# Prescription Drug Product Labeling; Medication Guide Requirements

> Briefs, arguments, decisions, and more.

URL: https://www.frixlaw.com/law-library/documents/fr%3A95-21020

## Record

- **Collection:** Federal Register
- **Document type:** Proposed Rule
- **Published:** August 24, 1995
- **Citation:** 60 FR 44182

## Text

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

[[Page 44187]]
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

[[Page 44188]]
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

[[Page 44189]]
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,

[[Page 44191]]
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 pro

[Text truncated at 120,000 characters. The full text is on the page linked above.]

---

Source: Frix Law Library, https://www.frixlaw.com/law-library/documents/fr%3A95-21020. Public record. Not legal advice.