in the spring of 1994. In one survey, 77
percent of the pharmacy manager respondents reported using printed
patient information supplied by commercial vendors; 64 percent reported
using printed patient information from pharmaceutical manufacturers;
and 17 percent reported using printed patient information from
nonprofit associations. In a separate survey, 93 percent of responding
community pharmacists indicated that they used printed patient
information. However, only 54 percent of pharmacists indicated that
they give out printed patient information with at least 75 percent of
all new prescriptions dispensed, and only 37 percent give out printed
patient information with at least 95 percent of all new prescriptions
dispensed. Sixty-eight percent of the pharmacists indicated that
computerized patient information was available in their pharmacy.
However, on average, the computerized patient information was reported
being accessed for patient counseling purposes an average of 86 times
per week. In contrast, the average number of prescriptions dispensed
per day was 131, suggesting that, even though available, patient
information systems are not being fully utilized.
However, there is preliminary evidence that the rates of
prescription drug information received by patients has increased
substantially in the past 2 years, based on comparison with the 32
percent of respondents in the 1992 FDA survey who reported receipt of
any written information in addition to the label on the container, and
the 23 percent who reported receiving ``longer'' information sheets and
brochures (not including sticker labels). The new evidence comes from
two recent patient surveys.
First, in July 1994, patients/caregivers who obtained a
prescription from a pharmacy within the past 6 months were surveyed for
the National Association of Boards of Pharmacy (Ref. 95). In this
survey, 64 percent of respondents said that they received printed
materials about their medication from the pharmacy. However, these data
cannot be examined further as a function of how much of this percentage
represents short ``sticker label'' information and how much represents
``longer'' information sheets and brochures. Second, a repeat of the
FDA patient information survey was conducted in December 1994 and
January 1995, with data collection cofunded by the Health Care
Financing Administration. Preliminary data from this survey also
support the occurrence of an increase in distribution of written
information to patients; 58 percent of patients reported receiving some
form of written information at the pharmacy. The rate of dissemination
of ``longer'' information (more than sticker labels) was 55 percent.
VI. Relationship To International Activities
On March 31, 1992, the European Community (EC) adopted a Directive
requiring its member States to refuse an application to place a
medicinal product for human use on the market if the product's user
package leaflet did not comply with the Directive (Ref. 71). The EC
based its mandatory leaflet program on the desirability of uniform
labeling among member countries and on consumer protection. The
Directive states that the leaflets are necessary in order to ensure
that medicinal products are used correctly on the basis of full and
comprehensible information.
A user package leaflet must accompany all human drug products
unless the manufacturer includes the required leaflet information on
the outer or immediate packaging. The EC leaflet must include the
following information:
(1) Identification of the product--Name of the product, active and
excipient ingredients, and pharmaceutical form;
(2) Therapeutic indications--All therapeutic indications are to be
listed unless the authorities find that the listing of certain
indications would have serious disadvantages for the patient;
(3) Information necessary before taking the product--
Contraindications, appropriate precautions for use, and special
warnings, which must include categories for children, breast-feeding
women, the elderly, and patients with special pathological conditions;
(4) Instructions for proper use--Dosage, method and frequency of
administration, any limitations on duration of treatment, action to be
taken in case of overdose, action to be taken in case of missed doses,
and risk of withdrawal, if any;
(5) Description of possible undesirable effects under ordinary
use--Including the action to be taken if the patient experiences an
adverse reaction, with mandatory language directing the patient to
contact his or her licensed practitioner if the patient experiences any
effect not listed on the leaflet;
(6) Expiration--Including a warning not to use after expiration,
instructions on proper storage, and description of visible signs of
deterioration, if any; and
(7) Last revision date of the leaflet.
The user package leaflet may contain pictograms or symbols, but may
not include language or symbols that the authorities regard as
promotional. The language must be clear and understandable, the print
must be clearly legible, and the leaflet must be offered in the
official languages of the country where the product is placed on the
market.
The Directive requires authorities to refuse a marketing
application if the product's leaflet does not comply with the
Directive. All changes to any contents of the leaflet that are covered
by the Directive, except for information relating to the summary of
characteristics, must be submitted to the authorities for approval. The
authorities may exempt a drug product from the Directive if the product
is not intended to be delivered to the patient for self-administration.
Enforcement provisions allow the authorities to withdraw a medicinal
product from the market until its leaflet complies with the Directive.
The Commission of the European Communities is directed to publish
guidelines concerning:
(1) Special warnings for certain categories of medicinal products;
(2) required information relating to self-medication; (3) legibility;
(4) methods to identify and authenticate medicinal products; and (5)
the list of excipients that must be featured on the labeling and the
manner in which they must be indicated.
Countries were directed to take whatever measures necessary to
comply with the Directive before January 1, 1993. The members were
directed to implement the Directive after January 1, 1994. In other
words, any application to place a medicinal product for human use on
the market or to renew a marketing authorization after January 1, 1994,
must include a user package leaflet that complies with the Directive.
Both the EC's leaflet program and FDA's proposed patient
information program share the same patient education goal of increasing
the safe and effective use of prescription drugs. Both patient
information efforts should provide basic information about product
[[Page 44196]]
identification, directions for use, indications, adverse drug
reactions, and precautions. Both programs also require that medication
information for patients be written in understandable language, be
devoid of promotional material, and be legibly printed. Both FDA and
the EC recognize that the role of the printed leaflet is to reinforce
the counseling that patients receive from health care professionals.
VII. Options Considered
FDA considered several alternative approaches that might remedy the
problems associated with inadequate communication of prescription drug
information to patients. From the literature reviewed, it was evident
that a multifaceted, broad-based medication labeling and education
program is needed that has as its central component the communication
of information between health professionals and patients.
At a minimum, understandable information about medications should
be supplied with new prescriptions for most products used without
direct medical supervision. Written information should be designed to
complement and reinforce oral counseling by prescribers and dispensers
and achieve the overall objective of enhancing patient understanding
and use of medications.
FDA examined a number of possible approaches in its consideration
of how best to achieve the desired objectives of enhancing patient
understanding and use of medications. After extensive deliberation and
consultation with concerned consumer groups, pharmaceutical industry
and pharmacy groups, and patient information suppliers, and careful
consideration of the regulatory options, FDA determined that a
combination of regulatory and voluntary efforts would take best
advantage of available expertise and resources. Recent increases in
pharmacy distribution of private-supplier patient medication
information were strongly factored into FDA's analysis.
The remainder of this section describes the various alternative
approaches considered, along with their advantages and disadvantages,
in terms of how they address two components of such systems: the
content of patient information and the distribution system involved. A
major difference in the alternatives is the extent of FDA's role in
determining the content of patient information. FDA's statutory
obligation is to ensure that prescription drugs and biological products
are labeled properly to encourage appropriate use. Traditionally, this
has meant that FDA approves, on a word-by-word basis, labeling (i.e.,
package inserts) for prescription medications. This requires extensive
resources for review and negotiation, and consequently would be
associated with slower implementation. In contrast, deferral of the
responsibility for reviewing content to private sector sources means
that there is no assurance that patients would not receive inaccurate,
incomplete, overly promotional or misleading information.
The alternatives also differ with regard to how patient information
would be distributed. The last five approaches presented focus solely
on the distribution of materials; they do not address content at all.
A. Continuation of the Status Quo
Should FDA decide to take no specific action, it would continue to
require patient labeling only for carefully selected drugs. Production
and distribution of patient information materials would depend
primarily on the private sector.
This system has the advantage of allowing the self-correcting
activities of an open marketplace to produce a wide variety of
materials. Economic burdens are placed on manufacturers, health care
providers, and dispensers only to the extent to which they wish to
participate voluntarily or are compelled to do so because of other laws
or regulations.
The disadvantage of this approach is that it has been in effect for
over a decade and has not adequately improved the flow of information
to patients. FDA has conducted and analyzed three surveys in the last
decade to evaluate the degree to which the private sector has
disseminated information to patients. Despite a variety of private
sector programs and an increasing recognition that patients need and
have a right to information about their medicines, a sizeable
proportion of patients still receive no substantial written
information. Further, initial evaluations indicate that written
information currently disseminated varies widely in quality.
B. No Prior FDA Review
Under this option, the content of patient information would not be
subject to prior review and approval by FDA. However, FDA would
establish general requirements for this information. Under one form of
this option, individuals preparing such information would be required
to submit copies to FDA for review at the time of initial
dissemination. Upon review, if FDA objected to any of the information,
it would request that the information be revised to meet FDA
requirements.
FDA would also require either that manufacturers supply dispensers
with this information or that dispensers obtain or create such
information and supply it to patients at the time of prescription
dispensing.
This alternative has the advantage of an extremely rapid
implementation period. Compliance with such a requirement would ensure
that virtually all products would be covered within a very short period
of time. If the system was imposed upon dispensers, the dispenser could
easily choose a single system that would impose as small a regulatory
burden as possible. Further, as multiple labeling systems would be
developed, the dispenser would have the option of utilizing several
systems simultaneously (selecting a different sheet for each product
from among the differing systems) or selecting from among several
systems to choose the best system to meet the needs of patients.
The major disadvantage of this approach was discussed above.
Specifically, FDA's experience with the review of promotional materials
issued by manufacturers (which utilizes a similar post-distributional
review system), as well as its review of current patient information
systems, suggests that considerable rewriting would be necessary to
ensure consistency with professional labeling, nonpromotional tone, and
lay language. This would also mean that patients might receive
inadequate or misleading information until revisions could be effected.
There would be considerable inefficiencies in the application of FDA
resources because the same information would need to be reviewed for
each of the systems submitted.
Despite these disadvantages, FDA has decided to propose a form of
this general approach as the primary component of the selected option.
It is discussed in more detail in section VIII. of this document.
C. FDA-Approved Patient Information
This approach defines both content and distributional requirements
for Medication Guides, which would be FDA-approved patient information
for most prescription drug products. Product sponsors would be required
to prepare Medication Guides and to submit them to FDA for review and
approval.
Prior FDA review of content has the advantage of ensuring that the
information is consistent with information provided to health
professionals, is nonpromotional, and is
[[Page 44197]]
written in lay language. A uniform format would allow patients to find
needed information easily and increase their ability and willingness to
use the information. Prior FDA review, however, has the disadvantage of
taking a long time to implement because of limited resources. FDA has
estimated that this approach would not be fully implemented for 10
years. In addition, mandated content does not allow for flexibility in
the marketplace. For example, changes to content could not easily be
made to account for changes in the state of knowledge about a product
or the way in which it is customarily used.
Distribution of Medication Guides would also be required.
Dispensers would be required to provide a Medication Guide to each
patient receiving an applicable prescription drug. Manufacturers would
be required to provide the dispenser with ``the means'' to ensure
distribution. Distribution would be required with new prescriptions and
on patient request when receiving a refill. Also considered, but
rejected because of the associated major increase in distribution
costs, was the option of requiring distribution with all (new and
refill) prescriptions.
The advantage of this distribution system is that it would ensure
that all patients receive written information about their medications.
The disadvantage of this system is that drug dispensers, i.e.,
pharmacists, would need to store printed Medication Guides or generate
computerized versions in the pharmacy. Even assuming that computer-
generated Medication Guides quickly became the norm, it would take time
to solve the logistical problem of integrating information from many
different manufacturers into a system usable at the pharmacy level.
D. Distribution-Focused Approaches
These options do not address the content of patient information.
They only describe different systems for distributing patient
information.
1. Unit-of-Use Packaging
This approach would require that patient information be distributed
in ``unit-of-use'' packaging. In this form of packaging, products are
prepackaged in standardized amounts that can be dispensed directly to
patients without the need for pharmacists to count out the specific
number of tablets, capsules, etc., prescribed. The prescription label
simply is applied to the unit-of-use package before dispensing to the
patient. This type of packaging is currently used for certain
prescription drug products dispensed in the United States (e.g., oral
contraceptives, creams and lotions) and for most prescription drug
products dispensed in Western Europe and in other parts of the world.
The advantage of unit-of-use packaging is that minimal time is
needed for the dispenser to retrieve, verify, and dispense patient
information. Except for packaging failures, prepackaging ensures that
the patient will receive medication information with each product
dispensed.
The disadvantage of unit-of-use packaging is that it requires more
space for shipping and storing than other forms of packaging. Although
the technology for unit-of-use packaging exists, it would be very
costly for manufacturers to add unit-of-use packaging to already
existing product lines. Wholesalers and retailers would need to
increase space to store these products.
2. Reference Book At Dispensing Site
This distribution system would require that there be a looseleaf
book located near where medications are dispensed. The book would
contain a compilation of patient information leaflets, kept up-to-date
by an individual at the site. Patients would be able to find the
page(s) within the book that described their medication(s) and read the
information during the time they were waiting for their prescription(s)
or at any other time the book was not being used.
The advantage of this system is that it would reduce the burden on
the dispenser of having to distribute a leaflet to each patient.
Because the information would be read at the pharmacy, there would be a
health professional present to answer any questions patients might have
after reading the material.
There are several disadvantages of such a system. It does not
provide patients with information that can be taken home for reading
and rereading when patients were ready to take their medication. The
system would not be viable for patients who do not pick up their own
medication. Mail-order pharmacies would need to utilize alternative
information systems. The system also requires patients to
``affirmatively seek,'' as opposed to ``passively receive,'' labeling
information. Although this additional search process appears to be
minimal, some patients would need help finding the particular pages
where their medication was listed, space would need to be set aside in
the pharmacy for such a book, and unless patients were guaranteed
privacy, there could be considerable barriers to obtaining information
for those concerned about this issue.
3. Interactive Computer Technology
Using available technology, computer systems could be placed in
pharmacies or physicians' offices to allow patients to view patient
information and print copies if desired. These ``information kiosks''
could also contain additional information, for example, suggestions for
lifestyle changes or general information about how to use medications
wisely.
The advantage of such a system is that only minimal direct input
from the health professional would be needed. It would be available to
anyone wishing to use it, and it could supply patients with additional
information. The interactive technology allows the information to be
focused on a particular patient's needs. The distribution system's
location would also ensure that health professionals would be nearby to
answer questions.
The disadvantage of this system is that not all patients would
receive information about their prescribed medications. Only those
patients with the time, skills, and assertiveness to seek out the
information actively would benefit. This could be a particular problem
for elderly patients who obtain a disproportionately high number of
prescriptions, because they may be intimidated by computer technology.
4. Distributing a Book to Consumers
Under this distribution system, each household in the country would
be provided a book of drug information. The book would be printed each
year and mailed to each household or delivered to prescription
dispensing sites where they could be obtained by a member of each
household that requests a copy. The advantage of such a system is that
it permits a once-a-year distribution of drug information, as opposed
to the distribution on a continuous basis for each new prescription
dispensed. It also provides patients with a convenient storage system
for compiling patient information sheets.
The disadvantage of such a system is that it is extremely
inefficient and costly. The book itself would be quite voluminous (the
most conservative estimate is over 1,000 pages) and therefore costly to
produce, distribute, and store. If provided without charge, one would
expect consumers to be quite liberal in requesting copies, resulting in
numerous copies within individual households; this would be both
wasteful
[[Page 44198]]
and costly. If the book was to be sold, it would provide a financial
barrier for people who could not afford to pay its price. It would need
to be updated yearly at least, quarterly at best, to provide up-to-date
information about new and already approved medications.
5. Telephone Counseling
This distribution option would require that manufacturers,
pharmacists, or the Federal Government establish telephone numbers to
be staffed by health professionals to answer questions about
medications and to send out patient information upon request. Patients
could listen to recordings on a number of topics, speak with
pharmacists about their prescribed medications, and/or request that
written information be mailed or faxed.
The advantage of such a system is that patients could obtain highly
specific feedback and interact more fully with a health professional.
If a single telephone number was established, patients could call it
for ``one-stop health information shopping.'' The system could be self-
supporting if patients were charged for the service (e.g., via a 900
telephone exchange). Technicians and health professionals would not
have to spend time dispensing individual patient information leaflets.
The disadvantages of such a system are that only those patients who
call the number would receive the necessary information. Research has
shown that it is difficult for patients to ask questions without having
sufficient background about the medication (as would be provided by
information provided with dispensed medications). Unless the patient
requests a copy of an information leaflet, this alternative does not
ensure that patients will receive complete and balanced information
(e.g., information about product risks). Charging for the information
would be a barrier for those who could not afford the telephone call.
VIII. Proposed Options and Implementation
FDA is proposing regulations that would require manufacturers to
provide pharmacists and other authorized dispensers with the means to
distribute FDA-approved Medication Guides for their products to help
ensure that patients receive adequate information about their
prescription drugs. However, FDA is proposing two alternative
approaches to how FDA could defer immediate implementation of a
comprehensive Medication Guide program for most outpatient drug and
biological products. These alternatives are explained in detail in this
section.
Regardless of the alternative chosen, FDA is also proposing
regulations that would require FDA-approved Medication Guides for
products that pose a serious and significant public health concern
requiring immediate distribution of FDA-approved patient information.
For these products, the regulations would become effective 30 days
following publication of the final rule. FDA anticipates that about 10
products or product classes would require such patient labeling each
year.
On some occasions, FDA has found it necessary to require that
patient labeling be prepared by the manufacturer for distribution with
the product because the agency believed that it was in the best
interest of the public health for patients to be informed about the
product's risks and benefits. In these instances, the agency believes
that the risks associated with using the product should be carefully
assessed in light of the product's potential benefits for the
individual patient. How the information is specifically presented to
the patient is particularly important to assure that the patient
understands the risks and consequences, including the significance of
proper adherence to directions.
FDA intends to use the following criteria to determine what
products or classes should be considered for FDA-approved Medication
Guides as products that pose a serious and significant public health
concern that requires immediate distribution of FDA-approved patient
information. FDA seeks comments on the appropriateness of these
criteria for selecting products for which FDA-approved patient labeling
could be required.
(a) Products for which patient labeling could help prevent serious
adverse effects. In these cases, the patient labeling would inform
patients about other products or foods which could interact with the
labeled product, certain activities (e.g., exposure to the sun,
driving) which would increase patient risk, or specific early warning
signals indicative of serious adverse effects (e.g., leg pains that
could signal a blood clot).
(b) Products that have significant risks about which the patient
should be made aware.
(c) Products that pose risks in particular patient populations
(e.g., pregnant women, geriatric patients, pediatric patients).
(d) Products for which patient adherence is crucial to either the
safety or efficacy of therapy with the product, and for which patient
labeling would help increase adherence.
In considering these criteria, FDA may also take into account how
many patients use the product. FDA also intends to obtain public input,
either through advisory committee deliberations or other public forums,
concerning the specific products or classes the agency feels should
have FDA-approved Medication Guides. FDA would notify affected
manufacturers by letter if and when one of their products is identified
as posing a serious and significant public health concern that requires
immediate distribution of FDA-approved patient information, and would
give the manufacturer sufficient time to produce a draft Medication
Guide for agency review.
Application for approval of a Medication Guide would be made via
one of two processes, depending on whether the product is already being
marketed or is in clinical development, pending approval. FDA believes
that in some cases a product already would be on the market when a
determination is made that the product poses a serious and significant
public health concern requiring immediate distribution of FDA-approved
patient information. It is often the case that once a product is used
widely in the general population, additional side effects, drug
interactions or other effects may be discovered that were not
identified during clinical trials of the product. For these products,
the manufacturer would submit a labeling supplement to the product's
New Drug Application (NDA). In some cases a serious or significant
public health concern may arise during drug development, prior to
approval. Under these circumstances, the agency may determine that the
benefits outweigh the risks, and will approve the product, only if
patients are made aware of the potential risks. For these products, the
manufacturer would submit a draft Medication Guide as part of the
product's NDA.
The agency does not believe that the requirement of a sponsor to
prepare a Medication Guide for distribution with the product would pose
an undue burden on the sponsor or slow down the approval process. Since
patient labeling would be based on the professional labeling, both
types of labeling can be developed simultaneously. The Information for
Patients section of the professional labeling is already being used by
many sponsors to include the kind of information that would be
appropriate for inclusion in Medication Guides. However, the agency
seeks comments concerning how development of patient labeling could
affect approval time or place an undue burden on sponsors.
[[Page 44199]]
A. Alternative Approaches
Under Alternative A, implementation of FDA's proposed regulations
for a comprehensive Medication Guide program would be deferred if
predetermined standards for the distribution of useful patient
information are met through voluntary programs within specified
timeframes. The agency would periodically evaluate attainment of the
performance standards. Proposed performance standards, timeframes and
the evaluation process are discussed in detail in this section.
Under Alternative B, FDA would only finalize the Medication Guide
program for products that pose a serious and significant public health
concern requiring immediate distribution of FDA-approved patient
information. The comprehensive program, as it relates to other
outpatient products, would not be finalized at this time. Instead, the
agency would incorporate the performance standards into a guidance
document. The agency would also evaluate, as under Alternative A,
whether these performance standards are met in the specified
timeframes. If they are not met, FDA would seek public comment on
whether the comprehensive Medication Guide program, as proposed in this
document, should be finalized and implemented, or whether, and what,
other steps should be taken to meet the patient information goals.
B. Performance Standards
The remainder of this section discusses proposed performance
standards for assessing the effectiveness of voluntary programs in
achieving patient education goals, how performance will be judged
against these standards, and how the results of such evaluations will
be publicly communicated. It is FDA's intention to work with the
private sector to develop reasonable standards that will protect and
promote consumer understanding of the directions, uses, and risks of
medications, and also to provide periodic feedback so that progress can
be monitored and corrective action taken.
As used in this section, the following terms are defined as
follows:
``Goal''--the broad objective to be sought. For example, Healthy
People 2000 specifies the broad goal that 75 percent of patients should
receive useful information.
``Standard or performance standard''--the basic requirement that
will be used to judge the degree to which progress has been made toward
achieving the specified goals.
``Components''--if there are multiple parts or dimensions upon
which performance standards must be judged, the components are an
enumeration of each of the parts of a standard. FDA has proposed seven
components to the useful information performance standard.
``Criteria''--for each of the components of a performance standard,
the basis upon which judgments will be made to determine if the
component has been successfully achieved. In this section, FDA lists
the seven proposed components of usefulness and describes the criteria
that will be used to judge whether each component has been met.
1. Overall Goal
The Public Health Services's (PHS) Healthy People 2000 enumerates a
variety of goals which are intended to focus public and private
resources on specific and achievable outcomes. Recently, PHS proposed
the addition of a new objective, 12.7: ``Increase to at least 75
percent the proportion of people who receive useful information
verbally and in writing for new prescriptions from prescribers or
dispensers.''
This objective recognizes the need for both oral and written
information to be given to patients along with new prescriptions. The
distribution rate of 75 percent is clearly delineated. However, the
goal does not specify what standards should be applied to determine
whether dispensed information is ``useful.''
FDA believes that useful information must be informative and usable
by patients to be deemed acceptable for meeting this goal. In section
VIII.B.3. of this document, FDA further delineates proposed performance
standards that may be used to judge the usefulness of written patient
information.
2. Distribution
As the performance standard for distribution of patient information
for the year 2000, FDA is proposing to use the Healthy People 2000 goal
that at least 75 percent of people receiving new prescriptions are
given useful written patient information. In addition, for the year
2006, FDA proposes that the distribution standard be increased such
that 95 percent of people who receive new prescriptions also receive
useful written patient information.
Generally, FDA envisions that the fulfillment of these standards
would entail the distribution of printed information. However, with
advancing technology, the development of disease management systems,
and the distribution of medication through new distribution channels
(e.g., mail-order pharmacies), new technologies may be developed that
fulfill the purposes of this standard without requiring paper-based
materials. To permit applicability of these standards to a changing
patient information landscape, FDA is proposing the following as a
definition of receipt of patient information: With new prescriptions,
patients must receive permanent, fully portable, and easily accessible
media that describe the prescription drug product.
The person who receives the information would be either the patient
for whom the product was prescribed or the patient's designee. The
information would have to be given to the patient at the dispensing
site without the patient's having to actively search for or select the
information. The information could be physically handed to the patient
or placed in a bag with the prescription in order to meet the
distribution standard. However, information that requires patients to
select from a display or requires a phone call or return of a postcard
would not meet the standard. Permanency of the media means that the
information can be repeatedly referenced and can be stored by the
patient for future use. Fully portable media means that persons
obtaining prescriptions can physically carry the information with them.
Easily accessible media means that the information is in a form that
can be expected to be readily accessed by patients. Information in the
form of a leaflet or brochure would meet the distribution standard, as
would an auditory device that plays the message each time a button is
pressed. Audiotapes, computer disks, videotapes or other media could
potentially meet the standard if the distributor can be assured that
the patient has all the devices necessary in his or her residence to
use the media distributed.
3. Useful Information
In specifying a performance standard for useful patient
information, FDA believes that there are several components that must
be taken into account. Each of these components must be satisfactory
for FDA to determine that patient information is useful. The seven
specific components proposed by FDA include scientific accuracy,
consistency with a standard format, nonpromotional tone and content,
specificity, comprehensiveness, understandable language, and
legibility.
In the section below, FDA further defines each of these components.
FDA invites comments on the appropriateness of these standards,
components, and criteria proposed to judge overall usefulness of
patient information.
[[Page 44200]]
FDA further wishes to acknowledge that the specifics of risk
information disclosure specified in the performance standards described
below may appear to be more detailed than are the specifics of benefits
disclosure. FDA believes that it is important to communicate benefits
information, as long as it is accurate and is not done in an
excessively promotional fashion. FDA believes that the reader will
infer many of the benefits of a prescription drug product from the
disclosure of how the product is used (its indication). For example, if
a product is described as being used to lower high blood pressure, the
inference is that use of this medication will benefit the patient by
lowering his or her blood pressure, along with reducing whatever
additional heart-related risks are associated with uncontrolled
elevated blood pressure. FDA also recognizes that benefits inferences
that need to be made concerning treatment of certain conditions are
more complex and may need to be more specifically defined for the
patient. Further, some conditions are more severely debilitating than
others. In some cases, it may be appropriate to include relatively more
extensive information about the benefits, and to be more reassuring
about the risks, of a product, especially when the benefit to risk
ratio clearly favors use of the medication.
a. Scientific accuracy. (1) Accuracy would be judged by review of
the materials for consistency with FDA-approved labeling. Approved uses
may be summarized in lay terms (e.g., ``treats certain heart
problems'') as opposed to enumerating specific medical indications.
However, limitations should also be noted (e.g., ``treats heart
disorders'' would not be acceptable). The content of certain patient
information may be written to apply to classes of drugs containing
products with different indications. In these instances, uses that do
not apply to the entire class should be qualified (e.g., ``some,'' or
``certain'' products treat * * *).
(2) Qualifications or limitations regarding the use of the product
should be described. For example, if a product is approved for use in
conjunction with a dietary or behavioral regimen, the patient
information should include reference to such a regimen.
(3) Additional uses that have not been approved by FDA should only
be referenced by a general statement (e.g., ``may be used for other
purposes as prescribed by your doctor''). Personalized information for
individual patients relevant to such a use may be added by a health
care provider as a matter of professional practice.
b. Consistency with suggested format. The order and headings used
should follow those specified for Medication Guides in the final rule
(see proposed Sec. 208.22(e)).
c. Nonpromotional tone and content. (1) The language used should be
educational in nature and avoid ``puffery'' or other promotional
terminology. There should be a ``fair balance'' in the description of
benefits and risks. The benefits should be described in terms of the
uses and effects of the individual medication. Discussion of
therapeutic options is acceptable. However, differences among therapies
should not be described in terms of express or implied unbalanced
comparisons of the advantages of the medication (excepting information
supplied for informed consent purposes). For example, phrases such as
``unlike other drugs * * * this drug * * *'' may be perceived as
promotional.
Advertising and labeling information directed to patients or
consumers, distributed by or on behalf of pharmaceutical manufacturers,
must meet the provisions of FDA regulations, including submission for
FDA review.
(2) The information should not be misleading in terms of the
description of individual drug effects or the overall impression
conveyed. Misleading information would include the use of formatting
techniques that emphasize benefits and de-emphasize risks.
d. Specificity. (1) The information provided should enable a
patient to use the product correctly. Proper use includes not only
directions for taking the medication, but also information about
avoiding negative consequences. Information should also be included
regarding proper monitoring of the impact of therapy by correctly
interpreting physical reactions to the drug. This would include, for
example, informing patients when to call their physician if they do not
notice signs of improvement. Risk information should include sufficient
detail for an average patient to understand the significance of the
hazard described. For example, if a drug causes birth defects when
taken in the second or third trimester of pregnancy, users should be
expressly informed that the drug may cause birth defects if used after
the third month of pregnancy. General references, such as ``tell the
doctor if you are pregnant,'' would be insufficient.
(2) Warnings denoting serious or life-threatening effects, even if
rare, should be expressly described. This information should not be
combined with other information in a fashion that reduces communication
of its significance. Additional contextual information should be
provided to help patients understand these important risks. This
contextual information may include statements of the likelihood of
occurrence, the reason why such effects may occur, how to prevent these
effects, how to monitor for early warning signs, and/or what to do if
such effects occur.
e. Comprehensiveness. (1) Information important for the patient to
know should be covered in each of the sections of the suggested format.
However, it need not be detailed or exhaustive. This would include
information necessary for patients to use the drug correctly, to
understand important limitations or precautions, and to know the risks
that may be assumed by taking the drug.
(2) Long lists of common and infrequent side effects need not be
included. The side effects mentioned should include rare, but serious
effects as well as common ones. The side effects may be summarized in
lay language (e.g., ``blood problems'') and need not be exhaustive.
However, the presentation should not diminish communication of the
potential hazard. Further, if long lists are included, they should not
diminish the significance of major warnings or side effects.
f. Understandable language. (1) The information provided should be
clearly written for the average person. FDA will not specify a reading
level due to concerns about the validity of readability tests as
applied to patient drug information. However, the principles of clear
writing, as described in a variety of manuals (Refs. 85, 86, 87 and 88)
should be followed. Technical terminology should be used only if the
terminology is explained and use of the terminology would help the
patient understand the material.
(2) Deletion or degradation of important risk, benefit, or
directions for use information cannot be justified by the need for
language simplification. Additional information, provided through both
print and other media, can be used to help communicate to populations
with literacy problems.
In general, the information should be likely to be understood by
the ordinary individual under customary conditions. While it is clear
that many patients will not be able to read English, FDA would not
consider this ability as a factor in determining information adequacy.
FDA would consider efforts by distributors to communicate with patients
of low literacy as consistent with a determination of overall adequacy.
Thus, distribution of otherwise
[[Page 44201]]
acceptable written materials that utilize simplified language,
pictograms, or other communication techniques would be encouraged.
Similarly, programs in foreign languages, braille, or other forms of
written communication that meet the literacy and information processing
needs and ability of selected patient populations would be encouraged.
g. Legibility. (1) The information presentation should permit an
interested reader to discern the important information. Type size,
white space, characters per inch, contrasting colors, and other graphic
elements should provide sufficient legibility to enable a typical
medication user to read the information. (Note that the typical
medication user is often an elderly person with less than perfect
vision.)
(2) The layout and graphic presentation should invite readership;
interested patients should want to read the material. The graphic
presentation should communicate that the material is usable, readable,
and comprehensible. The layout should not convey the impression that
the material is simply the ``small print'' presented for legal reasons
and unnecessary to read. Nor should it convey the impression that the
reader would be unable to understand the material because it is too
``dense.''
C. Evaluation
Since the revocation of the PPI regulation in 1982, FDA's
evaluation of the extent of distribution of patient information has
relied upon national telephone surveys of people who obtained new
prescriptions for themselves or a family member at retail pharmacies.
This form of research has the advantage of obtaining reports of recent
experiences from a representative sample of subjects. The obtained data
describe experiences related to obtaining prescription medicines at the
pharmacy, licensed practitioner's office, and other self-selected
sites. FDA intends to continue using this form of data collection to
monitor progress toward meeting the information distribution standard.
FDA will also collect and evaluate patient information to determine
whether it meets the usefulness standard. FDA will evaluate attainment
of these performance standards regardless of whether they are codified
in the rule (as under Alternative A) or described in a guidance
document (as under Alternative B).
1. Measurement of Distribution Rates
FDA anticipates conducting three iterations of these national
surveys in the approximately 11 years following publication of the
final rule. The first iteration will be conducted along with a
concomitant ``pharmacy shopping'' survey, to validate distribution
elements obtained by the national telephone survey. The second
iteration will be conducted in approximately the year 2000. The
distribution rates obtained from this iteration will be used to help
determine whether the standard of useful information distribution that
would result in continued deferral of further FDA action toward
implementing (Alternative A) or finalizing and implementing
(Alternative B) a comprehensive mandatory program has been met.
Similarly, the third survey iteration will be conducted approximately 6
years later. Together with the results of FDA's evaluation of patient
information usefulness, the distribution rates obtained from this final
iteration will determine whether the standard of useful information
distribution has been attained.
FDA encourages interested groups to sponsor similar distribution
rate evaluations in the intervening years to achieve a more complete
picture of the effectiveness of information distribution of the
voluntary programs. FDA will make its methodology and survey
questionnaire available to the public and will provide technical
assistance to any party interested in using this procedure.
One major limitation of the survey is that patient reports obtained
over the telephone cannot detail the type of information disseminated.
Further, these reports rely on patient memory, which may be subject to
distortions. Therefore, FDA will conduct a one-time-only pharmacy
``shopping'' survey to validate the telephone interviewing data related
to the distribution of written information with dispensed new
prescriptions. This will be a multiple city survey. Observers will pose
as patients and fill prescriptions for a commonly used drug. The
observers will collect written information disseminated to patrons.
They will also record oral interactions with pharmacy personnel and the
existence of collateral information available to patients.
Although FDA would also prefer to validate the reported data
concerning oral and written information obtained at the licensed
practitioner's office, there are numerous cost, methodological, and
logistical barriers to a data collection of such size and complexity.
FDA invites comments about the advisability of, and recommendations for
how to accomplish, validating these data.
Data from the shopping survey will be analyzed in conjunction with
a concomitant telephone survey to validate self-reported rates and to
help understand the degree to which any reporting biases may influence
the telephone survey results. The shopping survey will also obtain
information about the use of various commercial information systems at
pharmacies across the country. These data, along with obtainable
industry-trend data, will be used to project national totals of the
degree to which information is being disseminated to patients.
FDA will also collect sample patient information pieces from
commercial suppliers. The initial data collection will occur
immediately following publication of the final rule, with additional
collections occurring at 2-year intervals. Sample information sheets
will be obtained for commonly used medications. Rarely used medications
(not in the top 500 most commonly prescribed) and medications for which
patient information may be problematic (e.g., cancer chemotherapy,
major psychotropic medications) will not be included in these samples.
FDA will estimate the extent to which each system is used
nationally. FDA will also estimate the percentage of prescriptions
delivered through other distribution channels (e.g., mail-order
pharmacies, dispensing physicians) and the extent to which different
patient information systems are used in these distribution channels.
2. Determination of Information Usefulness
FDA will determine the degree to which obtained samples of patient
information meet the performance standard of useful information. The
samples will be evaluated on each component, using the criteria
described above. Each sample will be scored on each criterion, using
``acceptable'' and ``not acceptable'' cutoff points. As mentioned, FDA
believes that for a particular information sheet to be judged as
acceptable overall, it must receive an acceptable rating on each of the
individual components. However, the agency solicits comments regarding
this rule of operation.
In addition, FDA solicits comments regarding how many and what type
of drug products should be included in the patient information review,
and how each component of usefulness should be scored. FDA also intends
to hold a Part 15 Hearing or other public forum where interested
parties could provide recommendations and rationale for usefulness
components, associated criteria, and ratings systems for patient
information.
[[Page 44202]]
D. Feedback and Application of Standards
1. Reporting the Evaluation Results
Approximately every 2 years, FDA will issue a report on the overall
acceptability of written information, including ratings on each of the
components of usefulness. Newly updated distribution rates will also be
reported in relevant years (i.e., with the first, third, and sixth
information evaluations). In these years, the report will also provide
oral counseling rates.
FDA intends to estimate the percentage of patients receiving useful
information by multiplying the percentage of patients stating that they
received written information in the national survey by the percentage
of patient information sheets judged as useful (weighted by estimated
distribution rates for the sheets and the overall usefulness rating for
the sheets).
FDA plans to issue a report discussing the results of each survey.
The report will be in sufficient detail to permit an analysis of the
basis of the computed percentages. It will also describe the analysis
of each information sheet's performance on each of the usefulness
components.
2. Report Implications
If Alternative A is selected, FDA will continue to defer the
implementation date for the full Medication Guide program (except for
the section that requires Medication Guides for specific drugs which
FDA has determined have serious and significant public health concerns
requiring immediate distribution of FDA-approved patient information)
if the third evaluation report indicates that 75 percent of patients
receive useful information. FDA will continue to conduct these surveys
every 2 years. If the sixth evaluation report indicates that 95 percent
of patients receive useful information, FDA will propose revocation of
the sections of the rule that provide for implementation of a
comprehensive Medication Guide program.
If Alternative B is selected and the third evaluation report
indicates that 75 percent of patients receive useful information, FDA
would continue to leave unfinalized the proposal for a comprehensive
Medication Guide program. If this goal is not met, FDA would seek
public comment on whether the comprehensive Medication Guide program,
as proposed in this document, should be finalized and implemented, or
whether, and what, other steps should be taken to help ensure that the
goal is met. A similar judgment will be made based on whether the sixth
evaluation report indicates that 95 percent of patients receive useful
information.
In extrapolating from sample statistics to population parameters,
all measurement involves a certain degree of imprecision. An estimate
of expected sampling error for a simple random sample of 1,000 would be
approximately plus or minus 3 percentage points of the sample
statistic. FDA is proposing to use a relatively inclusive plus or minus
5 percentage points as the acceptable error (confidence interval at
=.95) for the standards for information distribution. Using
this interval means that the year 2000 standard would be met if it was
determined that between 70 percent and 80 percent of patients received
useful information. The year 2006 standard would be met if it was
determined that between 90 percent and 100 percent of patients received
useful information. FDA requests comments concerning whether this is
the most appropriate confidence interval to use.
Given the time necessary to implement an adequate patient
information program, by either a mandatory program or a continuation of
voluntary programs, FDA anticipates that the great majority of patients
should receive useful patient information by approximately 10 years
after the effective date of a final rule based on this proposal.
E. Medication Guide Program
The regulations set forth in this proposal describe a program that
requires manufacturers to prepare FDA-approved patient labeling
(Medication Guides) for their prescription drug products. The
regulations specify the format and content for such information. They
further specify that manufacturers must provide drug distributors and
authorized dispensers with sufficient copies of these Medication
Guides, or the means to produce sufficient copies, such that each
patient receives a Medication Guide with dispensed new prescriptions
and upon request with a refill.
Under Alternative A, in the event that the distribution and/or
``useful'' performance standards previously described are not met, the
final regulation based on this proposal (mandatory program) would be
fully implemented. An announcement of the institution of such a program
would be issued concurrently with the third or the sixth evaluation
report notice published in the Federal Register (no sooner than 5 years
or, if the rule continues to be deferred after the third evaluation
report, 11 years after the effective date of the final rule).
To implement this requirement, New Drug Application (NDA)
applicants and holders would be required to submit draft Medication
Guides for all submissions for new molecular entities (NME's) and for
new indications for approved products. In addition, concurrent with an
announcement that the regulations will be fully implemented, FDA would
publish an implementation schedule. This schedule would require that
application holders submit draft Medication Guides for specified NDA's.
FDA envisions that such a schedule would be based upon the most
frequently used products at the time. In order to avoid problems with
uneven competitive requirements, FDA would also consider the
simultaneous review of products within the same pharmacological or
therapeutic category.
Once an innovator drug Medication Guide was approved, manufacturers
of generic versions of the drug would also be required to prepare and
distribute Medication Guides modeled after the innovator's approved
Medication Guide.
Given the large number of drugs on the market, FDA envisions that
it would take approximately 10 years to complete approval for the vast
majority of Medication Guides. However, by implementing the Medication
Guide requirement as a function of the most popularly used products
first, a larger percentage of dispensed prescriptions would be covered.
Under Alternative B, if the distribution and/or ``useful''
performance standards are not met, FDA would seek comment on whether
the proposal requiring a comprehensive Medication Guide program, as
described in this document, should be finalized and implemented, or
whether, and what, other steps should be taken by FDA to ensure that
the patient information goals are met. Subsequent to this comment
period, either the Medication Guide regulations proposed in this
document would be finalized and implemented, or FDA would repropose a
different approach to helping to ensure attainment of the specified
goals.
IX. Conclusion
The long history of PPI's demonstrates that disagreements between
the public and private sectors in determining the best approach for
providing patient information have not served patients well. Since the
issue was first discussed in the 1970's, virtually all interested
parties have agreed that there is a critical need to better inform
patients
[[Page 44203]]
about their medications. Most of those who opposed PPI's accepted the
premise that patients needed to be better informed. However, opponents
argued that the private sector could do a better job of educating
patients if left unencumbered by Federal regulations. FDA came to the
same conclusion and withdrew requirements for the program. In the
ensuing decade, however, evaluations demonstrate that although many
private sector programs have been initiated, their impact on patient
education has been disappointingly low.
In the last 2 years, however, the increasing computerization of
pharmacies together with OBRA '90 requirements have apparently
contributed to an increase in the provision of oral and written patient
information. However, FDA's review of popular commercial systems in use
indicates that the quality of information provided is uneven. In the
interests of encouraging a continuation of this distribution trend, and
improving the value of the information to patients, FDA has concluded
that both standard- setting activities and the addition of a strong
incentive are appropriate and necessary.
Prior to developing this proposed rule, FDA met individually with
representatives of the pharmacy, pharmaceutical industry, patient
information producer, medical, and consumer communities. All of the
represented constituencies at these meetings indicated that they wanted
health professionals to provide patients with useful written
prescription drug information.
As mentioned above, in addition to soliciting written comments, FDA
intends to hold a Part 15 Hearing to solicit a broad range of views
about how best to measure usefulness of individual patient information
pieces. It should be clear to all parties, however, that FDA's concern
is not with the distribution of pieces of paper, but with the education
and empowerment of patients. Therefore, FDA intends to expand this
dialogue to solicit new ideas and feedback about other aspects of this
proposal, such as how medication adherence can be more effectively
facilitated, and new ideas about how to communicate information to
patients. FDA believes that presentations based upon research with
patients and consumers will be especially important; thus, FDA will
actively solicit such information. Developing systems that make maximal
use of technology and can be flexibly adapted to all patients, thus
providing useful and specific information, is the goal of FDA's broader
commitment to improving patient information. This goal will take an
active partnership to meet; it cannot be achieved by FDA alone.
Private sector efforts also will be needed to improve the basic
mechanism through which patient education about prescription medicines
occurs, i.e., oral counseling. In addition, programs are needed to
stimulate discussions about medications by health care professionals
when the medications are initially prescribed. Organizations that can
help determine the best mechanism for health professionals to introduce
and discuss patient medication information with patients would be vital
to the success of the program.
Additional programs also will be needed to provide educational aids
to patients with literacy problems to help them utilize medication
information most effectively. These programs must be diverse and
targeted to address the particular deficiencies causing the literacy
problem.
Data from the recent survey ``Adult Literacy in the United States''
(Ref. 72) indicate that most of the individuals who perform at the
lowest level of proficiency (from 66 to 75 percent) described
themselves as able to read or write English ``well'' or ``very well.''
They did not view themselves as deficient in any substantive fashion.
It would be inappropriate for health care professionals to withhold
information from patients merely on the premise that they may have some
difficulty understanding the information. Even with basic skills,
interested patients would be able to profit to some extent from the
documents. With additional help, the vast majority of patients would be
able to profit from improved information.
Of major importance to the success of improved patient information
would be private suppliers or organizations that can help pharmacies,
physicians' offices, and managed care organizations store, access,
produce, and/or distribute medication information. Groups that can
provide customized services to meet the individual needs of the vast
array of authorized dispensers would be of great service to help this
community meet the desired objectives. Such groups could expand the
provision of other information, such as disease information or general
information about using medicines safely, which would augment the
educational benefit for patients.
FDA welcomes comments about these topics and remains dedicated to
forging a medicine information delivery system that encourages, and
does not retard, the development of innovative communication systems.
X. Description of the Proposed Rule
The proposed rule, if finalized, would require a Medication Guide
for certain human prescription drug products, including biological
products. The rule would require manufacturers to prepare and
distribute, or provide the means for distributing, a Medication Guide
that would accompany prescription drug products that patients receive
and use on an outpatient basis without the direct supervision of a
health care professional. Medication Guides would be distributed with
all new prescriptions and with refills when requested by the patient.
Under Alternative A, the provisions in the proposed rule would be
deferred for a majority of the prescription drug and biological
products that otherwise would be affected in order to give voluntary
efforts an opportunity to achieve specific goals of distribution of
useful drug information within specified timeframes. The agency will
measure the success of the voluntary efforts by establishing
performance standards that measure both the distribution of patient
medication information and information usefulness. The agency will
conduct periodic evaluations to measure whether the performance
standards are met and will issue reports of the findings. If the
performance standards are not met by the end of each of two specified
timeframes, the provisions of the rule would be implemented.
For products that pose a serious and significant public health
concern requiring immediate distribution of patient information the
provisions would be implemented 30 days following publication of the
final rule.
Under Alternative B, FDA would also give voluntary efforts an
opportunity to achieve the goals of distribution of useful information
within specified timeframes. The difference, however, is that under
this option the agency does not intend to finalize immediately the
proposed performance standards, or the sections that defer
implementation, in the form of a regulation. Instead, the agency
intends to use the proposed performance standards as guidance for the
private sector. If the performance standards are not met at the
specified times, then the agency will seek public comment on whether a
comprehensive Medication Guide program, as described in this proposal,
should be finalized and implemented or whether, and what, other steps
should be taken to meet the patient information goals.
For Alternative B, FDA, however, does intend to finalize the
requirement for products that pose a serious and
[[Page 44204]]
significant public health concern requiring immediate distribution of
FDA-approved patient information. This provision would be implemented
30 days following publication of the final rule.
To be of value, product information must be understandable to
patients. The use of overly technical language may deter patients from
reading important information. Therefore, the proposed rule would
require that the Medication Guide be written in nontechnical language,
be nonpromotional in tone or content, be based on the professional
labeling for the drug product, and be presented in a uniform format.
The Medication Guide would contain a summary of the most important
information about a drug product, including the approved uses for the
product, circumstances under which the drug product should not be used,
serious adverse reactions, proper use of the product, cautions related
to proper use, and other general information.
Parties would be permitted to request an exemption for a particular
drug product from any of the specific requirements of the proposed
rule. The proposed rule would also permit the agency to exempt or defer
certain drug products from the requirement of a Medication Guide.
The proposed rule would require manufacturers to provide directly,
or supply the means to provide, sufficient numbers of the Medication
Guide to the distributor or dispenser of a prescription drug product.
The dispenser, in turn, would be required to provide the Medication
Guide to the patient. FDA is proposing to exempt qualifying small
retail pharmacy outlets from the requirement to dispense a Medication
Guide, except for products packaged in unit-of-use containers and for
products which the agency determines must be dispensed with a
Medication Guide.
Specific provisions of the proposed rule are as follows:
A. Scope and Implementation
Proposed Sec. 208.1(a) would limit the Medication Guide
requirements to human prescription drug products, including biological
drug products, administered primarily on an outpatient basis without
the direct supervision of a health professional. FDA is proposing this
limitation because, as discussed earlier in this preamble, the agency
believes that patients generally seek and are ready to receive and
understand information about their drug products after they have
received them. The Medication Guide would serve as an at-home reference
for patients when they are ready to self-administer products. The
proposed rule requires that a Medication Guide be dispensed with new
prescriptions, and with refills if requested by the patient. The
proposed rule would not apply to prescription drug products
administered in licensed practitioners' offices or institutional
settings, such as hospitals, nursing homes, or other long-term care
facilities, because FDA believes that the continuous presence of health
professionals in these settings gives patients the opportunity to ask
questions about their prescription drug products. The proposed rule
also would not apply in emergency situations because FDA believes
distribution of the Medication Guide in such situations would be
impractical. FDA has also provided an exemption for small retail
pharmacy outlets. Other dispensers which meet the small business
criteria set forth in the regulations would also qualify for such an
exemption.
Proposed Sec. 208.1(b) defers the implementation of the Medication
Guide provisions for all affected drug and biologic products, except
for the Sec. 208.1(d) products, until a determination is made by FDA
that certain performance standards have not been met.
Proposed Sec. 208.1(b)(1) would provide for the Medication Guide
provisions for all but the Sec. 208.1(d) products to be deferred if 75
percent of the patients receiving new prescription drugs or biologics
covered under these provisions receive useful patient information 5
years from the effective date of the final rule. If this standard is
met, FDA would continue to monitor the voluntary efforts for
distributing patient information. As proposed in Sec. 208.1(b)(2), if,
after an additional 6 years, 95 percent of the patients receiving new
prescription drugs or biologics covered under these provisions receive
useful patient information, the Medication Guide provisions would
continue to be deferred, except for the Sec. 208.1(d) products.
As described in greater detail previously, the agency will evaluate
both the distribution and usefulness of the information with regard to
specific criteria. Proposed Sec. 208.1(c) includes the seven proposed
components of the usefulness standard. An extensive discussion of the
specific criteria the agency proposes to use in evaluating achievement
of the usefulness standard is found in section VIII. of this document.
FDA is considering whether the details of these criteria should be
restated in the codified language, and invites comment on this issue.
Under Alternative A, if both of the requirements in proposed
Sec. 208.1(b) are met, the provisions of this part would be deferred
for all products except those that the agency determines pose a serious
and significant public health concern requiring immediate distribution
of patient information. In addition, under Alternative A, if both of
the requirements in proposed Sec. 208.1(b) are met, the agency intends,
at that time, to initiate notice and comment rulemaking to revoke
Sec. 208.1(b)(1) and (b)(2).
As discussed previously, under Alternative B, the agency does not
intend to finalize Sec. 208.1(b) and (c) immediately. Rather, if the
performance standards set forth in proposed Sec. 208.1(b) and (c) are
not met, the agency will again seek public comment on whether a
comprehensive mandatory Medication Guide program, as described in this
document, should be implemented or whether, and what, other steps
should be taken to meet the goals.
Under both alternatives, proposed Sec. 208.1(d) would allow FDA to
require that FDA-approved Medication Guides be distributed with certain
prescription drug products. See Section VIII. of this document for a
discussion of the criteria that would be used to determine the types of
products that may fall under Sec. 208.1(d).
B. Definitions
Proposed Sec. 208.3(a) would define ``authorized dispenser'' as an
individual who may legally dispense prescription drug products. FDA
believes that, in most instances, the authorized dispenser will be a
pharmacist.
Proposed Sec. 208.3(b) would define the phrase ``dispense to
patients'' as the act of delivering a prescription drug product to a
patient or an agent of the patient. Because the proposed rule would
apply only to drug products dispensed on an outpatient basis without
the direct supervision of health care professionals, proposed
Sec. 208.3(b) limits the scope of ``dispensing.'' For instance, the
definition of the phrase ``dispense to patients'' does not include the
delivery of a nonprescription drug product.
Proposed Sec. 208.3(c) would define ``distribute'' as ``the act of
delivering (other than by dispensing) a drug product to any person.''
Proposed Sec. 208.3(d) would define ``distributor'' as a person who
distributes a drug product. FDA notes that its interpretation of a
distributor has traditionally included repackers, and would do so here.
[[Page 44205]]
Proposed Sec. 208.3(e) would define ``licensed practitioner'' as an
``individual licensed, registered, or otherwise permitted by the
jurisdiction in which the individual practices to prescribe drug
products in the course of professional practice.''
Proposed Sec. 208.3(f) would define ``manufacturer'' as described
in Secs. 201.1 and 600.3(t) of this chapter.
Proposed Sec. 208.3(g) would define ``patient'' as any individual
with respect to whom a drug product is intended to be, or has been,
used.
C. Content of a Medication Guide
Proposed Sec. 208.20 would describe the content of a Medication
Guide. As stated earlier, FDA believes that the information in a
Medication Guide must be written in language that is easily understood
by patients. To ensure that information in a Medication Guide provides
a comprehensible and objective description of the drug product,
proposed Sec. 208.20(a)(1) would require that information be written in
English, presented in lay language, and would prohibit the use of
promotional language.
While FDA acknowledges that there is a significant minority of U.S.
citizens who speak Spanish as their primary language, it hesitates to
impose the additional burdens on manufacturers and dispensers that
would result from requiring the availability of Medication Guides
written in Spanish for these individuals. FDA also recognizes the many
other population segments who do not speak English as their primary
language. FDA requests comments concerning how it can most fairly and
effectively communicate patient medication information to these
populations.
Under proposed Sec. 208.20(a)(2), the Medication Guide must be
based on, and must not conflict with, the approved professional
labeling for the drug product. The Medication Guide should, in general,
provide a lay ``translation'' of those portions of the professional
labeling that are important for effective consumer understanding and
use of the product. This ``translation'' may include sufficient
background information or context to facilitate consumer understanding.
Proposed Sec. 208.20(b) lists specific types of information that must
be included in a Medication Guide. Under proposed Sec. 208.20(b)(1),
the Medication Guide would be required to identify the drug product
brand name (e.g., trademark name or proprietary name), if any, and
established name. If the product does not have an established name, the
proposed rule would require that the drug product be designated by its
active ingredients. In addition, the Medication Guide would include the
phonetic spelling of the brand name or the established name, whichever
name appears throughout the Medication Guide.
Because many people take a number of drug products, FDA believes
that it is important that patients be easily able to match a drug
product with the correct Medication Guide. Information could include
the color, shape, markings, and, if applicable, the drug product's code
imprint. There are a number of possible ways to provide this
information including: (1) A separate identification section, (2)
including the information in the personalized section (this optional
section of the Medication Guide is explained later in the preamble to
this proposal), or (3) providing preprinted stickers that would be
placed on the appropriate Medication Guide by the dispenser. An example
of one way to provide product identification information is displayed
in the sample Medication Guides in Appendix C.
Proposed Sec. 208.20(b)(2) would require a brief section concerning
the most important aspects of taking the drug product. This would
include the product's approved indications, especially important
instructions for proper use of the drug, and any significant warnings,
precautions, contraindications, serious adverse reactions, and
potential safety hazards.
Proposed Sec. 208.20(b)(3) would require the Medication Guide to
contain a statement identifying the product's indications, that is, the
uses identified in the indications and usage section of the approved
professional labeling. The Medication Guide may summarize indications
or omit rarely prescribed indications.
Proposed Sec. 208.20(b)(4) would require the Medication Guide to
identify the conditions under which the drug product is not to be used
for its labeled indications, i.e., contraindications to the product's
use. In nontechnical language, the labeling would describe the
contraindications specified in the professional labeling for the drug
product, reminding the patient, for example, to provide the licensed
practitioner with relevant medical history or information about other
drugs the patient is taking that may pose a significant
contraindication. Contraindications to use may include a previous
allergic reaction to the product, pregnancy, the patient's use of
certain other medications, or a particular condition that might make
the drug product less effective or dangerous.
Proposed Sec. 208.20(b)(4) would also require inclusion of the
steps the patient should take to remedy the situation should any of the
listed circumstances apply. This may include consulting with his or her
licensed practitioner before taking the drug, discontinuing use of the
product, etc.
Proposed Sec. 208.20(b)(5) would require the Medication Guide to
describe precautions related to the proper use of the drug product.
Under proposed Sec. 208.20(b)(5)(i), these precautions would include
activities the patient should avoid while taking the drug product, such
as driving or sunbathing, and list other drugs, foods, or substances,
including alcohol or tobacco products, the patient should avoid because
they may interact with the drug product. The information would help
patients use the drug product in a way that would promote its safety
and effectiveness.
Under proposed Sec. 208.20(b)(5)(ii), the Medication Guide must
also contain a statement regarding the product's use in pregnant women.
The statement must discuss any risks to the pregnant woman or the
fetus. Proposed Sec. 208.20(b)(5)(iii) through (b)(5)(vi) would also
require the Medication Guide to contain, if appropriate, precautionary
information about risks to a nursing infant, and any information on use
and risks for pediatric, geriatric, or other identifiable patient
populations.
Proposed Sec. 208.20(b)(6)(i) would require the Medication Guide to
list and describe adverse reactions associated with the use of the drug
product that are serious or occur frequently. This information would be
presented in a manner that would help patients understand and remember
it. Material presented under this provision would restate, in
nontechnical language, the information regarding the most significant
warnings and adverse reactions specified in the professional labeling.
In addition, where appropriate, the Medication Guide should inform the
patient what to do if they occur.
Organizing and explaining adverse reaction information for
different drug products may vary. For example, adverse reactions might
be organized by the organ systems in which they occur, by their
severity, by the frequency with which they occur, by a combination of
these approaches, or by any other appropriate method that would provide
patients with the information. In contrast to the professional
labeling, which often contains an exhaustive list of associated adverse
reactions, regardless of their frequency, the Medication Guide should
only list those adverse reactions that are meaningful to
[[Page 44206]]
the patient, in terms of seriousness, and/or frequency.
Proposed Sec. 208.20(b)(6)(ii) would require the Medication Guide
to discuss the risks, if any, to the patient of developing a tolerance
to or a dependence upon the drug product.
Proposed Sec. 208.20(b)(7) would require information concerning the
proper use of the drug product. Studies indicate that many patients do
not take prescription drugs properly (Refs. 3 and 4). Consequently,
proposed Sec. 208.20(b)(7)(i) would require a statement stressing the
importance of adhering to the dosing instructions. Under proposed
Sec. 208.20(b)(7)(ii), the Medication Guide would also contain any
special instructions on how to administer the drug; for example, proper
dosing intervals, whether the drug should be taken with food, or at a
period of time before or after eating. For products such as inhalers,
injectables, skin patches, and so on, that have special instructions
for administration, these instructions should be referenced in the
Medication Guide.
Proposed Sec. 208.20(b)(7)(iii) would require a statement of what a
patient should do in case of an overdose, i.e., contact the local
poison control center or hospital emergency room. Since FDA notes that
a significant number of patients fail to adhere to the dosing regimen,
proposed Sec. 208.20(b)(7)(iv) would require a statement of what a
patient should do if the patient misses taking a scheduled dose.
Proposed Sec. 208.20(b)(8) would also require the Medication Guide
to contain general information about the safe and effective use of
prescription drug products.
Patients may become concerned if their Medication Guide does not
include the purpose for which their health professional prescribed the
product. Therefore, proposed Sec. 208.20(b)(8)(i) would require
inclusion of the verbatim statement that ``Medicines are sometimes
prescribed for purposes other than those listed in a Medication
Guide.'' This statement would be juxtaposed with a statement
encouraging the patient to discuss any questions or concerns about the
drug product with a health professional.
Although health professionals understand that approved products may
be prescribed for other than FDA-approved indications, patients
typically do not possess this knowledge. Therefore, it is appropriate
to advise them of this fact, and that they should bring any concerns
they may have to the attention of a health professional. FDA believes
that these disclosures provide the necessary context to ensure that
patients will comprehend effectively medication information. The agency
stresses, however, that such ``contextual'' disclosure is inappropriate
for professional labeling, which is directed at health professionals
who are already aware of their freedom to prescribe medicines as they
see fit, as part of the practice of their profession.
FDA also notes that this statement is an acknowledgment about the
use of medicines in general, not about any particular product. The
agency will not sanction the use of this or similar statements
concerning unapproved uses in promotional labeling and advertising for
specific products.
Proposed Sec. 208.20(b)(8)(i) would also require a statement noting
that professional labeling for drug products may be available from the
patient's authorized dispenser or licensed practitioner. Many
individuals, including some pharmacists and licensed practitioners,
erroneously believe that State or Federal law prohibits providing a
drug product's professional package insert to patients. Moreover, the
professional labeling for a drug product provides the most detailed and
comprehensive information about prescription drug products and should
be available to any patient upon request. Although the professional
labeling for a drug product may be too technical for many patients to
understand, patients should be encouraged to learn more about their
medications and may seek to examine professional labeling. Authorized
dispensers and licensed practitioners are able to answer questions
about the professional labeling and thereby reduce the amount of
confusion produced by its technical language.
Proposed Sec. 208.20(b)(8)(ii) would require a statement informing
the patient that the drug product has been prescribed for the sole
purpose of treating the patient's condition and must not be used for
other conditions or given to other persons. This statement is intended
to caution against the dangers of self-diagnosis and lay diagnoses in
general. A licensed practitioner prescribes a particular drug to treat
a certain condition in a certain individual. Use of the drug by lay
persons to treat another condition in the same individual may be, at
best, ineffective and, at worst, directly hazardous to a patient's
health or indirectly hazardous by delaying proper diagnosis and
treatment. Use of the drug by another individual, without a
professional evaluation of the individual's medical condition and
history, could be life-threatening.
Section 208.20(b)(8)(iii) would require the manufacturer's,
packer's, or distributor's name and address; or the name and address of
the dispenser of the drug product; or for biological products, the
name, address, and license number of the manufacturer. This information
could assist the manufacturer or distributor and FDA in tracing and, if
necessary, recalling the drug product. Furthermore, providing names and
addresses would enable patients to contact a manufacturer or
distributor if they have any questions about the drug product.
Section 208.20(b)(8)(iv) would require the date of the most recent
revision to the Medication Guide. This will enable patients and
authorized dispensers with multiple versions of a Medication Guide to
determine which Medication Guide contains the most current information.
The contents of a Medication Guide may vary based on the product's
dosage form, bioavailability, or extent of systemic exposure, as stated
in the product's labeling. For example, some topical prescription drug
products that are not systemically absorbed may not require a statement
regarding the activities, drugs, foods, or other substances that a
patient should avoid when taking the drug product, or information on
risks from use of the drug product during pregnancy, labor, delivery,
or nursing. FDA encourages manufacturers, distributors, and others who
have questions on the preparation or content of their Medication Guide
to contact FDA.
The Medication Guide shall be dispensed as approved by FDA without
the inclusion of any additional information. However, authorized
dispensers may, and are encouraged to, personalize the Medication Guide
document by including, for example, the prescription number, the name,
address, and/or telephone number of the authorized dispenser and/or
licensed practitioner, and information personally identifying the
patient and relevant demographic or medical information (that does not
violate the patient's privacy). This information may precede or follow
the required information in the Medication Guide, but in no instance
should the information be more prominent or obscure any required
information. Authorized dispensers and licensed practitioners are also
permitted and encouraged to supply special instructions regarding the
product's use directly before or following information in the
Medication Guide.
D. Format for a Medication Guide
FDA believes that the Medication Guide should have a uniform format
so
[[Page 44207]]
patients can become familiar with the type and location of specific
information. The proposed rule would require the Medication Guide to
contain identical section headings, a consistent order of information,
the use of highlighting techniques, and a minimum type size.
A ``shell'' of the proposed uniform format is displayed in Appendix
A of this document. FDA chose different drugs to illustrate the uniform
format, and these examples may be found in Appendix B of this document.
Examples of the Medication Guide using alternative formats are
displayed in Appendix C of this document. FDA invites comment on these
alternative formats. These Medication Guide models were prepared solely
by FDA for illustrative purposes and do not represent approved labeling
by the agency.
The proposed rule would allow the Medication Guide to reach
consumers through a variety of methods, ranging from traditional
preprinted inserts to state-of-the-art, computer-generated material.
The agency recognizes that the level of information technology varies
widely across the country. For instance, while most pharmacies are now
equipped with computers, both the ability to access outside materials
and the print quality of computer-generated documents can vary greatly.
Thus, the proposed Medication Guide regulations are designed to
accommodate these varying levels of technology and not hinder
technological advances or improvements in the transmission of patient
information.
Proposed Sec. 208.22(a), would establish a minimum 10-point type
size for the Medication Guide (1 point = 0.0138 inches). This
requirement applies to all sections of the Medication Guide except the
name and address of the manufacturer and the revision date. FDA
believes that this type size is necessary to facilitate easy reading by
elderly patients. However, as legibility is determined by additional
graphic factors, proposed Sec. 208.22(b) would require that the print
be legible and clearly presented.
Additionally, FDA is proposing to amend the professional labeling
regulation at 21 CFR 201.57, which requires the professional labeling
to reprint, in its entirety, any patient labeling for a drug product.
The proposed amendment would clarify that the 10-point minimum type
size does not apply to any patient labeling or Medication Guide that is
reprinted in the professional labeling.
FDA recognizes that the communication of important information
requires graphic emphasis to highlight certain portions of the text.
The graphic emphasis selected should be appropriate to the particular
method of printing the Medication Guide. Thus, while multiple colors
may be used for emphasis in preprinting the Medication Guide, the use
of dot-matrix computers would require boldfacing, underlining, or some
other highlighting method.
As stated earlier in the preamble, the agency acknowledges that
there are many forms of commercially available, consumer-oriented
medication information. To enable patients to recognize that the
Medication Guide is the ``official'' patient labeling for a particular
drug product, proposed Sec. 208.22(c) would require every Medication
Guide to contain the words ``Medication Guide'' prominently at the top
of the first page of each Medication Guide. It would also require, at
the bottom of the Medication Guide, the verbatim statement that ``This
Medication Guide has been approved by the U.S. Food and Drug
Administration.'' Section 208.22(d) would require the brand and
established name to be prominently displayed. The established name
shall not be less than one-half the height of the brand name.
In order to organize the information in the Medication Guide,
proposed Sec. 208.22(e) would require that the content requirements
listed in Sec. 208.20 be placed under specified headings. These
headings would also be placed in a specified order so that the patient
can easily find the information. The proposed headings are in question
form and would include:
(1) ``What is the most important information I should know about
(name of drug)?;''
(2) ``What is (name of drug)?;''
(3) ``Who should not take (name of drug)?;''
(4) ``How should I take (name of drug)?;''
(5) ``What should I avoid while taking (name of drug)?;''
(6) ``What are the possible side effects of (name of drug)?''
The Medication Guides for certain drugs may require additional
headings, e.g., ``How should I store (name of drug)?'' (See Ceclor for
oral suspension draft Medication Guide in Appendix B of this document.)
The agency invites comments on alternative headings. Examples of
alternative headings appear in the Medication Guide models published in
Appendix C of this document.
In developing these model Medication Guide formats, FDA has
reviewed the formats used in a variety of patient information leaflet
systems and in patient information books. The agency has tentatively
concluded that the preferred format is the one that provides consumers
with questions about their medication and answers to these questions
and that organizes the information in a way similar to the professional
labeling. This will help manufacturers to prepare the Medication Guide
and place information in a consistent section of the Medication Guide.
Patients will obtain information that is consistent with professional
labeling. FDA intends to evaluate this (and other possible) formats
during the comment period for this proposal.
FDA recognizes that there are important differences between
labeling directed toward professionals and the Medication Guide
directed toward patients. The format for the Medication Guide should
help emphasize the most important information the patient needs to know
to use the drug product properly and to communicate with his or her
health care professional. Major sections of the professional labeling,
such as the Clinical Pharmacology section, that are useful to health
care professionals, are not likely to be as useful to patients
(although conclusions from that section, such as effects of food on
absorption, may be important). Similarly, other information, such as
complete lists of reported adverse reactions, may overwhelm the patient
or obscure the most important information. Thus, to facilitate the
communication of information to patients in a meaningful fashion, the
Medication Guide will be expected to summarize and distill the contents
of the professional labeling into terms that are more understandable
and useful to the layperson. On the other hand, it is not expected that
the Medication Guide will omit serious or potentially adverse
consequences of using the medicine that are important for patients to
know.
FDA will also permit the addition of ``contextual'' information,
not included in the professional labeling, to help patients understand
the labeling information despite their lack of background and training
in medicine.
FDA is aware that excessive length may discourage use of Medication
Guides and interfere with the communication of important messages. FDA
will therefore attempt to limit the amount of information included in
the Medication Guide, focusing on and emphasizing the most important
information for the patient (e.g., by changes in typeface, use of white
space or contrast, underlining). The Medication Guide samples reprinted
in the appendices to this document
[[Page 44208]]
provide examples of how FDA believes a Medication Guide should be
formatted, composed, and otherwise structured for the patient. In
addition to inviting general comments on these formats, FDA invites
comments on whether the Medication Guide should be printed on paper of
a specific size and whether a page limit (e.g., two pages) is
appropriate.
E. Distributing and Dispensing of a Medication Guide
The proposed rule is intended to ensure that consumers receive
patient labeling information, but permits manufacturers, distributors,
and dispensers to provide information in addition to that required
under the proposed rule. The agency has designed the distribution and
dispensing requirements to be flexible and to accommodate the increased
use of computers and other technological advances in pharmacies.
Proposed Sec. 208.24(a) would establish distribution requirements
for drug products in finished dosage form that are packaged in large
volume containers. Under the proposal, a manufacturer that ships a
large volume container of a finished dosage form to a distributor or an
authorized dispenser would be required to provide the Medication Guide
in sufficient numbers, or the means to produce the Medication Guide in
sufficient numbers to enable the authorized dispenser to provide a
Medication Guide to each patient receiving the drug product.
The reference to the ``means to produce the Medication Guide in
sufficient numbers'' signifies that a manufacturer is not limited to
providing hard copies of the Medication Guide to its distributors and
authorized dispensers. Instead, the manufacturer can satisfy its
distribution requirements by giving distributors and authorized
dispensers the ``means'' to produce the Medication Guide in sufficient
numbers. For example, the manufacturer could provide computer software
that enables the distributor or authorized dispenser to print the
Medication Guide. However, FDA cautions that if a manufacturer elects
to give distributors and authorized dispensers the ``means'' to produce
the Medication Guide, it must give the individual distributor or
authorized dispenser an effective means, including resources and
materials, to produce the Medication Guide. In other words, FDA would
not consider a manufacturer to have complied with its regulatory
obligations if it gave incompatible software to a distributor or
authorized dispenser or provided items that would require the
distributor or authorized dispenser to purchase other machines, goods,
or services in order to produce a Medication Guide.
For each drug product requiring a Medication Guide, proposed
Sec. 208.24(a)(2) would require manufacturers to place a label on each
large volume container of finished dosage form instructing authorized
dispensers to distribute the Medication Guide. This is necessary
because FDA intends to phase in Medication Guide requirements, and
authorized dispensers will need to know which drug products have
required patient labeling and which ones do not yet have such
requirements.
The proposed rule would establish similar requirements for
distributors who provide drug products to authorized dispensers.
FDA recognizes the complexity of the drug distribution system and
encourages the development of innovative methods to meet the
requirements of this section. The agency intends to consult with
interested parties so that distribution problems may be identified and
solutions developed.
For drugs in unit-of-use containers, proposed Sec. 208.24(c) would
require the manufacturer and distributor to provide the Medication
Guide with each package that is intended to be dispensed to patients.
The agency notes that this requirement, if finalized, would be
consistent with EC requirements on patient leaflets in unit-of-use
packaging.
The proposed rule, at Sec. 208.24(d), would also enable
manufacturers and distributors to have other persons meet their
distribution and dispensing requirements. For example, manufacturers
could enter into a contract with a third party to provide the
Medication Guide to distributors and dispensers. Such third party
information systems already exist in other contexts; for example, the
agency is aware that a third party vendor routinely collects and
publishes drug identification information which poison control centers
and other health organizations use to identify drug products.
Proposed Sec. 208.24(e) would require, in the absence of an
exemption under proposed Sec. 208.26, that an authorized dispenser
provide a Medication Guide to the patient (or the patient's agent) at
the time a prescription drug product is dispensed under a new
prescription, and when requested by the patient for refill
prescriptions.
Section 510 of the act (21 U.S.C. 360) requires all persons engaged
in the manufacture, preparation, propagation, compounding, or
processing of a drug to register with FDA and provide the agency with a
list of drug products in commercial distribution. Under section
510(g)(1) of the act, however, pharmacies which conform to local laws,
which are regularly engaged in dispensing prescription drugs upon
prescriptions of licensed practitioners, and which do not manufacture,
prepare, propagate, compound, or process drugs for sale other than in
the regular course of dispensing drugs at retail, are exempt from the
registration and listing requirements. The preparation and/or
distribution of Medication Guides by a pharmacy does not diminish this
exemption. Accordingly, under proposed Sec. 208.24(f), authorized
dispensers are not subject to section 510 of the act solely because of
an act performed by the authorized dispenser to comply with this
regulation.
F. Exemptions and Deferrals
The regulatory requirements presented in proposed Sec. 208.20 are
intended to be exhaustive as to the content of Medication Guides.
Nevertheless, FDA realizes that some requirements in proposed
Sec. 208.20 may be inapplicable, unnecessary, or contrary to a
patient's best interests for a particular drug product. Accordingly,
proposed Sec. 208.26(a) would advise manufacturers to contact FDA if
they believe that certain requirements are inapplicable, unnecessary,
or contrary to the patient's best interest.
Proposed Sec. 208.26(a) would also allow FDA to determine that
certain information should be omitted from the Medication Guide for a
particular drug product. This determination would occur at the time a
Medication Guide was submitted as part of a marketing application. The
agency may also, on its own initiative or in consultation with a
manufacturer, determine that any or all of the Medication Guide
requirements should be deferred or exempted for a specific drug
product.
The agency expects that the Medication Guide will facilitate
communication between the health professional and patient, thereby
enhancing the proper use of prescription drug products and helping to
reduce the incidence of noncompliance and adverse reactions. FDA
emphasizes, however, that the Medication Guide is not intended to
displace or substitute for professional judgment. A practitioner may
feel that, in certain cases, a patient may be adversely affected by the
contents of a Medication Guide.
Consequently, under proposed Sec. 208.26(b), the authorized
dispenser of a prescription drug product would not
[[Page 44209]]
be required to provide a Medication Guide to a patient if the licensed
practitioner who prescribes the drug product directs that the
Medication Guide be withheld. The agency believes that prescribers
should not direct dispensers to routinely withhold a Medication Guide
from patients but should do so only when it is in the best interests of
the specific patient involved.
In addition, FDA believes that authorized dispensers, as a result
of their personal contact with a specific patient or a patient's
family, often have information relevant to a decision to withhold a
Medication Guide for a specific product. For example, an elderly
patient functioning at a relatively low level of awareness of his
cancer may have been prescribed a product that provides only palliative
care, or a schizophrenic patient may have been prescribed a clearly
anti-psychotic drug. Under such circumstances, the patient, and the
course of therapy, may be adversely affected by the contents of a
Medication Guide. Under these circumstances, where there are
significant concerns about potential adverse effects of a Medication
Guide, FDA would permit authorized dispensers to use their professional
judgment in determining whether a particular patient would be best
served by withholding the Medication Guide for a particular product.
However, such an action should be based on the professional judgment of
the authorized dispenser in each specific situation, and Medication
Guides should not routinely be withheld for specific drug classes or
specific patient characteristics. The agency invites comments on how
best to implement this exemption.
FDA notes that under proposed Sec. 208.26(b), the authorized
dispenser must provide the Medication Guide to any patient who requests
one. In addition, FDA has determined that for particular products
patient information should be provided to all patients. Section
208.26(b) therefore provides that this exemption does not apply if FDA
determines that a Medication Guide for a particular product should be
provided to all patients under all circumstances.
Proposed Sec. 208.26(c) would permit manufacturers, distributors,
or authorized dispensers to provide drug products without a Medication
Guide in emergency situations and in cases where the manufacturer,
distributor, or authorized dispenser has made a good faith effort to
obtain a Medication Guide for the drug product, but does not have a
Medication Guide available for the patient. The manufacturer,
distributor, or authorized dispenser would be required to document its
good faith effort to obtain a Medication Guide. This provision is
intended to address those situations where the Medication Guide is
unavailable and would not prohibit authorized dispensers from providing
a prescription drug product to a patient. For example, if an authorized
dispenser is utilizing computer-generated Medication Guides and the
computer system breaks down, or if an authorized dispenser had
exhausted its supply of the Medication Guide for a particular drug
product and was unable to secure an additional supply of the Medication
Guide, proposed Sec. 208.26(c) would permit the authorized dispenser to
provide the drug product to the patient without a Medication Guide.
Proposed Sec. 208.26(d) would exempt certain authorized dispensers
from the requirement, in Sec. 208.24(e), to provide a Medication Guide
directly to each patient when dispensing a prescription drug product.
This proposed exemption would apply to retail pharmacy outlets or other
dispensers which: (1) Dispense, on average during the previous calendar
year, no more than 300 outpatient prescription drugs per week; (2) have
gross annual sales of no more than $5.0 million or are part of a
business entity (i.e., sole proprietorship, partnership, or
corporation) that has gross annual sales of no more than $5.0 million;
and (3) make available to patients a compilation of current Medication
Guides for reading in the drug product dispensing area.
FDA is proposing this exemption because it has determined, based on
the agency's regulatory impact analysis in section XII. of this
document, that the proposed regulation would have a significant
economic impact on the operations of many smaller retail pharmacy
outlets. Many larger pharmacies--members of chain drug stores and
pharmacies in large food/drug combination stores--have computerized
systems that can be used in dispensing Medication Guides to patients.
Smaller pharmacies, however, will generally need to purchase computer
equipment or they will incur costs for lost time and storage space by
using preprinted Medication Guides.
This proposed exemption would not apply to drugs dispensed in unit-
of-use containers. In this situation, the impact of the proposed
regulation on smaller pharmacies would be less because the drug product
is individually prepared for the patient by the manufacturer, and
already includes the Medication Guide.
In addition, the proposed exemption would not apply when the agency
determines, for safety or other reasons, that a particular drug product
must be dispensed with a Medication Guide. For example, FDA currently
requires that patient labeling must be dispensed with Accutane to
ensure its safe use, i.e., to warn patients about its association with
birth defects.
Exempted pharmacies must maintain a current compilation of
Medication Guides available for consumers to consult in an accessible
area, such as near the counter or the patient counseling area.
This proposed exemption is intended to lessen the economic impact
of complying with the proposed Medication Guide dispensing requirements
for smaller pharmacies and other dispensers. FDA invites general
comments on this exemption and specific comments on the proposed
threshold level (300 prescriptions per week) and whether this proposed
exemption should be permanent or merely extend the time necessary for
smaller pharmacies to comply with the exemption, for example by
providing a 10-year extension for small businesses to comply with the
requirements.
G. Miscellaneous Amendments
The proposed rule would also amend the provisions pertaining to
NDA's, product license applications (PLA's) and abbreviated new drug
applications (ANDA's) and abbreviated antibiotic drug applications
(AADA's) to require applicants to include a Medication Guide as part of
their labeling. The agency intends to review the Medication Guide along
with the proposed professional labeling for the drug product or review
the Medication Guide as it would review any proposed labeling change
for a drug product that requires prior approval. Although the
Medication Guide program would be implemented gradually if the
performance standards are not met, its requirements would ultimately
apply to all prescription drug products that patients primarily self-
administer without the direct supervision of a health care
professional. Therefore, as labeling, the proposed rule would expressly
require that the Medication Guide be submitted as part of an NDA, PLA,
or ANDA.
For applicants with approved products, the proposed rule would
amend the regulations governing supplemental applications to require
applicants to obtain prior FDA approval of any change to a Medication
Guide. FDA is proposing to require prior approval of such changes,
including the addition of any warning or adverse reaction, or even
minor editorial
[[Page 44210]]
changes. As stated earlier, the Medication Guide is directed to
consumers who may be distracted or overwhelmed by excessive
information. Consequently, the agency will attempt to ensure that the
Medication Guide contains information that consumers should know and
can understand.
XI. Legal Authority
The act (21 U.S.C. 321 et seq.) authorizes FDA to regulate the
marketing of drug products so that the products are safe and effective
for their intended uses and are properly labeled. In order to carry out
the public health protection purposes of the act, FDA: (1) Monitors
drug manufacturers and distributors to help make certain that drug
products are manufactured and distributed under conditions that ensure
their identity, strength, quality, and purity; (2) approves new drugs
for marketing only if they have been shown to be safe and effective;
and (3) monitors drug labeling and prescription drug advertising to
help ensure that they provide accurate information about drug products.
A major part of FDA's efforts regarding the safe and effective use
of drug products involves FDA's review, approval, and monitoring of
drug labeling. Under section 502(a) of the act (21 U.S.C. 352(a)), a
drug product is misbranded if its labeling is false or misleading in
any particular. In addition, under section 505(d) and (e) of the act
(21 U.S.C. 355(d) and (e)), FDA must refuse to approve an application
and may withdraw the approval of an application if the labeling for the
drug is false or misleading in any particular.
Section 201 of the act (21 U.S.C. 321), the ``Definitions'' section
of the act, describes the concept of ``misleading'' in the context of
labeling and advertising. Section 201(n) of the act (21 U.S.C. 321(n))
explicitly provides that in determining whether the labeling of a drug
is misleading, there shall be taken into account not only
representations or suggestions made in the labeling, but also the
extent to which the labeling fails to reveal facts that are material in
light of such representations or material with respect to the
consequences which may result from use of the drug product under the
conditions of use prescribed in the labeling or under customary or
usual conditions of use.
These statutory provisions, combined with section 701(a) of the act
(21 U.S.C. 371(a)), clearly authorize FDA to promulgate a regulation
designed to ensure that patients using prescription drugs will receive
information that is material with respect to the consequences which may
result from the use of a drug product under its labeled conditions.
This interpretation of the act and the agency's authority to require
patient labeling for prescription drug products has been upheld. (See
Pharmaceutical Manufacturers Association v. Food and Drug
Administration, 484 F. Supp. 1179 (D. Del. 1980), aff'd per curiam, 634
F. 2d 106 (3rd Cir. 1980)).
For generic drug products, section 505(j)(2)(A)(v) of the act (21
U.S.C. 355(j)(2)(A)(v)) provides additional legal authority for a
Medication Guide. Section 505(j)(2)(A)(v) of the act requires an ANDA
to contain information to show that the proposed generic drug product's
labeling is the same (with some exceptions) as that of the
corresponding reference listed drug. Thus, because a Medication Guide
is drug labeling, FDA proposes to require generic drug product
manufacturers to develop a Medication Guide that is the same as the one
for the reference listed drug, except for differences attributable to
legal or regulatory requirements (such as uses protected by patent) or
because the generic drug product and the reference listed drug are
produced or distributed by different manufacturers. If an ANDA or AADA
fails to contain such information, this failure may be grounds for
refusing to approve the ANDA or AADA under section 505(j)(3)(G) of the
act (21 U.S.C. 355(j)(3)(G)).
In addition, for biological products, section 351 of the Public
Health Service Act (42 U.S.C. 262) authorizes the imposition of
restrictions through regulations ``designed to insure the continued
safety, purity, and potency'' (including effectiveness) of the
products. Biological product licenses are to be ``issued, suspended,
and revoked as prescribed by regulations'' (42 U.S.C. 262(d)(1); see 21
CFR 601.4 through 601.6). The requirements of this proposed regulation
on Medication Guides are designed, in part, to insure the continued
safe and effective use of licensed biological products. Therefore, the
agency may refuse to approve PLA's, or may revoke already approved
licenses, for biological products that do not comply with the
requirements of the final rule on Medication Guides.
Based upon these authorities, the agency proposes to require
manufacturers of prescription drug products, including biological
products, to disclose information about their products in the form of
patient labeling. Just as scientific standards for evaluating a drug
product's safety and effectiveness and manufacturing practices have
evolved since enactment of the act in 1938, standards for appropriate
labeling for drug products must also change as data are compiled about
the effects of labeling on patients' safe and effective use of drug
products.
XII. Analysis of Impacts
FDA has examined the impacts of the proposed rule under Executive
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-345).
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). The agency believes that
this proposed rule is consistent with the principles set out in the
Executive Order.
The distribution of useful patient information will result in
significant consumer benefit, but may also entail costs to industry.
Some of the regulatory alternatives examined by the agency entail
potential regulatory costs well in excess of $100 million. Even though
the selected option is estimated to have associated costs well below
this amount, FDA has prepared a preliminary economic analysis in
accordance with Executive Order 12866 and the Regulatory Flexibility
Act.
This preliminary economic analysis evaluates the costs and benefits
of implementing FDA's proposal. This proposal states that in the
absence of continued voluntary efforts to provide useful information to
patients who purchase prescription drug or biological products,
manufacturers of these products will be required to prepare and
distribute patient information labeling that will accompany any new
prescriptions. The objective of the proposed rule is to improve public
health by allowing patients to make more informed uses of their
medications. FDA has found that patients often fail to adhere to
medication regimens or to recognize signs and symptoms of both
preventable and unpreventable adverse drug reactions. These failures
frequently prolong recovery or even contribute to additional illnesses.
Because patients who receive understandable information about their
drug therapies are better able to benefit from their medications, FDA
believes that implementation of the proposed regulations will
significantly enhance the public health. Although many programs that
offer patient prescription drug information currently exist, this
proposal is expected to increase the use and quality of such
information, and provide standards for
[[Page 44211]]
guiding and assessing the adequacy of voluntary programs.
FDA has proposed to institute a comprehensive program of FDA-
approved patient information only if the private sector does not meet
defined goals for the distribution and adequacy of patient information.
These goals are both reasonable and attainable. It is FDA's hope that
the voluntary programs will achieve the desired goals and that
consequently a government-imposed program will not be required.
However, this was FDA's hope in 1982 when the initial PPI regulations
were withdrawn. To provide sufficient incentive to meet distribution
and quality goals for written patient information, FDA is proposing two
alternatives that could result in a comprehensive program requiring
FDA-approved Medication Guides, but no sooner than 5 years from the
effective date of the final rule.
To estimate the costs of such a regulation, we have prepared a
worst-case analysis that assumes no increase in the current state of
distribution and quality of dispensed patient information, assumed to
be at about 50 percent. This worst-case estimate is that the program
would have annual gross costs of approximately $56 million, assuming
neither inflation nor discounting. Thus, FDA estimates that the cost of
this regulation would range from zero (if distribution and quality
standards would have been achieved despite the promulgation of this
rule) to $56 million (if the current state of private sector issuance
of patient information would have remained unchanged.)
The proposed labeling would take the form of patient information
sheets, called Medication Guides. These sheets would accompany new
prescriptions for outpatient human drug and biological products, and
would also be available upon request for refill prescriptions.
If the regulation is implemented, Medication Guides would be
developed by drug manufacturers. They would be approved by FDA and
would contain information designed to increase patient awareness of the
proper use of the accompanying products. These information sheets would
be distributed to the patient at the time the prescription is dispensed
at the retail pharmacy (or other dispensing outlet). While
manufacturers would be responsible for ensuring that adequate
information is available to the dispenser, the dispenser would
ultimately provide the information to the patient at the time the
prescription is filled. The agency has taken the burden of small,
retail pharmacies into account, and exempted certain low-volume outlets
from this proposal.
In 1980, the agency issued a similar regulatory proposal calling
for PPI's, initially to cover 10 drugs and drug classes. That rule was
revoked in 1982 to permit the private sector to implement information
programs without Government intervention. In the intervening years, FDA
has conducted periodic surveys of patients who have obtained new
prescriptions. FDA found in the latest survey that the proportion of
patients receiving written drug information (other than the
prescription label on the container) had increased from 16 percent in
1982 to 58 percent in 1994. Preliminary analyses of FDA's most recent
survey indicate that 55 percent of patients obtain more substantial
information than brief stickers.
Other surveys of the pharmacy sector have also shown gains in
distribution of written information. A 1992 survey of retail pharmacies
conducted by the University of Mississippi showed that 77 percent of
all pharmacies distribute printed patient counseling information (Ref.
76). A 1994 Consumer Patient Counseling Survey conducted for the
National Association of Boards of Pharmacy (Ref. 95) showed that 64
percent of all patients or caregivers stated that they received printed
materials about the medication from the pharmacy.
The agency believes that the availability of patient information
should continue to grow. While there is little doubt that patient
information activities have increased since the 1980 PPI proposal, a
sizeable proportion of the patient population remains underinformed.
FDA believes that a regulatory process that encourages or augments
private sector initiatives will best meet the needs of these
underserved patients.
OBRA '90 currently requires that pharmacists offer counseling to
patients who receive State-assisted services. Many States have extended
OBRA's requirements to additional patients. Required counseling under
OBRA is limited to oral, face-to-face counseling between the patient
and the dispensing pharmacist. Written material may be used as an
adjunct, but cannot be substituted for oral counseling. Numerous
studies have shown that counseling is most effective in modifying
behavior when achieved through a combination of oral and written media.
Thus, FDA believes that Medication Guides, or other voluntary written
information, will complement OBRA requirements and provide more
effective and comprehensive patient counseling.
A. Affected Sectors
The economic effects of the proposed regulations, if implemented,
will vary with the number of affected drug products, prescriptions, and
retail pharmacies. The number of affected drug products will dictate
the number of separate Medication Guides that will be developed, the
number of prescriptions will dictate the number of Medication Guides
that will be distributed, and the number of pharmacies will dictate the
number of facilities that will maintain equipment to distribute
Medication Guides. To determine an initial baseline for this analysis,
the discussion that follows is based on the assumption that voluntary
information programs will not meet the distribution and quality
standards for voluntarily-supplied patient information, and that the
Medication Guide program will therefore be fully implemented.
Medication Guides must be available for most prescription drug and
biological products dispensed outside of institutional environments
(such as hospitals and nursing homes). The agency envisions an
implementation period of 10 years, so that early resources may be spent
developing Medication Guides for therapies that may pose public health
concerns, as well as for new products. Over time, however, this
analysis assumes that all prescription products that are the subject of
approved NDA's and ANDA's will be accompanied by Medication Guides. FDA
examined currently marketed drug products and their historical rates of
introduction to arrive at an estimated 3,350 separate drug products
that will require separate Medication Guides, as shown in Table 1.
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[GRAPHIC][TIFF OMITTED]TP24AU95.013
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[[Page 44213]]
The 3,350 drug products will eventually require separate Medication
Guides. To develop these, FDA estimates that companies will select
``models'' from already existing materials. These models would be
updated by the manufacturer. Once a manufacturer has developed a model
it would be submitted to FDA for approval. The approved Medication
Guide will then serve as a model for other similar drugs within the
same therapeutic category, saving additional developmental costs. FDA
analysis indicates that 461 guides will serve as ``innovator'' or
``model'' Medication Guides. These can serve as models for 782 similar
``category'' products (within narrowly-defined therapeutic categories)
which, in turn, can be copied on a word-for-word basis for 2,107
generic drugs.
About 2.2 billion prescriptions were dispensed from retail
pharmacies during 1992, according to data included in the
``Prescription Drug Marketing Simulation Model'' developed by the NACDS
(Ref. 75). The proposed regulation, if fully implemented, will require
Medication Guides to accompany each new prescription, as well as be
available upon request for refill prescriptions. For cost calculation
purposes, FDA has assumed that prescriptions dispensed via unit-of-use
packaging would include Medication Guides whether the prescriptions are
new or refills. Since approximately 24 percent of all prescriptions, or
525 million prescriptions, are issued in unit-of-use packages, an
additional 1,661 million prescriptions would need to be prepared by a
pharmacist. Of these, FDA estimates that approximately 55 percent, or
914 million, would be for new prescriptions. FDA also estimates that 5
percent of the 1,661 on-site, pharmacy- prepared prescriptions, or 83
million, would be for patient requests for Medication Guides for refill
prescriptions. Thus, as shown in Table 1, the agency estimates that if
the proposal were fully implemented, Medication Guides would be issued
for 525 million unit-of-use prescriptions, 914 million other new
prescriptions, and 83 million refill prescriptions, for a total of
1,522 million Medication Guides. This would cover 70 percent of all
prescriptions.
However, pharmacies consist of both commercial and noncommercial
outlets. The NACDS (Ref. 75) included a distribution of pharmacy
outlets by type. The agency has allocated these outlets into three
categories: Independent pharmacies (up to three outlets that fill
prescriptions), chain pharmacies (four or more outlets under the same
management, including food outlets and mail-order companies), and
noncommercial outlets (Health Maintenance Organizations (HMO's)),
hospitals, ambulatory care units, and physician offices), as shown in
Table 2. Average prescription volume by outlet type is derived from the
NACDS survey. Independent, community pharmacies are estimated to
average approximately 530 prescriptions per week, while an average
chain pharmacy averages over 825 weekly prescriptions. Overall, the
agency estimates that the typical pharmacy dispenses approximately 600
prescriptions per week.
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B. Gross Costs of Compliance
FDA estimated the regulatory costs of this proposed regulation by
developing the costs for dispensing Medication Guides at a typical (600
prescriptions per week) pharmacy. These costs were divided by the
number of dispensed Medication Guides to derive a cost per Medication
Guide, as well as multiplied by the number of outlets to derive a total
cost of compliance. While this methodology may overstate unit costs for
large outlets and understate unit costs for small outlets, due to
economies of scale, these effects would tend to balance in the
aggregate.
Because voluntary efforts exist to provide patient information, and
these efforts are expected to expand, the incremental costs of
compliance are only those above the costs of providing patient
information that would accrue in the absence of this proposal. The
agency has initially assumed that 50 percent of all patients currently
receive patient information. Thus, gross costs are reduced to account
for current activities. If private sector initiatives continue to grow
in the absence of this regulation, the actual incremental compliance
costs will be even further reduced. In fact, if all affected pharmacies
would voluntarily dispense adequate, written patient information, the
incremental costs of this proposal would be zero. However, to develop a
baseline for analysis, the agency has assumed that the current baseline
of 50 percent compliance will remain constant throughout the study
period. This strategy results in the most conservative (i.e., the
highest possible) estimate of costs.
Costs to manufacturers include the cost of developing Medication
Guides and submitting them for FDA review. Costs to pharmacies include
the cost of printing and dispensing Medication Guides with
prescriptions.
1. Manufacturers
The worst-case scenario would require manufacturers of new drugs to
develop Medication Guides with no prior model or prototype, for
example, for a newly approved drug in a new therapeutic class.
According to Merck Pharmaceuticals, it took 6 months of calendar time
to develop, test, and revise an FDA-approved PPI to accompany a recent
new drug. FDA assumes that a totally new Medication Guide could be
developed within this timeframe, and would require a total of 2 months
of full-time effort by manufacturers. This effort would include
scientific research associates, regulatory affairs officials, and
legal/scientific reviewers. Assuming an annual average professional
labor cost of $70,000, each model Medication Guide would cost industry
between $11,000 and $12,000.
The majority of Medication Guides (those for which there are models
in the same therapeutic class) would be very similar to their
applicable model guides in content. FDA expects that the cost for
developing these ``category'' Medication Guides should be less than
half of the model development cost, or approximately $5,000.
Medication Guides for generic drugs should be virtually identical
to the originator product's Medication Guide, except for the name,
description, and patent-protected information. Therefore, FDA estimates
that the cost of developing generic Medication Guides would be
approximately one-tenth the cost of developing a category Medication
Guide, or $500.
Total industry costs of developing Medication Guides, if voluntary
efforts do not continue to grow, are found by multiplying the
applicable development cost by the expected number of products shown in
Table 1. By the 10th year of implementation, all products would have
Medication Guides at a cost to industry of approximately $10.5 million
for development. Given the proposed phase-in plan, the agency expects
annual development costs to equal approximately $1.3 million by year
10. As new products continue to be marketed, FDA expects this
equilibrium to be maintained.
According to data developed by FDA, approximately 24 percent of all
prescriptions are dispensed in unit-of-use packaging. These
prescriptions would require preprinted Medication Guides that would
likely be included in the packaging provided by the manufacturer prior
to shipping. Thus, 525 million preprinted Medication Guides will be
required by the 10th year of implementation.
According to purchasers, the cost of preprinted patient information
sheets is currently about $0.025 per page. These sheets include
customized information such as company address, phone numbers, logo,
and other information. A supplier of patient information sheets (USP)
lists a price of $2.10 for a pad of 50 sheets ($0.042 per sheet), but
the order form provides for substantial discounts for bulk orders. FDA
has assumed a cost of $0.025 per preprinted patient information sheet,
for a total annual printing cost of $13.1 million. The agency believes
that current packaging technology would allow for insertion of
Medication Guides into unit-of-use packaging with little additional
cost.
Prescriptions in other than unit-of-use packaging will likely be
dispensed with Medication Guides that are generated at the retail
pharmacy via computer. Many of the technologies for transmitting
automated information to retail pharmacies are already in place.
Distributor-based electronic information networks offer nationwide
computer ties designed to influence as well as facilitate
pharmaceutical care. According to one industry analyst, ``Nearly 95
percent of all pharmacies in the U.S. have at least some computer link
to a point-of-sale system that allows them to participate in these
point-of-sale networks.'' (Ref. 73).
Although a precise prediction of future technologies remains
speculative, FDA believes that the current availability of computers in
almost all pharmacies indicates that patient information would be
available in an automated format.
A number of possibilities would be available for the distribution
of automated data to pharmacies. Although each individual manufacturer
could distribute data disks to all pharmacies purchasing their drugs,
this approach would entail routine shipments of hundreds of thousands
of data disks and require expensive recordkeeping systems to avoid
sending duplicate disks. It is far more likely that conventional market
forces would lead to more rational information systems.
Logical models for distributing computerized information data bases
include the third parties that already accumulate and disseminate these
data. Because the regulation will impose the initial responsibility for
information distribution on manufacturers, yet the pharmacies will need
to augment their computer systems, the precise outcome of these market
forces is uncertain. However, there are several reasons to believe that
competitive considerations would prompt manufacturers to coordinate
with third party data bases for the distribution of Medication Guides.
First, several vendors, such as the USP, Medi-Span, Inc., and the
ASHP, already provide computerized drug information data bases. Thus,
comparable systems are already in place. Second, the responsiveness of
the private sector to the demand for Government-mandated information
has been vividly demonstrated by the proliferation of vendors of
chemical data bases following the promulgation of the Occupational
Safety and Health Administration's ``Hazard Communication Standard.''
Finally,
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pharmaceutical manufacturers would vigorously support the development
of a data distribution network that reduces the costs of printing and
shipping large volumes of paper. The initial mechanism could reasonably
involve manufacturer price discounts, rebates, or other like incentives
designed to encourage pharmacies to use commercial data bases.
For this preliminary study, the costs of disseminating computerized
data are considered pharmacy costs, via the purchase of software and
updates, although part of this burden may be passed back to the
manufacturers or distributors through various incentive programs. Table
3 indicates that the total annual gross costs to manufacturers of
preparing Medication Guides and printing those used in unit-of-use
packages would be expected to reach $14.4 million, if the proposed
regulation is fully implemented.
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2. Pharmacies
FDA has estimated the costs for a typical pharmacy that dispenses
600 prescriptions per week to comply with the proposed regulation.
These costs include hardware (including a computer with sufficient hard
disk space and a dedicated printer), supplies, space, and time to
retrieve and dispense the Medication Guide.
a. Hardware. An estimate of the required hard disk space to operate
a drug information network was developed from current requirements of
the MEDTEACH program offered by ASHP, which provides 427 drug
monographs to customers in disk form (each monograph contains
information similar to that envisioned in a Medication Guide). The
installation program requires two disks and quarterly updates or
revisions are offered to all users.
ASHP reports that the current program and data require 3.1
megabytes of hard disk space. A program accounting for 1,000 monographs
would require 6 megabytes. Because the proposed regulations, if
implemented, would require 3,350 specific Medication Guides, the
required disk space would ultimately be almost 20 megabytes. Hard disks
exceeding 400 megabytes are now common at a price of under $1.00 per
megabyte, and the technology is steadily advancing. FDA foresees no
difficulty in meeting the longer term requirements for computer disk
space, at an average amortized annual cost of only $6.
Dedicated printers would be required to generate the large numbers
of Medication Guides. Dot matrix printers can be purchased for about
$300, and are assumed to have a useful life of 4 years, which results
in an amortized cost per printer of $87 per year (at 6 percent
interest). Laser printers are assumed to cost $1,000 and also have a 4-
year useful life, yielding an amortized annual cost of $289 per
printer.
FDA found that the relatively slower dot-matrix printers would be
adequate for most outlets. The dispensing clerk or pharmacist would
complete other filing or labeling activities while the printer was
operating.
b. Supplies. On the assumption that each computer-generated
Medication Guide would fill two pages, FDA estimates that dot-matrix
printers would require ribbon replacement every 1,250 pages, or 625
Medication Guides. Dot-matrix ribbons are estimated to cost $8. In
addition, office supply catalogs indicate that the cost of bulk
computer paper ranges from less than $0.005 to $0.01 per page. This
study uses $0.007 per page as a mid-point in this range for a cost of
$0.014 per 2-page Medication Guide.
A typical pharmacy is estimated to dispense 600 prescriptions per
week. Twenty-four percent of these prescriptions (144) are dispensed in
unit-of-use packaging, so a total of 456 prescriptions per week may
require site-generated Medication Guides. The proposed regulation
requires Medication Guides to accompany new prescriptions (55 percent
of the total) as well as be available upon request. Thus, 60 percent of
the affected prescriptions are expected to be accompanied by Medication
Guides. This represents about 275 per week, or 14,300 per year when
fully implemented.
The typical pharmacy would then require 23 ribbon replacements per
year (almost one ribbon every 2 weeks) for an annual cost of $184. In
addition, 28,600 pages of computer paper would cost a pharmacy $200 per
year. The gross annual cost of supplies for providing Medication Guides
at a typical pharmacy is therefore estimated to equal $384.
c. Software. Several companies, including the USP and ASHP,
currently sell computerized patient information disks to pharmacies.
Although these packages have limited coverage, and typically contain
data for only the 200 top-selling drugs, FDA believes that such
organizations could rapidly compile and market comprehensive Medication
Guide data bases. Based on current costs for these software and data
packages, this study assumes an initial cost of $400 and quarterly
updates of $50 each. When these costs are amortized over a 4-year
period, the resultant annual cost to the pharmacy equals $315.
d. Storage. Using computers to print Medication Guides would also
add costs for storage, because an additional printer and paper would
require approximately 2 square feet within the prescription preparation
area. For example, 1,000 sheets of paper may be stored in a stack of
only 1.5 inches. Storage space would still be available below the
preparation counter, so FDA assumes that potential displacement of
equipment would be equal to 1 square foot of floor space.
The conventional means of obtaining the economic cost of a
productive resource is to estimate the market price of that resource.
An annual rental charge of $7.50 per square foot of pharmacy space was
obtained from survey data contained in the 1992 Lilly Digest (Ref. 78).
Alternative approaches note that, in the short run, added storage
requirements could impose additional opportunity costs if the turnover
of goods could not be increased elsewhere in the pharmacy, which
suggests a cost of storage based on displaced sales. FDA believes that
this method likely overstates regulatory costs, both from a societal
perspective (because the loss in sales to any one outlet would be
gained by another) and an individual outlet perspective (because the
average return per square foot of space exceeds the marginal return).
That is, outlets would minimize any burden by displacing lower return
items. Nevertheless, FDA has derived the value of sales per square foot
from the 1992 Lilly Digest of independent pharmacies, and has used an
annual cost of $104 per pharmacy per square foot to account for annual
storage costs to the typical pharmacy. (Annual sales per square foot of
pharmacy equal $360, and pharmacies have an average 29 percent gross
sales margin. Thus, $360 x .29 = $104).
e. Time. Computerized pharmacies would incur relatively low burdens
of time, because Medication Guides would be printed as other labeling
and dispensing activities were occurring. However, pharmacists would
remain responsible for ensuring that the correct Medication Guide
accompanies each prescription. FDA has assumed that a minimum of 5
seconds of pharmacist time would be needed to verify each selection.
Since the annual number of Medication Guides per typical pharmacy would
equal 14,300, a pharmacist would be expected to spend almost 20 hours
per year verifying Medication Guides.
The 1992 Lilly Digest reported average hourly wage rates of $30 for
pharmacist/proprietors. Using this as a basis, the total annual cost of
time would equal $600 for the typical pharmacy.
Although it is possible that this patient information would cause
returns of drugs and additional questions of pharmacists, FDA is
unaware of any study that confirms this hypothesis. The agency's 1980
economic analysis cited a contracted survey that indicated that no
additional pharmacist time was required to address these concerns (Ref.
62). FDA invites additional public comment and data on more recent
experience.
f. Total compliance costs to pharmacies. The sum of the annual
costs of printers, supplies, software, storage, and time equal almost
$1,500 for the typical pharmacy when, and if, the proposed regulations
are fully implemented. This equals almost $0.105 per pharmacy-printed
Medication Guide. Table 3 contains the total gross annual costs for the
pharmacy sector.
Total annual gross costs to the retail pharmacy sector will equal
$106.7
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million if this regulation is fully implemented. This amount is found
by multiplying the cost per pharmacy by the 71,367 universe of outlets
shown in Table 2.
3. Total Annual Gross Costs of Developing and Dispensing Medication
Guides
The estimated annual gross costs of developing and issuing
Medication Guides include the annual costs to manufacturers of
developing Medication Guides, in general, and printing unit-of- use
Medication Guides ($14.4 million), and the total annual cost to retail
pharmacies of printing and dispensing Medication Guides ($106.7
million). Thus, the total gross annual compliance cost of this proposal
is estimated to equal $121.1 million. The estimated average cost to
distribute one Medication Guide, whether via unit-of-use packaging or
printed at a retail pharmacy, equals $0.08. This reflects the higher
cost of printing Medication Guides on-site as well as the lower cost of
including Medication Guides with unit-of-use packaging.
This estimate does not take into account the existence of current
voluntary patient information programs. It also assumes static
technologies and prescription demand.
C. Incremental Compliance Costs
As discussed earlier, the agency has assumed that current voluntary
programs account for 50 percent of the market. Such programs include
retail pharmacies that currently provide patient information,
manufacturers that provide mandated patient information for certain
individual drug products and product classes, mail-order pharmacies
that routinely provide this information, and general unit-of-use
packaging. Given the current state of patient information, the agency
expects that the cost of achieving compliance with this proposal, if no
further gains in patient information occur, would be only 50 percent of
the total gross costs. Thus, the annual incremental cost of this
proposal is estimated to be a maximum of $60.5 million (including those
Medication Guides dispensed in unit-of-use packages). If private
patient information programs continue to increase, on their own, the
incremental cost of any regulatory plan would be even lower. In
addition, this estimate does not account for the agency's proposal to
allow an exemption for small-volume pharmacies. The cost implications
of this exemption are discussed in the following section.
D. Small Pharmacy Exemption
The Regulatory Flexibility Act requires Federal agencies to prepare
a regulatory flexibility analysis if a proposed regulation is expected
to have a significant impact on a substantial number of small entities.
FDA believes that compliance with the requirements for Medication
Guides could have a significant impact on the operations of many small,
independent pharmacies. The agency therefore proposes to exempt from
most of the Medication Guide requirements any retail outlet that
dispenses an average of fewer than 300 prescriptions per week, as long
as total company annual sales do not exceed $5.0 million.
1. Disproportionate Costs
Although pharmacies that dispense the largest volumes of
prescriptions would incur the greatest absolute costs, small pharmacies
would bear a proportionally higher burden. Based on the assumptions
previously discussed, for a typical outlet dispensing 600 prescriptions
per week, the average gross cost to provide a Medication Guide is
$0.105. The cost for a small outlet dispensing only 200 prescriptions
per week would total about $0.177. This disparity reflects the ability
of larger outlets to spread the fixed annual regulatory costs (printer,
storage, and software) over more prescriptions.
In some circumstances, regulatory costs can be imposed without
inflicting noticeable change to the affected industry sectors. However,
in recent years, independent community pharmacies have faced rapidly
growing competitive pressure from new sources of retail prescriptions,
especially mail-order companies and HMO's. A 1992 study prepared for
the NACDS (Ref. 75) projected independent pharmacy's share of
prescriptions to decrease from 41 percent to 29 percent during the
1990's. IMS America (Ref. 77) reports that since 1990, the number of
independent retail pharmacies decreased by 15 percent.
In general, the profitability of retail pharmacies varies in direct
proportion to sales volume. For example, a survey of independent
pharmacists (Ref. 78) reports that a typical independent pharmacy
earned income (combined pretax net store profit and proprietor/manager
salary) of $88,000 during 1991. Figure 1 shows that very small
independent pharmacies (fewer than 150 prescriptions per week) earned
total pretax incomes of only 26 percent of the industry average.
Independent pharmacies dispensing between 150 and 300 prescriptions per
week earned total income of only 51 percent of the industry average.
These limited profits suggest that it would be difficult for small
outlets to finance additional regulatory costs.
FDA is aware of the economic problems of the small retail pharmacy
and is reluctant to impose additional economic burdens on this sector.
Since scant public health benefits would be lost by excluding the
smallest pharmacies from the requirement to dispense Medication Guides,
the agency proposes exempting these pharmacies from the proposed
regulation.
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2. Outlet Characteristics
To estimate the number of outlets that would be eligible for a
small business exemption, FDA constructed a distribution of retail
pharmacy outlets by prescription volume. This distribution was
developed by merging data from two main sources: the 1992 Lilly Digest
of Independent Pharmacies (Ref. 78) and an earlier NACDS study (Ref.
79). Although the Lilly Digest reported data for a self-selected sample
of independent pharmacies, it provides the most detailed data available
for that sector. The NACDS sampled all pharmacies with six or more
outlets. Data are shown in Table 4.
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Because the methodology of these studies varied, FDA standardized
the data by adjusting and interpolating between ranges to develop an
outlet size distribution for the entire retail sector. The three
defined categories of retail outlets were analyzed separately:
Independent Outlets--The 1992 Lilly Digest of independent
pharmacies reports prescription volume in terms of prescriptions per
day. FDA assumed that pharmacies were open an average of 12 hours a
day, and calculated the dispensing days per week from reported weekly
hours of operation per cohort. The establishments were then
interpolated into cohorts of 100 weekly prescriptions.
Chain Outlets--A distribution of chain outlets was constructed from
a May 1990 report entitled ``An Assessment of Chain Pharmacies' Costs
of Dispensing a Third Party Prescription'' (Ref. 79) prepared for the
NACDS. This report sampled all pharmacies with six or more outlets
(including food/drug combinations, general merchandisers, discounters,
etc.) and presented a volume distribution by units of annual
prescriptions. The agency divided annual prescriptions by 52 to arrive
at weekly rates, and again interpolated into cohorts of 100 weekly
prescriptions. For the purposes of this analysis, mail-order pharmacies
were considered chain outlets.
Other Outlets--Estimates for prescription volumes for other outlets
were constructed separately. Hospitals and HMO's reported average
weekly prescriptions of approximately 350 per week. Physician's offices
and ambulatory care units averaged approximately 100 prescriptions per
week. While outlets in this category account for 15 percent of all
outlets, they account for less than 4 percent of all prescriptions, and
most of these are distributed in unit-of-use packaging. The agency
considers this sector to be minimally affected by this proposal and did
not analyze its characteristics in detail.
Thus, the agency considered the small business impact on the 60,608
commercial, retail outlets that dispensed about 2.1 billion
prescriptions per year. Approximately 54 percent of these outlets are
independent while 46 percent are chain outlets.
Figure 2 illustrates the relationship between prescription volume
and volume market share, and it shows that outlets dispensing 300 or
fewer prescriptions per week account for almost 20 percent of all
outlets. However, their dispensed prescriptions account for fewer than
6 percent of all prescriptions.
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3. Independent Outlets and Chain Outlets
Independent outlets are typically smaller than chain outlets. As
indicated in Figure 3, over 2 percent of all independent pharmacies
dispense fewer than 100 weekly prescriptions, while only 0.9 percent of
all chain outlets are so small. Conversely, about 7.5 percent of all
independent outlets dispense more that 1,200 weekly prescriptions while
almost 17 percent of all chain outlets are that large. This results in
chain outlets accounting for 26 percent of all outlets with fewer than
100 weekly prescriptions, but 66 percent of all outlets dispensing more
than 1,200 weekly prescriptions.
Moreover, chain outlets earn more store revenue on nonpharmacy
items. An annual survey conducted by the Drug Store News (Ref. 80)
shows that prescription sales account for only 24 percent of total
store sales in chain outlets, but 64 percent of sales in independent
outlets. In comparison, a typical independent outlet that dispenses
fewer than 300 weekly prescriptions has average annual gross revenues
of less than $300,000. A typical chain outlet that dispenses the same
number of prescriptions will have gross revenues of over $1 million. As
the average chain operates 47 separate outlets, these data suggest that
very few chain outlets would be eligible for the small business
exemption.
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4. Impact of Small Pharmacy Exemption
FDA proposes to exempt small pharmacies from the Medication Guide
requirements if three conditions are met. The first two conditions are
based on outlet characteristics. Based on distributions of prescription
volume, a proposed outlet size limit of 300 prescriptions per week
would exempt about 19 percent of all commercial pharmacies. However,
the objective of the exemption is to minimize burdens on small
business. Thus, company size, rather than outlet size alone, must be
considered. FDA has adopted the Small Business Administration's limit
of $5.0 million in annual company sales as an additional criterion for
exemption. Thus, an outlet that is a subsidiary of a company with total
sales of more than $5.0 million, regardless of sales at the specific
outlet, would not qualify for the exemption.
Given these two criteria, FDA estimates that the proposed exemption
would cover about 14 percent of all commercial outlets, primarily
independent pharmacies. Altogether, these pharmacies dispense only
about 4 percent of all prescriptions. Thus, although a substantial
proportion of the smallest community pharmacies would be spared
additional costs, the distribution of Medication Guides by outlets
dispensing 96 percent of all prescriptions would be required. Moreover,
since patients obtaining unit-of-use prescriptions would receive
Medication Guides despite the small pharmacy exemption, it is likely
that at least 97 percent of all new prescriptions would be accompanied
by patient information.
The third condition is that exempted outlets make available a
compilation of Medication Guides for reading in the dispensing or
counseling area.
FDA calculates that this small pharmacy exemption would reduce the
compliance costs of these proposed regulations to retail pharmacies by
7 percent, while having virtually no effect on manufacturers' costs.
This would reduce the expected annual incremental regulatory cost of
compliance to $56.3 million. Figure 4 displays these estimates for
various exemption options for the retail pharmacy sector.
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E. Regulatory Options
Section VII. of this document discussed the advantages and
disadvantages of several alternatives to the proposed regulations. The
current section presents rough estimates of their potential costs.
Option A, Continuation of the Status Quo, would continue current
practice. Under this option, FDA would continue to request patient
information on an ad hoc basis for specific drug products. Some
pharmacies would continue to purchase private product information
systems from a variety of vendors for patient distribution, but they
would continue to do so voluntarily. Thus, this option would impose no
new incremental costs.
Option B, No Prior FDA Review, would require that patient
information be dispensed with all drug products, but such information
would not be approved by the agency prior to distribution. One form of
this option reflects the proposed voluntary approach. Over time,
compliance costs would approach those estimated for the proposed
regulations.
Option C-1, FDA-Approved Patient Information Available with New
Prescriptions and Upon Request, would require that a Medication Guide
be provided with new prescriptions and upon request for refills. This
is the proposed regulatory option only if voluntary information efforts
are unsuccessful. As derived above, the annual incremental costs to the
affected sectors are estimated to reach $56.3 million by the 10th year
after implementation, assuming a small business exemption.
Option C-2, FDA-Approved Patient Information Available with All
Prescriptions, would require that a Medication Guide be provided with
both new and refill prescriptions. Although the cost per Medication
Guide dispensed decreases slightly because fixed costs are distributed
over more guides, the estimated annual incremental costs of compliance
for this option are over 40 percent higher than if Medication Guides
were only required for new prescriptions and on request for refills.
The estimated annual incremental cost of this option is over $80
million.
Option D-1, Unit-of-Use Packaging, would require that all
prescription drugs, together with Medication Guides, be dispensed in
unit-of-use packaging. FDA does not have sufficient information to
develop full cost estimates for this option, but believes the
requirement would impose additional costs for both new packaging and
increased storage space, while reducing product preparation costs. The
following projections illustrate the potential magnitude for several of
these categories.
The cost to manufacturers of developing and printing the Medication
Guides to be enclosed in each drug package would reach about $50
million annually. In addition, the PMA estimated in 1979 that it would
cost manufacturers between $25-$29 million to move to unit-of-use
packaging. Updating that estimate to current dollars results in
approximately $55 million. Moreover, there are about 67 percent more
prescription products available today than in 1979, which would boost
this estimate further.
Retail pharmacies and wholesalers would need to devote more storage
space to unit-of-use drugs. Estimates from the United Kingdom suggest
that this type of packaging may increase storage requirements by 40
percent (Ref. 73). A typical pharmacy uses about 500 square feet of
floor space. If the 40 percent increment is representative, an annual
rental fee of $7.50 per square foot would cost each pharmacy about
$1,500. The total annual cost for retail storage would equal $107
million. FDA assumes that wholesalers would experience additional
storage costs.
The reduced time for pharmacists to dispense unit-of-use products
would offset some of these cost increases. Kaiser Permanente, for
example, has estimated that unit-of-use packaging generates time and
supply savings of between $0.50 to $1.00 per prescription, although
they note that increased packaging costs offset about half of these
savings. Other enterprises report lower savings (Ref. 73). FDA
recognizes that strict requirements for unit-of-use packaging would
have important consequences on these sectors and solicits additional
public comment to allow the agency to understand better the associated
costs and savings.
Option D-2, Reference Book at Dispensing Site, would require only
that a book of Medication Guides be made available at the dispensing
site. Under this option, manufacturers would continue to bear the same
development costs, but the burden on retail pharmacies would be
minimal. Even if the insertion of each new or revised Medication Guide
into looseleaf binders took only 30 seconds, 200 to 300 annual
revisions would entail annual incremental costs to pharmacies of over
$2.2 million.
Option D-3, Interactive Computer Technology, would permit
pharmacies to provide computer access to consumers in lieu of being
handed a written Medication Guide. For example, consumers could be
directed to a computer kiosk to retrieve automated information. If most
consumers opted to print Medication Guides for new prescriptions, the
annualized cost of this alternative per pharmacy might average about
$100 for computer and printer equipment, $300 for software updates, and
$400 for computer supplies. Further, the rental value of a 3 x 3 square
foot cubicle in each pharmacy could add another $70 per year (or over
$900 if displaced sales are used to value space). These assumptions
imply a total annual incremental cost of about $38 million (about $70
million if displaced sales are used to value space).
Option D-4, Distribution of Books to Consumers, requires sending or
distributing Medication Guide books to each household. The complete
book would eventually include several thousand pages and is assumed to
cost $5.00 to print. Consequently, if 50 percent of the nation's 95
million households received an annually updated book, the cost of
printing would amount to $237.5 million. If the books were distributed
from pharmacies, there would be additional costs for storage. If they
were annually mailed to each consumer's residence, at a per book postal
rate of approximately $2.00, this amounts to an additional $190
million.
Finally, FDA considered option D-5, Telephone Counseling, which
would require manufacturers of prescription drug and biological
products to provide patients with a number to access counseling via
telephone. While FDA encourages manufacturers to provide this service
voluntarily, the agency believes that this form of oral counseling
should be considered an adjunct, not a replacement, for written
information. One large, mail-order company reports that about 10
percent of its new prescription customers utilize a toll-free number.
This percentage may be an upper-bound, however, when applied to retail
outlets where pharmacists are available for counseling at the time of
purchase. FDA estimates that if 5 to 10 percent of all new prescription
purchases resulted in 3-minute telephone conversations, the annual cost
of employing pharmacists to answer these calls would reach $82 to $164
million. In addition, the average telephone charges may equal about
$0.30 per minute, adding $50 to $100 million in annual costs. Thus, the
estimated incremental costs for this option range from $65 to $132
million.
[[Page 44230]]
F. Benefits
The primary objective of the proposed regulation is to enhance the
nation's public health by allowing patients to make better use of their
medications. FDA believes that the distribution of written prescription
drug information to patients, when combined with licensed practitioner
and/or pharmacist counseling, would accomplish this goal in two ways.
First, it would reduce the incidence of therapeutic failures due to
poor compliance with drug regimens. Second, it would decrease the
number of preventable adverse drug reactions and preventable drug-drug
and drug-food reactions. FDA believes that both outcomes are at least
partly attainable with adequate patient knowledge. While there are no
definitive studies that would allow FDA to develop precise measures of
the present and future levels of these key health variables, this
section presents the agency's best assessment of the expected values.
There is substantial literature on the extent of patient
noncompliance with prescription drugs. Although a large number of
national programs have been initiated to improve patient information
and education, this research continues to demonstrate that
noncompliance with prescription drug regimens remains a public health
concern. A 1990 NCPIE report found that about one-third of patients
fail to take their prescribed medications (Ref. 3). An overview of
patient compliance studies found that rates of compliance for long-term
therapy tend to converge to 50 percent (Ref. 4). Other studies
examining the literature on compliance rates in discrete patient
populations suggest that pediatric nonadherence to therapeutic regimens
exceeds 50 percent (Ref. 5), noncompliance rates for unsupervised
psychiatric outpatients range from 25 to 50 percent (Refs. 6 and 7),
and noncompliance in the elderly ranges from 26 to 59 percent (Ref. 8).
Therefore, FDA has concluded that current patient noncompliance rates
range from 30 to 50 percent.
This research also provides evidence that patient noncompliance
with prescribed drug regimens is directly related to therapeutic
failure with serious health consequences, including blindness, cardiac
arrest, and death (Refs. 9 and 10).
A 1990 Office of the Inspector General report found that the
process of patient education can save time by reducing calls or visits
to the licensed practitioner or pharmacist and by reducing the number
of hospitalizations resulting from patients' failures to follow
prescribed drug regimens (Ref. 17).
The economic burden to consumers and society of these preventable
drug-related illnesses include the direct costs of additional or
prolonged treatments by physicians or hospitals and the indirect costs
of lost work-time, reduced productivity, and wasted expenditures on
drugs whose efficacy is canceled or reduced by inappropriate or
improper use. However, only a few studies have addressed the economic
costs associated with drug noncompliance. More than 125,000
hospitalizations, and 20 million lost work-days (with lost earnings of
$1.5 billion in 1984) were attributed to drug noncompliance related to
cardiovascular disease (Ref. 15). A 1990 study of 315 elderly patients
found that hospitalization costs totaled approximately $293,000 for all
drug-related admissions (Ref. 8) (About $224,000 was attributable to
adverse drug reactions and $77,300 for drug noncompliance.) A recent
report (Ref. 81) by the Task Force for Compliance, a group of 22 major
pharmaceutical companies, estimated that the annual economic costs of
noncompliance exceed $100 billion. They attribute these costs to added
hospital admissions ($25 billion), prescriptions ($8 billion), nursing
home admissions ($5 billion), and lost productivity (over $50 billion).
The most comprehensive recent study employed a meta-analysis to
measure the extent and direct costs of hospital admissions related to
drug therapy noncompliance, using data on 2,942 hospital admissions
from seven studies. Only published studies that met a strict definition
of noncompliance (overuse, underuse, or erratic use) were included. The
analysis found that 5.3 percent of annual hospital admissions, or 1.94
million admissions, were due to drug noncompliance, at a cost of $8.5
billion in 1986. The author noted that these results were similar to a
1974 Task Force on Prescription Drugs that estimated hospital costs of
$3 billion in 1976 dollars for all drug-related admissions (Ref. 15).
As noted above, a precise quantitative measure of the benefits that
would result from the increased availability of patient information is
not possible, but FDA relied on the studies described above to develop
an illustrative example of the potential magnitude of expected
benefits. For its best estimate, FDA drew on the 1990 meta-analysis
(Ref. 15) to assume that about 5 percent of the nation's 35 million
annual hospital admissions are due to noncompliance with prescribed
drug regimens. The average cost of each drug-related hospital admission
is unknown, but the average cost for all inpatient hospital and
physician services is estimated at almost $9,000 per admission (based
on 1987 National Medical Expenditure Survey data, updated to 1993 by
the Medical Care CPI). As shown in Table 5, the costs of these hospital
admissions, based on an average 7-day stay, project to about $15.6
billion per year.
BILLING CODE 4160-01-P
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[GRAPHIC][TIFF OMITTED]TP24AU95.021
BILLING CODE 4160-01-C
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No comparable studies examined the nonhospital-related costs of
drug noncompliance. However, as stated above, FDA found that from 30 to
50 percent of all patients do not currently adhere to prescribed drug
regimens. Because an estimated 150 million U.S. consumers use at least
one prescription drug per year, about 60 million patients (150
million x 40 percent) are at increased risk of added illness. FDA used
this figure, together with an estimated incidence rate of 5 percent, to
derive a conservative estimate of the percentage of the noncomplying
population that would incur other direct medical costs, such as
additional medications and physician visits. As shown, the total annual
costs of noncompliance, including hospital admissions and other direct
costs, are estimated to be about $15.7 billion.
In addition, adverse drug reactions continue to be a significant
health problem. FDA believes that appropriate information can moderate
these incidents by warning patients about necessary precautions and
heightening their ability to understand and respond to adverse
reactions. A review of the relevant research in this area indicates
that the incidence of adverse drug reactions responsible for hospital
admissions ranges from 0.3 to 16.8 percent (Refs. 8, 11, 12, 13, and
14). According to extrapolations from a sample of emergency rooms,
approximately 5 percent of drug-related admissions were associated with
adverse encounters with OTC drug products, and thus would not be
affected by this proposal (Ref. 83). In addition, investigators have
estimated that between 48 percent (Ref. 74) and 55 percent (Ref. 84) of
all hospital admissions related to adverse reactions are preventable.
Thus, using 50 percent as an estimate of preventable adverse reactions,
the agency expects that approximately 47 percent (95 percent x 50
percent) of all hospital admissions associated with adverse drug
reactions are potentially preventable by the distribution of quality
patient information. This equals 1.4 percent of all hospital
admissions. As shown in Table 5, these assumptions imply that the costs
of preventable adverse drug reactions amount to about $4.4 billion per
year. Moreover, although the incidence of adverse drug reactions in
ambulatory patients has been reported at 20 percent (Ref. 48), FDA is
still examining these data and has not derived estimates of the related
costs. In sum, FDA finds that a partial tally of the direct medical
costs associated with the additional or prolonged illnesses that result
from both noncompliance with prescription drugs and preventable adverse
drug reactions adds up to about $20.1 billion a year. Note that this
estimate does not include the economic costs of lost productivity. As
mentioned above, one pharmaceutical industry task force estimated the
annual economic cost of noncompliance related to lost productivity as
over $50 billion (Ref. 81).
The realized benefits of increased patient information will depend
on the ensuing changes in patient behavior. Several studies since 1982
have found increases in compliance as a result of written information
alone or in combination with oral counseling. The rate was as high as
79 percent in the case of a comprehensive patient education program
that included additional features (Ref. 74), although in most cases
there were more modest increases. Of the studies involving only written
information, one found a 30 percent increase in compliance (Ref. 48)
and another a 50 percent increase among patients taking penicillin, but
no significant difference among patients taking nonsteroidal anti-
inflammatory drugs (Ref. 47). Other studies using only written
materials found no significant changes in compliance (Refs. 44 and 52).
Two studies using both oral and written information showed increased
compliance, with increases of 12 to 14 percent (Ref. 49) and 23 percent
(Ref. 7). In another study, however, there was no significant effect of
oral and written information on compliance (Ref. 66). These studies
varied by type of patient, medication, and illness (chronic or acute),
definition of compliance, length of therapy, and presence of noticeable
symptoms. Such factors may explain the wide variation in the reported
effects of written information on drug utilization behavior.
The agency does not anticipate that required patient information
would avert the majority of the costs associated with drug-related
illnesses. Even with current levels of patient information, significant
levels of noncompliance still occur. However, the above studies
indicate that understandable information has a significant impact on
patient compliance and awareness. Although data are not available to
present a precise forecast of the resulting health changes, the agency
notes that the health costs described above imply that if patient
information was to result in even a 10 percent reduction in adverse
outcomes, this would result in benefits of $2 billion per year. A 5-
percent improvement would produce annual benefits of $1 billion. Even a
1 percent reduction in these health care expenditures would more than
offset the costs of these proposed regulations.
The agency notes that while these figures are only illustrative, it
believes that the assumptions upon which they are based are
conservative and that the projected range of benefits is reasonable.
Moreover, this quantitative estimate does not account for the potential
avoidance of catastrophic effects, such as avoidable death, permanent
disability, or prolonged hospitalization. The costs of these more
severe consequences, at even very low incidence rates, would be
substantial.
G. Preliminary Conclusion
Given the enormous benefits in cost savings and improved health
care of this program, FDA believes that the economic costs of these
regulations are justified. The agency expects concerns to be raised
during the comment period about the apparent imbalance in bearing the
direct burden of the costs of these proposed regulations, especially as
borne by drug manufacturers and retail pharmacies should preapproved
Medication Guides be required.
The agency acknowledges that manufacturers would have the primary
responsibility for providing required labeling for drug and biological
products. FDA has recognized this concern in this proposal by requiring
manufacturers to provide the means for the dispenser to generate a
sufficient number of Medication Guides. However, as a practical matter,
there is a strong possibility that the impact of the proposed patient
labeling program, if fully implemented in the absence of satisfactory
voluntary efforts, would place a greater share of the financial burden
on the retail pharmacy sector rather than the manufacturer. The agency
is soliciting guidance on how the costs of a required Medication Guide
program could be allocated in a fair and reasonable fashion.
Accordingly, in addition to the comments on the reasonableness of the
estimates described above, the agency seeks comments on: (1) How
manufacturers and pharmacies can share the costs of producing and
dispensing Medication Guides; for example, by providing materials,
computer support, subsidies, or in some other fashion; and (2) the role
third-party intermediaries could play in interfacing between
manufacturers and pharmacies, and how they could mitigate costs.
XIII. Environmental Impact
The agency has determined under 21 CFR 25.24(a)(8) and (a)(11) that
this action is of a type that does not
[[Page 44233]]
individually or cumulatively have a significant effect on the human
environment. Therefore, neither an environmental assessment nor an
environmental impact statement is required.
XIV. Paperwork Reduction Act of 1980
This proposed rule contains information collections which have been
submitted for approval to the Office of Management and Budget under the
Paperwork Reduction Act of 1980. The title, description, and respondent
description of the information collection are shown below, with an
estimate of the annual reporting and recordkeeping burden. Included in
the estimate is the time for reviewing instructions, gathering and
maintaining the data needed, and completing and reviewing the
collection of information.
Title: Medication Guide for Prescription Drug Products.
Description: The information collection requirements would impose
reporting requirements on manufacturers and a recordkeeping requirement
on dispensers. However, until at least the year 2000, this burden would
only be required for a small subset of products that pose a serious and
significant public health concern requiring immediate distribution of
FDA-approved patient information. For these products, manufacturers
would be required to develop Medication Guides and submit them to FDA
for approval; dispensers would be required to document a good faith
effort to obtain Medication Guides when their supply is low or
depleted.
Description of Respondents: Businesses.
Estimated Annual Reporting and Recordkeeping Burden
------------------------------------------------------------------------
Annual Annual
21 CFR section number of Annual Average burden burden
responses frequency per response hours
------------------------------------------------------------------------
208.26(c)........ 521 NA 30 min.......... 261
314.50 (c)(2)(i), 10 1 320 hrs......... 3,200
(d)(5)(vi)(b),
and (e)(2)(ii);
and 601.2(a).
314.70(b)(3)(ii). 20 1 160 hrs......... 3,200
314.94 (a)(8)(i), 10 1 16 hrs.......... 160
(a)(8)(ii),
(a)(8)(iii), and
(a)(8)(iv); and
314.97.
----------------------------
Total...... ........... ........... 6,821
------------------------------------------------------------------------
The agency has submitted a copy of this proposed rule to the Office
of Management and Budget (OMB) for its review of these information
collections. Send comments regarding this burden estimate or any other
aspect of this collection of information, including suggestions for
reducing this burden, to FDA's Dockets Management Branch (address
above) and to the Office of Information and Regulatory Affairs, OMB,
Washington, DC 20503.
XV. Federalism
Executive Order 12612, Federalism, is intended to ``restore the
division of governmental responsibilities between the national
government and the States that was intended by the Framers of the
Constitution and to ensure that the principles of federalism
established by the Framers guide the Executive departments and agencies
in the formulation and implementation of policies.'' Section 3(d)(3) of
Executive Order 12612 states that, when national standards are
required, agencies must consult appropriate State officials and
organizations. Section 4(d) requires agencies that foresee any possible
conflict between State laws and federally protected interests to
consult, to the extent practicable, appropriate officials and
organizations representing the States to avoid such conflict.
FDA is aware that several States have laws or regulations that
require pharmacists to counsel patients on the use of prescription drug
products. The agency does not believe its proposed rule on Medication
Guides conflicts with such laws or regulations because the proposed
rule would not affect any oral counseling requirement imposed by State
laws or regulations. Nevertheless, the agency will continue to examine
State laws for federalism purposes and invites comments from interested
persons, particularly with respect to State initiatives to provide
information on prescription drug products to patients.
XVI. References
The following information has been placed on display in the Dockets
Management Branch (address above) where it may be seen by interested
persons between 9 a.m. and 4 p.m., Monday through Friday.
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Used in Home Health Care,'' Department of Health and Human Services,
Publication FDA 93-4258, 1993.
86. Doak, C. C., L. G. Doak, and J. H. Root, ``Teaching Patients
With Low Literacy Skills,'' Philadelphia, J. B. Lippincott Co.,
1985.
87. Felker, D. B., F. Pickering, V. R. Charrow, V. M. Holland, and
J. C. Redish, Guidelines for Document Designers, Washington, DC,
American Institutes for Research, 1981.
88. Mettger, W. and J. Mara, ``Clear and Simple: Developing Print
Materials for Low-literacy Readers,'' Bethesda, MD, National Cancer
Institute, 1992.
89. Morris, L. A., M. Mazis, and E. Gordon, ``A Survey of the
Effects of Oral Contraceptive Patient Information,'' Journal of the
American Medical Association, 238(23):2504-2508, 1977.
90. Morris, L. A., A. Myers, P. Gibbs, and C. Lao, ``Estrogen PPIs:
An FDA Survey,'' American Pharmacy, NS20(6):22-26, 1980.
91. Lamb, G. C., S. S. Green, and J. Heron, ``Can Physicians Warn
Patients of Potential Side Effects Without Fear of Causing Those
Side Effects?,'' Archives of Internal Medicine, 154:2753-2756, 1994.
92. Kessler, D. A., ``Communicating With Patients About Their
Medications,'' New England Journal of Medicine, 325:1650-1652, 1991.
93. Scheman, C. R., ``Patient Information and Education About Drugs:
The FDA Perspective,'' Drug Information Journal, 27:1133-1136, 1993.
94. Morris, L. A., D. Brinberg, R. Klimberg, L. Millstein, and C.
Rivera, ``Consumer Attitudes About Advertisements for Medicinal
Drugs,'' Social Science and Medicine, 22:629-638, 1986.
95. National Association of Boards of Pharmacy, ``Consumer Patient
Counseling Survey,'' 1994.
List of Subjects
21 CFR Part 201
Drugs, Labeling, Reporting and recordkeeping requirements.
21 CFR Part 208
Drugs, Patient labeling, Reporting and recordkeeping requirements.
21 CFR Part 314
Administrative practice and procedure, Confidential business
information, Drugs, Reporting and recordkeeping requirements.
21 CFR Part 601
Administrative practice and procedures, Biologics, Confidential
business information.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, it is
proposed that Chapter I of Title 21 of the Code of Federal Regulations
be amended to read 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 revising paragraph (f)(2) to read
as follows:
Sec. 201.57 Specific requirements on content and format of labeling
for human prescription drugs.
* * * * *
(f) * * *
(2) Information for patients: This subsection of the labeling shall
contain information to be given to patients for safe and effective use
of the drug, e.g., precautions concerning driving or the concomitant
use of other substances that may have harmful additive effects. Any
printed patient information or Medication Guide required under this
chapter to be distributed to the patient shall be referred to under the
``Precautions'' section of the labeling and the full text of such
patient information or Medication Guide shall be reprinted at the end
of the labeling. The print size requirements for patient information or
the Medication Guide set forth in Sec. 208.22 of this chapter, however,
do not apply to patient information or the Medication Guide that is
reprinted in the professional labeling.
* * * * *
3. New part 208 is added to read as follows:
PART 208--MEDICATION GUIDE FOR PRESCRIPTION DRUG PRODUCTS
Subpart A--General Provisions
Sec.
208.1 Scope and implementation.
208.3 Definitions.
Subpart B--General Requirements for a Medication Guide
208.20 Content of a Medication Guide.
208.22 Format for a Medication Guide.
208.24 Distributing and dispensing a Medication Guide.
208.26 Exemptions and deferrals.
Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 510,
701, 704 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321,
331, 351, 352, 353, 355, 356, 357, 360, 371,
[[Page 44236]]
374); Sec. 351 of the Public Health Service Act (42 U.S.C. 262).
Subpart A--General Provisions
Sec. 208.1 Scope and implementation.
(a) This part sets forth requirements for patient labeling for
human prescription drug products, including biological products. It
applies only to those human prescription drug products administered
primarily on an outpatient basis without direct supervision by a health
professional. This part shall apply to new prescriptions and upon
request by the patient for refill prescriptions. This part does not
apply to prescription drug products administered in an institutional
setting (such as hospitals, nursing homes, or other health care
facilities), or in emergency situations.
(b) Except as provided in paragraph (d) of this section, the
provisions of this part are deferred until a determination is made by
FDA that either of the following performance standards has not been
met:
(1) by (insert date 5 years from the effective date of the final
rule), 75 percent of patients receiving new prescription drugs or
biologics that are covered under these provisions receive useful
patient information as described in paragraph (c) of this section, or
(2) by (insert date 11 years from the effective date of the final
rule), 95 percent of the patients receiving new prescription drugs or
biologics that are covered under these provisions receive useful
patient information as described in paragraph (c) of this section.
(c) Determination of useful patient information will be based on
scientific accuracy, consistency with the format in Sec. 208.22,
nonpromotional tone and content, specificity, comprehensiveness,
understandable language, and legibility.
(d) This part shall apply without deferral to human prescription
drug products and biological products that FDA determines pose a
serious and significant public health concern requiring immediate
distribution of FDA-approved patient information.
Sec. 208.3 Definitions.
For purposes of this part, the following definitions shall apply:
(a) Authorized dispenser means an individual licensed, registered,
or otherwise permitted by the jurisdiction in which the individual
practices to provide drug products on prescription in the course of
professional practice.
(b) Dispense to patients means the act of delivering a prescription
drug product to a patient or an agent of the patient either:
(1) By a licensed practitioner or an agent of a licensed
practitioner, either directly or indirectly, for self- administration
by the patient, or the patient's agent, or outside the licensed
practitioner's direct supervision; or
(2) By an authorized dispenser or an agent of an authorized
dispenser under a lawful prescription of a licensed practitioner.
(c) Distribute means the act of delivering, other than by
dispensing, a drug product to any person.
(d) Distributor means a person who distributes a drug product.
(e) Licensed practitioner means an individual licensed, registered,
or otherwise permitted by the jurisdiction in which the individual
practices to prescribe drug products in the course of professional
practice.
(f) Manufacturer means the manufacturer as described in Secs. 201.1
and 600.3(t) of this chapter.
(g) Patient means any individual, with respect to whom a drug
product is intended to be, or has been, used.
Subpart B--General Requirements for a Medication Guide
Sec. 208.20 Content of a Medication Guide.
(a) A Medication Guide shall meet all of the following conditions:
(1) The Medication Guide shall be written in English, in
nontechnical language, and shall not be promotional in tone or content.
(2) The Medication Guide shall be based on, and shall not conflict
with, the approved professional labeling for the drug product under
Sec. 201.57 of this chapter.
(b) A Medication Guide shall contain the following:
(1) The brand name (e.g., the trademark or proprietary name), if
any, and established name. Those products not having an established
name shall be designated by their active ingredients. The Medication
Guide shall include the phonetic spelling of either the brand name or
the established name, whichever is used throughout the Medication
Guide.
(2) A summary section containing the drug product's approved
indications, critical aspects of proper use, significant warnings,
precautions, and contraindications, serious adverse reactions, and
potential safety hazards.
(3) A section that identifies a drug product's indications for use.
The Medication Guide may not identify an indication unless the
indication is identified in the indications and usage section of the
professional labeling for the product required under Sec. 201.57 of
this chapter.
(4) Information on circumstances under which the drug product
should not be used for its labeled indication (its contraindications).
The Medication Guide shall contain directions regarding what to do if
any of the contraindications apply to a patient, such as contacting the
licensed practitioner or discontinuing use of the drug product.
(5) A statement or statements of precautions the patient should
take to ensure proper use of the drug, including:
(i) A statement that identifies activities (such as driving or
sunbathing), and drugs, foods, or other substances (such as tobacco or
alcohol) that the patient should avoid;
(ii) A statement of the risks to the mother and fetus from the use
of the drug during pregnancy;
(iii) A statement of the risks of the drug product to a nursing
infant;
(iv) A statement of pediatric indications, if any. If the drug
product has specific hazards associated with its use in pediatric
patients, a statement of the risks;
(v) A statement of geriatric indications, if any. If the drug
product has specific hazards associated with its use in geriatric
patients, a statement of the risks; and
(vi) A statement of special precautions, if any, that apply to the
safe and effective use of the drug product in other identifiable
patient populations.
(6)(i) A statement of the possible adverse reactions from the use
of the drug product which are serious or occur frequently.
(ii) A statement of the risks, if any, to the patient of developing
a tolerance to, or dependence on, the drug product.
(7) Information on the proper use of the drug product, including:
(i) A statement stressing the importance of adhering to the dosing
instructions.
(ii) A statement describing any special instructions on how to
administer the drug product.
(iii) A statement of what the patient should do in case of overdose
of the drug product.
(iv) A statement of what the patient should do if the patient
misses taking a scheduled dose of the drug product.
(8) General information about the safe and effective use of
prescription drug products, including:
(i) The verbatim statement that ``Medicines are sometimes
prescribed for purposes other than those listed in a Medication Guide''
followed by a statement that the patient should ask the health
professional about any concerns,
[[Page 44237]]
and a reference to the availability of professional labeling;
(ii) A statement that the drug product not be used for other
conditions or given to other persons;
(iii) The name and place of business of the manufacturer, packer,
or distributor, as required for the label of the drug product under
Sec. 201.1 of this chapter, or the name and place of business of the
dispenser of the drug product or for biological products, the name,
address, and license number of the manufacturer; and
(iv) The date, identified as such, of the most recent revision of
the Medication Guide placed immediately after the last section.
Sec. 208.22 Format for a Medication Guide.
A Medication Guide shall be printed in accordance with the
following specifications:
(a) The letter height or type size shall be no smaller than 10
points (1 point = 0.0138 inches) for all sections of the Medication
Guide, except the manufacturer's name and address and the revision
date.
(b) The Medication Guide shall be legible and clearly presented.
Where appropriate, the Medication Guide shall also use boxes, bold or
underlined print, or other highlighting techniques to emphasize
specific portions of the text.
(c) The words ``Medication Guide'' shall appear prominently at the
top of the first page of a Medication Guide. The verbatim statement
``This Medication Guide has been approved by the U.S. Food and Drug
Administration'' shall appear at the bottom of a Medication Guide.
(d) The brand and established name shall be immediately below the
words ``Medication Guide.'' The established name shall be no less than
one-half the height of the brand name.
(e) The Medication Guide shall use the following headings:
(1) ``What is the most important information I should know about
(name of drug)?''
(2) ``What is (name of drug)?''
(3) ``Who should not take (name of drug)?''
(4) ``How should I take (name of drug)?''
(5) ``What should I avoid while taking (name of drug)?''
(6) ``What are the possible side effects of (name of drug)?''
Sec. 208.24 Distributing and dispensing a Medication Guide.
(a) For a large volume container of finished dosage form:
(1) Each manufacturer shall provide to each distributor to which it
ships a large volume container of finished dosage form either:
(i) The Medication Guide in sufficient numbers; or
(ii) The means to produce the Medication Guide in sufficient
numbers to permit the distributor to comply with paragraph (b) of this
section.
(2) The label of each large volume container of finished dosage
form shall instruct the authorized dispenser to provide a Medication
Guide to each patient to whom the drug product is dispensed.
(b) Each manufacturer or distributor shall provide to each
authorized dispenser to which it ships the drug product either:
(1) The Medication Guide in sufficient numbers; or
(2) The means to produce the Medication Guide in sufficient numbers
to permit the authorized dispenser to provide the Medication Guide to
each patient receiving a new prescription for a drug product or
requesting a Medication Guide.
(c) For a drug product in a unit-of-use container, the manufacturer
and distributor shall provide a Medication Guide with each package of
the drug product that the manufacturer or distributor intends to be
dispensed to patients.
(d) The requirements of this section can be met by the manufacturer
or distributor or by any other person acting on behalf of the
manufacturer or distributor. Nothing in this section prohibits a
manufacturer or distributor from meeting the requirements with a
Medication Guide printed by the distributor or authorized dispenser.
(e) Each authorized dispenser of a prescription drug product
subject to this part shall, when the product is dispensed (to a patient
or to a patient's agent), for new prescriptions and upon request by the
patient for refill prescriptions, provide a Medication Guide directly
to each patient (or to the patient's agent), unless an exemption
applies under Sec. 208.26.
(f) An authorized dispenser is not subject to section 510 of the
Federal Food, Drug, and Cosmetic Act, which requires the registration
of producers of drugs and the listing of drugs in commercial
distribution solely because of an act performed by the authorized
dispenser under part 208.
Sec. 208.26 Exemptions and deferrals.
(a) The Food and Drug Administration (FDA) on its own initiative or
in response to a written request from an applicant, may exempt or defer
any or all Medication Guide requirements on the basis that the
requirement is inapplicable, unnecessary, or contrary to the patient's
best interests. Requests from applicants should be submitted to the
director of the FDA division responsible for reviewing the marketing
application for the drug product, or for a biological product, to the
application division in the office with product responsibility.
(b) If the licensed practitioner who prescribes a drug product, or
the authorized dispenser who dispenses a drug product, determines that
it is not in the patient's best interest to receive a Medication Guide
because of significant concerns about the effect of a Medication Guide,
the licensed practitioner may direct that the Medication Guide not be
provided to the patient, or the authorized dispenser may withhold the
Medication Guide. However, the authorized dispenser of a prescription
drug product shall provide a Medication Guide to any patient who
requests it when the drug product is dispensed regardless of any such
direction by the licensed practitioner or the authorized dispenser.
This exemption from providing a Medication Guide does not apply if FDA
determines that a Medication Guide for a particular product should be
provided to all patients under all circumstances.
(c) A Medication Guide is not required to be dispensed to patients
in emergency situations or where the manufacturer, distributor, or
authorized dispenser, after documenting a good faith effort to obtain a
Medication Guide for the patient, does not have a Medication Guide
available for the patient.
(d)(1) An authorized dispenser, as defined in Sec. 208.3(a), shall
be exempt from the dispensing requirements of Sec. 208.24(e) when the
following conditions are met:
(i) The authorized dispenser dispensed, in the previous calendar
year, no more than an average of 300 outpatient prescription drug
products per week; and
(ii) The authorized dispenser, or its business entity, has gross
annual sales of no more than $5.0 million; and
(iii) The authorized dispenser makes available to patients a
compilation of current Medication Guides for reading in the dispensing
or counseling area.
(2) This exemption does not apply to a drug dispensed in a unit-of-
use container or a drug which the agency determines must be dispensed
with a Medication Guide.
[[Page 44238]]
PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG OR AN
ANTIBIOTIC DRUG
4. The authority citation for 21 CFR part 314 is revised to read as
follows:
Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701,
704, 721 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321,
331, 351, 352, 353, 355, 356, 357, 371, 374, 379e).
5. Section 314.50 is amended by revising the first and third
sentences of the introductory text, paragraph (c)(2)(i), the first
sentence of paragraph (d)(5)(vi)(b), paragraph (e)(2)(ii), and the
fourth sentence in paragraph (k)(1) to read as follows:
Sec. 314.50 Content and format of an application.
Applications and supplements to approved applications are required
to be submitted in the form and contain the information, as appropriate
for the particular submission, required under this section. * * * An
application for a new chemical entity will generally contain an
application form, an index, a summary, five or six technical sections,
case report tabulations of patient data, case report forms, drug
samples, and labeling, including, if applicable, any Medication Guide
required under part 208 of this chapter. * * *
* * * * *
(c) * * *
(2) * * *
(i) The proposed text of the labeling, including, if applicable,
any Medication Guide required under part 208 of this chapter, for the
drug, with annotations to the information in the summary and technical
sections of the application that support the inclusion of each
statement in the labeling, and, if the application is for a
prescription drug, statements describing the reasons for omitting a
section or subsection of the labeling format in Sec. 201.57 of this
chapter.
* * * * *
(d) * * *
(5) * * *
(vi) * * *
(b) The applicant shall, under section 505(i) of the act, update
periodically its pending application with new safety information
learned about the drug that may reasonably affect the statement of
contraindications, warnings, precautions, and adverse reactions in the
draft labeling and, if appropriate, any Medication Guide required under
part 208 of this chapter. * * *
* * * * *
(e) * * *
(2) * * *
(ii) Copies of the label and all labeling for the drug product
(including, if applicable, any Medication Guide required under part 208
of this chapter) for the drug product (4 copies of draft labeling or 12
copies of final printed labeling).
* * * * *
(k) * * *
(1) * * * Information relating to samples and labeling (including,
if applicable, any Medication Guide required under part 208 of this
chapter), is required to be submitted in hard copy. * * *
* * * * *
6. Section 314.70 is amended by revising paragraph (b)(3) to read
as follows:
Sec. 314.70 Supplements and other changes to an approved application.
* * * * *
(b) * * *
(3) Labeling. (i) Any change in labeling, except one described in
paragraphs (c)(2) or (d) of this section.
(ii) If applicable, any change to a Medication Guide required under
part 208 of this chapter.
* * * * *
7. Section 314.94 is amended by revising paragraph (a)(8) to read
as follows:
Sec. 314.94 Content and format of an abbreviated application.
* * * * *
(a) * * *
(8) Labeling--(i) Listed drug labeling. A copy of the currently
approved labeling (including, if applicable, any Medication Guide
required under part 208 of this chapter) for the listed drug referred
to in the abbreviated new drug application, if the abbreviated new drug
application relies on a reference listed drug.
(ii) Copies of proposed labeling. Copies of the label and all
labeling for the drug product (including, if applicable, any Medication
Guide required under part 208 of this chapter) for the drug product (4
copies of draft labeling or 12 copies of final printed labeling).
(iii) Statement on proposed labeling. A statement that the
applicant's proposed labeling (including, if applicable, any Medication
Guide required under part 208 of this chapter) is the same as the
labeling of the reference listed drug except for differences annotated
and explained under paragraph (a)(8)(iv) of this section.
(iv) Comparison of approved and proposed labeling. A side-by-side
comparison of the applicant's proposed labeling (including, if
applicable, any Medication Guide required under part 208 of this
chapter) with the approved labeling for the reference listed drug with
all differences annotated and explained. Labeling (including the
container label, package insert, and, if applicable, Medication Guide)
proposed for the drug product must be the same as the labeling approved
for the reference listed drug, except for changes required because of
differences approved under a petition filed under Sec. 314.93 or
because the drug product and the reference listed drug are produced or
distributed by different manufacturers. Such differences between the
applicant's proposed labeling and labeling approved for the reference
listed drug may include differences in expiration date, formulation,
bioavailability, or pharmacokinetics, labeling revisions made to comply
with current FDA labeling guidelines or other guidance, or omission of
an indication or other aspect of labeling protected by patent or
accorded exclusivity under section 505(j)(4)(D) of the act.
* * * * *
PART 601--LICENSING
8. The authority citation for 21 CFR part 601 is revised to read as
follows:
Authority: Secs. 201, 501, 502, 503, 505, 510, 513-516, 518-520,
701, 704, 721, 801 of the Federal Food, Drug, and Cosmetic Act (21
U.S.C. 321, 351, 352, 353, 355, 360, 360c-360f, 360h-360j, 371, 374,
379e, 381); secs. 215, 301, 351, 352 of the Public Health Service
Act (42 U.S.C. 216, 241, 262, 263); secs. 2-12 of the Fair Packaging
and Labeling Act (15 U.S.C. 1451-1461).
9. Section 601.2 is amended in paragraph (a) by revising the first
sentence to read as follows:
Sec. 601.2 Applications for establishment and product licenses;
procedures for filing.
(a) General. To obtain a license for any establishment or product,
the manufacturer shall make application to the Director, Center for
Biologics Evaluation and Research, on forms prescribed for such
purposes, and in the case of an application for a product license,
shall submit data derived from nonclinical laboratory and clinical
studies which demonstrate that the manufactured product meets
prescribed standards of safety, purity, and potency; with respect to
each nonclinical laboratory study, either a statement that the study
was conducted in compliance with the requirements set forth in part 58
of this chapter, or, if the study was not conducted in compliance with
such regulations, a brief statement of the
[[Page 44239]]
reason for the noncompliance; statements regarding each clinical
investigation involving human subjects contained in the application,
that it either was conducted in compliance with the requirements for
institutional review set forth in part 56 of this chapter or was not
subject to such requirements in accordance with Sec. 56.104 or
Sec. 56.105 of this chapter, and was conducted in compliance with
requirements for informed consent set forth in part 50 of this chapter;
a full description of manufacturing methods; data establishing
stability of the product through the dating period; sample(s)
representative of the product to be sold, bartered, or exchanged or
offered, sent, carried, or brought for sale, barter, or exchange;
summaries of results of tests performed on the lot(s) represented by
the submitted sample(s); and specimens of the labels, enclosures,
containers, and, if applicable, any Medication Guide required under
part 208 of this chapter proposed to be used for the product. * * *
* * * * *
Dated: July 17, 1995.
David A. Kessler,
Commissioner of Food and Drugs.
Donna E. Shalala,
Secretary of Health and Human Services.
Note: The following appendixes will not appear in the Code of
Federal Regulations.
BILLING CODE 4160-01-P
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APPENDIX A--A ``shell'' of the proposed uniform format
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BILLING CODE 4160-01-C
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APPENDIX B--Several sample Medication Guides using the proposed
uniform format
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Appendix C--Several Sample Medication Guides Using Alternative
Formats
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[FR Doc. 95-21020 Filed 8-23-95; 8:45 am]
BILLING CODE 4160-01-C
