[Federal Register Volume 60, Number 164 (Thursday, August 24, 1995)]
[Proposed Rules]
[Pages 44182-44252]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-21020]




[[Page 44181]]

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Part VII





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



_______________________________________________________________________



21 CFR Part 201, et al.



Prescription Drug Product Labeling; Medication Guide Requirements; 
Proposed Rule

  Federal Register / Vol. 60, No. 164 / Thursday, August 24, 1995 / 
Proposed Rules   

[[Page 44182]]


DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 201, 208, 314, and 601

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


Prescription Drug Product Labeling; Medication Guide Requirements

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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

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 

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nursing home admissions (Refs. 4 and 57).
    In a broad review of the effects of written information, Ley (Ref. 
36) concluded that most of the studies examined found positive effects 
resulting from the provision of written information to patients. Out of 
32 studies examining effects on knowledge, 97 percent found increases; 
of the 25 studies examining compliance, 60 percent found increases; and 
in 7 studies examining therapeutic benefit, 57 percent found increases.
    It should be noted that ``compliance'' represents a broad range of 
behaviors that are difficult to measure (Ref. 51). Several studies that 
have sought to measure the effects of written information have failed 
to find compliance improved by written information (Ref. 44, 52 through 
55). However, in a critical review of the methodologically rigorous 
studies of interventions to improve compliance, Haynes et al. (Ref. 56) 
concluded that compliance with short-term treatments can be improved by 
clear instructions, including written information, as well as by other 
interventions. Compliance with long-term treatments is more difficult 
to achieve; no single intervention has been shown to be effective on 
its own. Rather, improved compliance with long-term regimens requires a 
combination of interventions, including clear instructions enhanced by 
written information.
3. Written Patient Information Does Not Have Negative Consequences
    There has been speculation about the potential adverse effects of 
providing information about medications to patients. However, the 
studies suggest that written information does not increase reports of 
adverse events (Refs. 38, 42, 44, 45, 48, 52, 53, 62 and 91), nor does 
oral information (Ref. 65). Two studies that appear to indicate the 
opposite are flawed. In one case, the authors admit that the written 
information given to patients was inadequate (Ref. 52) and, in the 
other, statistical analyses were performed by combining control and 
experimental groups inappropriately (Ref. 50). A study of psychiatric 
patients was inconclusive on this point (Ref. 66).
    Studies do not show evidence of decreased compliance as a result of 
written information (Refs. 52 and 66) or evidence of increased anxiety 
levels (Ref. 60).
4. Relative Effectiveness of Oral and Written Patient Information
    Studies examining the relative effectiveness of printed and oral 
medication information are scarce. However, one study shows that 
provision of printed information is more effective in increasing 
patients' knowledge than oral information, and that a combination of 
the two is best. The authors believe that written materials, 
particularly those containing information about side effects, may be 
more effective and timely and less alarming to patients than oral 
information because most side effects do not occur until after the 
medication has been taken for a while (Ref. 67). One author suggests 
that written information should be used to supplement oral instructions 
that should be tailored to meet the particular beliefs, concerns, and 
expectations of the individual patient (Ref. 38).
    One meta-analysis of the literature, published in 1983 by the 
Pharmaceutical Manufacturers Association (PMA) (Ref. 68), merits 
special attention because it purports to demonstrate that PPI's about 
drugs have almost no effect in improving knowledge or compliance. After 
careful review of this analysis, FDA has concluded that the methodology 
was flawed and should not be relied upon with regard to the effects of 
written drug information on compliance. The details of the study and 
FDA's analysis of its methodology follow.
    In 1983, PMA funded a grant to assess the literature regarding 
mechanisms for improving patients' knowledge and use of prescription 
drugs. The authors performed a meta-analysis of studies selected from 
the patient education/compliance literature. They examined eight 
different strategies to improve patient knowledge and use of 
prescription drugs: Counseling, group education, behavior modification, 
counseling plus materials, materials alone, memory aids, counseling 
plus memory aids, and PPI's. The authors concluded that seven of the 
strategies improved patient knowledge and use by 24 percent to 72 
percent; however, PPI's had practically no effect in improving patient 
knowledge or compliance. They concluded that PPI's were an ineffective 
tool to improve patients' knowledge about or use of medication.
    FDA staff reviewed the meta-analysis and found its conclusions to 
be unsupported by the analysis performed by its authors. There are 
major definitional and methodological problems with the authors' 
analysis.
    First, the inclusion criteria used were not rigorously followed. 
Following Kanouse, et al. (Ref. 69), the authors of the meta-analysis 
defined PPI's as ``standardized leaflets which accompany a prescription 
drug as it is dispensed to the patient and which are designed to inform 
patients about a drug's actions, indications, and proper use, and to 
alert them about risks, necessary precautions, and possible side 
effects.'' However, as a practical matter, the authors sorted studies 
meeting this definition into two analytical groups (``materials'' and 
``PPI's''). They placed studies in the PPI category if the authors of 
that study called the leaflets ``PPI's'' as opposed to ``written'' 
information. The ``materials'' group included studies that did not 
designate the written materials as PPI's.
    Second, the PMA authors used a different analytical procedure for 
the PPI section of their analysis than for the remaining sections. 
Selecting test and control groups for the meta-analysis is a vital 
aspect of this type of analysis because it seeks to estimate the effect 
size of the difference between these groups. For all but a few studies 
examined in the meta-analysis, a group of subjects that received an 
intervention (e.g., counseling) was compared to a group that did not 
receive the intervention (e.g., no counseling). However, for the PPI 
analysis in 27 of the 28 studies examined, the test group was compared 
to a group that received an alternative version of that PPI. Thus, for 
PPI's, the authors compared intervention to intervention rather than 
intervention to control.
    The 27 PPI studies included in the meta-analysis were from FDA-
funded studies that had been conducted by the Rand Corp. These Rand 
studies examined 12 different formats for communicating information to 
patients for each of three drugs: erythromycin (an antibiotic), 
flurazepam (a sleeping pill), and estrogens (for postmenopausal 
symptoms). The Rand studies included no-intervention control groups for 
erythromycin and flurazepam. For estrogens, the Rand study included a 
control group composed of patients receiving the FDA-approved PPI for 
estrogens. Citing incompatibility of the data offered by Rand with 
meta-analytical procedures, the authors of the PMA-funded study 
selected the intervention group that they believed should have 
performed worst (i.e., was less sound educationally) to serve as the 
control group.
    The authors of the Rand studies concluded that PPI's lead to 
reliable gains in drug knowledge. This conclusion directly contradicts 
the PMA meta-analysis conclusion that was based primarily on Rand study 
results. The Rand studies were designed only to compare the effects of 
variations in style of information presentation within PPI's. Each of 
the PPI's studied by Rand 

[[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 product's potential benefits for the 
individual patient. How the information is specifically presented to 
the patient is particularly important to assure that the patient 
understands the risks and consequences, including the significance of 
proper adherence to directions.
    FDA intends to use the following criteria to determine what 
products or classes should be considered for FDA-approved Medication 
Guides as products that pose a serious and significant public health 
concern that requires immediate distribution of FDA-approved patient 
information. FDA seeks comments on the appropriateness of these 
criteria for selecting products for which FDA-approved patient labeling 
could be required.
    (a) Products for which patient labeling could help prevent serious 
adverse effects. In these cases, the patient labeling would inform 
patients about other products or foods which could interact with the 
labeled product, certain activities (e.g., exposure to the sun, 
driving) which would increase patient risk, or specific early warning 
signals indicative of serious adverse effects (e.g., leg pains that 
could signal a blood clot).
    (b) Products that have significant risks about which the patient 
should be made aware.
    (c) Products that pose risks in particular patient populations 
(e.g., pregnant women, geriatric patients, pediatric patients).
    (d) Products for which patient adherence is crucial to either the 
safety or efficacy of therapy with the product, and for which patient 
labeling would help increase adherence.
    In considering these criteria, FDA may also take into account how 
many patients use the product. FDA also intends to obtain public input, 
either through advisory committee deliberations or other public forums, 
concerning the specific products or classes the agency feels should 
have FDA-approved Medication Guides. FDA would notify affected 
manufacturers by letter if and when one of their products is identified 
as posing a serious and significant public health concern that requires 
immediate distribution of FDA-approved patient information, and would 
give the manufacturer sufficient time to produce a draft Medication 
Guide for agency review.
    Application for approval of a Medication Guide would be made via 
one of two processes, depending on whether the product is already being 
marketed or is in clinical development, pending approval. FDA believes 
that in some cases a product already would be on the market when a 
determination is made that the product poses a serious and significant 
public health concern requiring immediate distribution of FDA-approved 
patient information. It is often the case that once a product is used 
widely in the general population, additional side effects, drug 
interactions or other effects may be discovered that were not 
identified during clinical trials of the product. For these products, 
the manufacturer would submit a labeling supplement to the product's 
New Drug Application (NDA). In some cases a serious or significant 
public health concern may arise during drug development, prior to 
approval. Under these circumstances, the agency may determine that the 
benefits outweigh the risks, and will approve the product, only if 
patients are made aware of the potential risks. For these products, the 
manufacturer would submit a draft Medication Guide as part of the 
product's NDA.
    The agency does not believe that the requirement of a sponsor to 
prepare a Medication Guide for distribution with the product would pose 
an undue burden on the sponsor or slow down the approval process. Since 
patient labeling would be based on the professional labeling, both 
types of labeling can be developed simultaneously. The Information for 
Patients section of the professional labeling is already being used by 
many sponsors to include the kind of information that would be 
appropriate for inclusion in Medication Guides. However, the agency 
seeks comments concerning how development of patient labeling could 
affect approval time or place an undue burden on sponsors. 

[[Page 44199]]


A. Alternative Approaches

    Under Alternative A, implementation of FDA's proposed regulations 
for a comprehensive Medication Guide program would be deferred if 
predetermined standards for the distribution of useful patient 
information are met through voluntary programs within specified 
timeframes. The agency would periodically evaluate attainment of the 
performance standards. Proposed performance standards, timeframes and 
the evaluation process are discussed in detail in this section.
    Under Alternative B, FDA would only finalize the Medication Guide 
program for products that pose a serious and significant public health 
concern requiring immediate distribution of FDA-approved patient 
information. The comprehensive program, as it relates to other 
outpatient products, would not be finalized at this time. Instead, the 
agency would incorporate the performance standards into a guidance 
document. The agency would also evaluate, as under Alternative A, 
whether these performance standards are met in the specified 
timeframes. If they are not met, FDA would seek public comment on 
whether the comprehensive Medication Guide program, as proposed in this 
document, should be finalized and implemented, or whether, and what, 
other steps should be taken to meet the patient information goals.
B. Performance Standards

    The remainder of this section discusses proposed performance 
standards for assessing the effectiveness of voluntary programs in 
achieving patient education goals, how performance will be judged 
against these standards, and how the results of such evaluations will 
be publicly communicated. It is FDA's intention to work with the 
private sector to develop reasonable standards that will protect and 
promote consumer understanding of the directions, uses, and risks of 
medications, and also to provide periodic feedback so that progress can 
be monitored and corrective action taken.
    As used in this section, the following terms are defined as 
follows:
    ``Goal''--the broad objective to be sought. For example, Healthy 
People 2000 specifies the broad goal that 75 percent of patients should 
receive useful information.
    ``Standard or performance standard''--the basic requirement that 
will be used to judge the degree to which progress has been made toward 
achieving the specified goals.
    ``Components''--if there are multiple parts or dimensions upon 
which performance standards must be judged, the components are an 
enumeration of each of the parts of a standard. FDA has proposed seven 
components to the useful information performance standard.
    ``Criteria''--for each of the components of a performance standard, 
the basis upon which judgments will be made to determine if the 
component has been successfully achieved. In this section, FDA lists 
the seven proposed components of usefulness and describes the criteria 
that will be used to judge whether each component has been met.
1. Overall Goal
    The Public Health Services's (PHS) Healthy People 2000 enumerates a 
variety of goals which are intended to focus public and private 
resources on specific and achievable outcomes. Recently, PHS proposed 
the addition of a new objective, 12.7: ``Increase to at least 75 
percent the proportion of people who receive useful information 
verbally and in writing for new prescriptions from prescribers or 
dispensers.''
    This objective recognizes the need for both oral and written 
information to be given to patients along with new prescriptions. The 
distribution rate of 75 percent is clearly delineated. However, the 
goal does not specify what standards should be applied to determine 
whether dispensed information is ``useful.''
    FDA believes that useful information must be informative and usable 
by patients to be deemed acceptable for meeting this goal. In section 
VIII.B.3. of this document, FDA further delineates proposed performance 
standards that may be used to judge the usefulness of written patient 
information.
2. Distribution
    As the performance standard for distribution of patient information 
for the year 2000, FDA is proposing to use the Healthy People 2000 goal 
that at least 75 percent of people receiving new prescriptions are 
given useful written patient information. In addition, for the year 
2006, FDA proposes that the distribution standard be increased such 
that 95 percent of people who receive new prescriptions also receive 
useful written patient information.
    Generally, FDA envisions that the fulfillment of these standards 
would entail the distribution of printed information. However, with 
advancing technology, the development of disease management systems, 
and the distribution of medication through new distribution channels 
(e.g., mail-order pharmacies), new technologies may be developed that 
fulfill the purposes of this standard without requiring paper-based 
materials. To permit applicability of these standards to a changing 
patient information landscape, FDA is proposing the following as a 
definition of receipt of patient information: With new prescriptions, 
patients must receive permanent, fully portable, and easily accessible 
media that describe the prescription drug product.
    The person who receives the information would be either the patient 
for whom the product was prescribed or the patient's designee. The 
information would have to be given to the patient at the dispensing 
site without the patient's having to actively search for or select the 
information. The information could be physically handed to the patient 
or placed in a bag with the prescription in order to meet the 
distribution standard. However, information that requires patients to 
select from a display or requires a phone call or return of a postcard 
would not meet the standard. Permanency of the media means that the 
information can be repeatedly referenced and can be stored by the 
patient for future use. Fully portable media means that persons 
obtaining prescriptions can physically carry the information with them. 
Easily accessible media means that the information is in a form that 
can be expected to be readily accessed by patients. Information in the 
form of a leaflet or brochure would meet the distribution standard, as 
would an auditory device that plays the message each time a button is 
pressed. Audiotapes, computer disks, videotapes or other media could 
potentially meet the standard if the distributor can be assured that 
the patient has all the devices necessary in his or her residence to 
use the media distributed.
3. Useful Information
    In specifying a performance standard for useful patient 
information, FDA believes that there are several components that must 
be taken into account. Each of these components must be satisfactory 
for FDA to determine that patient information is useful. The seven 
specific components proposed by FDA include scientific accuracy, 
consistency with a standard format, nonpromotional tone and content, 
specificity, comprehensiveness, understandable language, and 
legibility.
    In the section below, FDA further defines each of these components. 
FDA invites comments on the appropriateness of these standards, 
components, and criteria proposed to judge overall usefulness of 
patient information.

[[Page 44200]]

    FDA further wishes to acknowledge that the specifics of risk 
information disclosure specified in the performance standards described 
below may appear to be more detailed than are the specifics of benefits 
disclosure. FDA believes that it is important to communicate benefits 
information, as long as it is accurate and is not done in an 
excessively promotional fashion. FDA believes that the reader will 
infer many of the benefits of a prescription drug product from the 
disclosure of how the product is used (its indication). For example, if 
a product is described as being used to lower high blood pressure, the 
inference is that use of this medication will benefit the patient by 
lowering his or her blood pressure, along with reducing whatever 
additional heart-related risks are associated with uncontrolled 
elevated blood pressure. FDA also recognizes that benefits inferences 
that need to be made concerning treatment of certain conditions are 
more complex and may need to be more specifically defined for the 
patient. Further, some conditions are more severely debilitating than 
others. In some cases, it may be appropriate to include relatively more 
extensive information about the benefits, and to be more reassuring 
about the risks, of a product, especially when the benefit to risk 
ratio clearly favors use of the medication.
    a. Scientific accuracy. (1) Accuracy would be judged by review of 
the materials for consistency with FDA-approved labeling. Approved uses 
may be summarized in lay terms (e.g., ``treats certain heart 
problems'') as opposed to enumerating specific medical indications. 
However, limitations should also be noted (e.g., ``treats heart 
disorders'' would not be acceptable). The content of certain patient 
information may be written to apply to classes of drugs containing 
products with different indications. In these instances, uses that do 
not apply to the entire class should be qualified (e.g., ``some,'' or 
``certain'' products treat * * *).
    (2) Qualifications or limitations regarding the use of the product 
should be described. For example, if a product is approved for use in 
conjunction with a dietary or behavioral regimen, the patient 
information should include reference to such a regimen.
    (3) Additional uses that have not been approved by FDA should only 
be referenced by a general statement (e.g., ``may be used for other 
purposes as prescribed by your doctor''). Personalized information for 
individual patients relevant to such a use may be added by a health 
care provider as a matter of professional practice.
    b. Consistency with suggested format. The order and headings used 
should follow those specified for Medication Guides in the final rule 
(see proposed Sec. 208.22(e)).
    c. Nonpromotional tone and content. (1) The language used should be 
educational in nature and avoid ``puffery'' or other promotional 
terminology. There should be a ``fair balance'' in the description of 
benefits and risks. The benefits should be described in terms of the 
uses and effects of the individual medication. Discussion of 
therapeutic options is acceptable. However, differences among therapies 
should not be described in terms of express or implied unbalanced 
comparisons of the advantages of the medication (excepting information 
supplied for informed consent purposes). For example, phrases such as 
``unlike other drugs * * * this drug * * *'' may be perceived as 
promotional.
    Advertising and labeling information directed to patients or 
consumers, distributed by or on behalf of pharmaceutical manufacturers, 
must meet the provisions of FDA regulations, including submission for 
FDA review.
    (2) The information should not be misleading in terms of the 
description of individual drug effects or the overall impression 
conveyed. Misleading information would include the use of formatting 
techniques that emphasize benefits and de-emphasize risks.
    d. Specificity. (1) The information provided should enable a 
patient to use the product correctly. Proper use includes not only 
directions for taking the medication, but also information about 
avoiding negative consequences. Information should also be included 
regarding proper monitoring of the impact of therapy by correctly 
interpreting physical reactions to the drug. This would include, for 
example, informing patients when to call their physician if they do not 
notice signs of improvement. Risk information should include sufficient 
detail for an average patient to understand the significance of the 
hazard described. For example, if a drug causes birth defects when 
taken in the second or third trimester of pregnancy, users should be 
expressly informed that the drug may cause birth defects if used after 
the third month of pregnancy. General references, such as ``tell the 
doctor if you are pregnant,'' would be insufficient.
    (2) Warnings denoting serious or life-threatening effects, even if 
rare, should be expressly described. This information should not be 
combined with other information in a fashion that reduces communication 
of its significance. Additional contextual information should be 
provided to help patients understand these important risks. This 
contextual information may include statements of the likelihood of 
occurrence, the reason why such effects may occur, how to prevent these 
effects, how to monitor for early warning signs, and/or what to do if 
such effects occur.
    e. Comprehensiveness. (1) Information important for the patient to 
know should be covered in each of the sections of the suggested format. 
However, it need not be detailed or exhaustive. This would include 
information necessary for patients to use the drug correctly, to 
understand important limitations or precautions, and to know the risks 
that may be assumed by taking the drug.
    (2) Long lists of common and infrequent side effects need not be 
included. The side effects mentioned should include rare, but serious 
effects as well as common ones. The side effects may be summarized in 
lay language (e.g., ``blood problems'') and need not be exhaustive. 
However, the presentation should not diminish communication of the 
potential hazard. Further, if long lists are included, they should not 
diminish the significance of major warnings or side effects.
    f. Understandable language. (1) The information provided should be 
clearly written for the average person. FDA will not specify a reading 
level due to concerns about the validity of readability tests as 
applied to patient drug information. However, the principles of clear 
writing, as described in a variety of manuals (Refs. 85, 86, 87 and 88) 
should be followed. Technical terminology should be used only if the 
terminology is explained and use of the terminology would help the 
patient understand the material.
    (2) Deletion or degradation of important risk, benefit, or 
directions for use information cannot be justified by the need for 
language simplification. Additional information, provided through both 
print and other media, can be used to help communicate to populations 
with literacy problems.
    In general, the information should be likely to be understood by 
the ordinary individual under customary conditions. While it is clear 
that many patients will not be able to read English, FDA would not 
consider this ability as a factor in determining information adequacy. 
FDA would consider efforts by distributors to communicate with patients 
of low literacy as consistent with a determination of overall adequacy. 
Thus, distribution of otherwise 

[[Page 44201]]
acceptable written materials that utilize simplified language, 
pictograms, or other communication techniques would be encouraged. 
Similarly, programs in foreign languages, braille, or other forms of 
written communication that meet the literacy and information processing 
needs and ability of selected patient populations would be encouraged.
    g. Legibility. (1) The information presentation should permit an 
interested reader to discern the important information. Type size, 
white space, characters per inch, contrasting colors, and other graphic 
elements should provide sufficient legibility to enable a typical 
medication user to read the information. (Note that the typical 
medication user is often an elderly person with less than perfect 
vision.)
    (2) The layout and graphic presentation should invite readership; 
interested patients should want to read the material. The graphic 
presentation should communicate that the material is usable, readable, 
and comprehensible. The layout should not convey the impression that 
the material is simply the ``small print'' presented for legal reasons 
and unnecessary to read. Nor should it convey the impression that the 
reader would be unable to understand the material because it is too 
``dense.''

C. Evaluation

    Since the revocation of the PPI regulation in 1982, FDA's 
evaluation of the extent of distribution of patient information has 
relied upon national telephone surveys of people who obtained new 
prescriptions for themselves or a family member at retail pharmacies. 
This form of research has the advantage of obtaining reports of recent 
experiences from a representative sample of subjects. The obtained data 
describe experiences related to obtaining prescription medicines at the 
pharmacy, licensed practitioner's office, and other self-selected 
sites. FDA intends to continue using this form of data collection to 
monitor progress toward meeting the information distribution standard. 
FDA will also collect and evaluate patient information to determine 
whether it meets the usefulness standard. FDA will evaluate attainment 
of these performance standards regardless of whether they are codified 
in the rule (as under Alternative A) or described in a guidance 
document (as under Alternative B).
1. Measurement of Distribution Rates
    FDA anticipates conducting three iterations of these national 
surveys in the approximately 11 years following publication of the 
final rule. The first iteration will be conducted along with a 
concomitant ``pharmacy shopping'' survey, to validate distribution 
elements obtained by the national telephone survey. The second 
iteration will be conducted in approximately the year 2000. The 
distribution rates obtained from this iteration will be used to help 
determine whether the standard of useful information distribution that 
would result in continued deferral of further FDA action toward 
implementing (Alternative A) or finalizing and implementing 
(Alternative B) a comprehensive mandatory program has been met. 
Similarly, the third survey iteration will be conducted approximately 6 
years later. Together with the results of FDA's evaluation of patient 
information usefulness, the distribution rates obtained from this final 
iteration will determine whether the standard of useful information 
distribution has been attained.
    FDA encourages interested groups to sponsor similar distribution 
rate evaluations in the intervening years to achieve a more complete 
picture of the effectiveness of information distribution of the 
voluntary programs. FDA will make its methodology and survey 
questionnaire available to the public and will provide technical 
assistance to any party interested in using this procedure.
    One major limitation of the survey is that patient reports obtained 
over the telephone cannot detail the type of information disseminated. 
Further, these reports rely on patient memory, which may be subject to 
distortions. Therefore, FDA will conduct a one-time-only pharmacy 
``shopping'' survey to validate the telephone interviewing data related 
to the distribution of written information with dispensed new 
prescriptions. This will be a multiple city survey. Observers will pose 
as patients and fill prescriptions for a commonly used drug. The 
observers will collect written information disseminated to patrons. 
They will also record oral interactions with pharmacy personnel and the 
existence of collateral information available to patients.
    Although FDA would also prefer to validate the reported data 
concerning oral and written information obtained at the licensed 
practitioner's office, there are numerous cost, methodological, and 
logistical barriers to a data collection of such size and complexity. 
FDA invites comments about the advisability of, and recommendations for 
how to accomplish, validating these data.
    Data from the shopping survey will be analyzed in conjunction with 
a concomitant telephone survey to validate self-reported rates and to 
help understand the degree to which any reporting biases may influence 
the telephone survey results. The shopping survey will also obtain 
information about the use of various commercial information systems at 
pharmacies across the country. These data, along with obtainable 
industry-trend data, will be used to project national totals of the 
degree to which information is being disseminated to patients.
    FDA will also collect sample patient information pieces from 
commercial suppliers. The initial data collection will occur 
immediately following publication of the final rule, with additional 
collections occurring at 2-year intervals. Sample information sheets 
will be obtained for commonly used medications. Rarely used medications 
(not in the top 500 most commonly prescribed) and medications for which 
patient information may be problematic (e.g., cancer chemotherapy, 
major psychotropic medications) will not be included in these samples.
    FDA will estimate the extent to which each system is used 
nationally. FDA will also estimate the percentage of prescriptions 
delivered through other distribution channels (e.g., mail-order 
pharmacies, dispensing physicians) and the extent to which different 
patient information systems are used in these distribution channels.
2. Determination of Information Usefulness
    FDA will determine the degree to which obtained samples of patient 
information meet the performance standard of useful information. The 
samples will be evaluated on each component, using the criteria 
described above. Each sample will be scored on each criterion, using 
``acceptable'' and ``not acceptable'' cutoff points. As mentioned, FDA 
believes that for a particular information sheet to be judged as 
acceptable overall, it must receive an acceptable rating on each of the 
individual components. However, the agency solicits comments regarding 
this rule of operation.
    In addition, FDA solicits comments regarding how many and what type 
of drug products should be included in the patient information review, 
and how each component of usefulness should be scored. FDA also intends 
to hold a Part 15 Hearing or other public forum where interested 
parties could provide recommendations and rationale for usefulness 
components, associated criteria, and ratings systems for patient 
information. 

[[Page 44202]]


D. Feedback and Application of Standards

1. Reporting the Evaluation Results
    Approximately every 2 years, FDA will issue a report on the overall 
acceptability of written information, including ratings on each of the 
components of usefulness. Newly updated distribution rates will also be 
reported in relevant years (i.e., with the first, third, and sixth 
information evaluations). In these years, the report will also provide 
oral counseling rates.
    FDA intends to estimate the percentage of patients receiving useful 
information by multiplying the percentage of patients stating that they 
received written information in the national survey by the percentage 
of patient information sheets judged as useful (weighted by estimated 
distribution rates for the sheets and the overall usefulness rating for 
the sheets).
    FDA plans to issue a report discussing the results of each survey. 
The report will be in sufficient detail to permit an analysis of the 
basis of the computed percentages. It will also describe the analysis 
of each information sheet's performance on each of the usefulness 
components.
2. Report Implications
    If Alternative A is selected, FDA will continue to defer the 
implementation date for the full Medication Guide program (except for 
the section that requires Medication Guides for specific drugs which 
FDA has determined have serious and significant public health concerns 
requiring immediate distribution of FDA-approved patient information) 
if the third evaluation report indicates that 75 percent of patients 
receive useful information. FDA will continue to conduct these surveys 
every 2 years. If the sixth evaluation report indicates that 95 percent 
of patients receive useful information, FDA will propose revocation of 
the sections of the rule that provide for implementation of a 
comprehensive Medication Guide program.
    If Alternative B is selected and the third evaluation report 
indicates that 75 percent of patients receive useful information, FDA 
would continue to leave unfinalized the proposal for a comprehensive 
Medication Guide program. If this goal is not met, FDA would seek 
public comment on whether the comprehensive Medication Guide program, 
as proposed in this document, should be finalized and implemented, or 
whether, and what, other steps should be taken to help ensure that the 
goal is met. A similar judgment will be made based on whether the sixth 
evaluation report indicates that 95 percent of patients receive useful 
information.
    In extrapolating from sample statistics to population parameters, 
all measurement involves a certain degree of imprecision. An estimate 
of expected sampling error for a simple random sample of 1,000 would be 
approximately plus or minus 3 percentage points of the sample 
statistic. FDA is proposing to use a relatively inclusive plus or minus 
5 percentage points as the acceptable error (confidence interval at 
=.95) for the standards for information distribution. Using 
this interval means that the year 2000 standard would be met if it was 
determined that between 70 percent and 80 percent of patients received 
useful information. The year 2006 standard would be met if it was 
determined that between 90 percent and 100 percent of patients received 
useful information. FDA requests comments concerning whether this is 
the most appropriate confidence interval to use.
    Given the time necessary to implement an adequate patient 
information program, by either a mandatory program or a continuation of 
voluntary programs, FDA anticipates that the great majority of patients 
should receive useful patient information by approximately 10 years 
after the effective date of a final rule based on this proposal.

E. Medication Guide Program

    The regulations set forth in this proposal describe a program that 
requires manufacturers to prepare FDA-approved patient labeling 
(Medication Guides) for their prescription drug products. The 
regulations specify the format and content for such information. They 
further specify that manufacturers must provide drug distributors and 
authorized dispensers with sufficient copies of these Medication 
Guides, or the means to produce sufficient copies, such that each 
patient receives a Medication Guide with dispensed new prescriptions 
and upon request with a refill.
    Under Alternative A, in the event that the distribution and/or 
``useful'' performance standards previously described are not met, the 
final regulation based on this proposal (mandatory program) would be 
fully implemented. An announcement of the institution of such a program 
would be issued concurrently with the third or the sixth evaluation 
report notice published in the Federal Register (no sooner than 5 years 
or, if the rule continues to be deferred after the third evaluation 
report, 11 years after the effective date of the final rule).
    To implement this requirement, New Drug Application (NDA) 
applicants and holders would be required to submit draft Medication 
Guides for all submissions for new molecular entities (NME's) and for 
new indications for approved products. In addition, concurrent with an 
announcement that the regulations will be fully implemented, FDA would 
publish an implementation schedule. This schedule would require that 
application holders submit draft Medication Guides for specified NDA's. 
FDA envisions that such a schedule would be based upon the most 
frequently used products at the time. In order to avoid problems with 
uneven competitive requirements, FDA would also consider the 
simultaneous review of products within the same pharmacological or 
therapeutic category.
    Once an innovator drug Medication Guide was approved, manufacturers 
of generic versions of the drug would also be required to prepare and 
distribute Medication Guides modeled after the innovator's approved 
Medication Guide.
    Given the large number of drugs on the market, FDA envisions that 
it would take approximately 10 years to complete approval for the vast 
majority of Medication Guides. However, by implementing the Medication 
Guide requirement as a function of the most popularly used products 
first, a larger percentage of dispensed prescriptions would be covered.
    Under Alternative B, if the distribution and/or ``useful'' 
performance standards are not met, FDA would seek comment on whether 
the proposal requiring a comprehensive Medication Guide program, as 
described in this document, should be finalized and implemented, or 
whether, and what, other steps should be taken by FDA to ensure that 
the patient information goals are met. Subsequent to this comment 
period, either the Medication Guide regulations proposed in this 
document would be finalized and implemented, or FDA would repropose a 
different approach to helping to ensure attainment of the specified 
goals.

IX. Conclusion

    The long history of PPI's demonstrates that disagreements between 
the public and private sectors in determining the best approach for 
providing patient information have not served patients well. Since the 
issue was first discussed in the 1970's, virtually all interested 
parties have agreed that there is a critical need to better inform 
patients 

[[Page 44203]]
about their medications. Most of those who opposed PPI's accepted the 
premise that patients needed to be better informed. However, opponents 
argued that the private sector could do a better job of educating 
patients if left unencumbered by Federal regulations. FDA came to the 
same conclusion and withdrew requirements for the program. In the 
ensuing decade, however, evaluations demonstrate that although many 
private sector programs have been initiated, their impact on patient 
education has been disappointingly low.
    In the last 2 years, however, the increasing computerization of 
pharmacies together with OBRA '90 requirements have apparently 
contributed to an increase in the provision of oral and written patient 
information. However, FDA's review of popular commercial systems in use 
indicates that the quality of information provided is uneven. In the 
interests of encouraging a continuation of this distribution trend, and 
improving the value of the information to patients, FDA has concluded 
that both standard- setting activities and the addition of a strong 
incentive are appropriate and necessary.
    Prior to developing this proposed rule, FDA met individually with 
representatives of the pharmacy, pharmaceutical industry, patient 
information producer, medical, and consumer communities. All of the 
represented constituencies at these meetings indicated that they wanted 
health professionals to provide patients with useful written 
prescription drug information.
    As mentioned above, in addition to soliciting written comments, FDA 
intends to hold a Part 15 Hearing to solicit a broad range of views 
about how best to measure usefulness of individual patient information 
pieces. It should be clear to all parties, however, that FDA's concern 
is not with the distribution of pieces of paper, but with the education 
and empowerment of patients. Therefore, FDA intends to expand this 
dialogue to solicit new ideas and feedback about other aspects of this 
proposal, such as how medication adherence can be more effectively 
facilitated, and new ideas about how to communicate information to 
patients. FDA believes that presentations based upon research with 
patients and consumers will be especially important; thus, FDA will 
actively solicit such information. Developing systems that make maximal 
use of technology and can be flexibly adapted to all patients, thus 
providing useful and specific information, is the goal of FDA's broader 
commitment to improving patient information. This goal will take an 
active partnership to meet; it cannot be achieved by FDA alone.
    Private sector efforts also will be needed to improve the basic 
mechanism through which patient education about prescription medicines 
occurs, i.e., oral counseling. In addition, programs are needed to 
stimulate discussions about medications by health care professionals 
when the medications are initially prescribed. Organizations that can 
help determine the best mechanism for health professionals to introduce 
and discuss patient medication information with patients would be vital 
to the success of the program.
    Additional programs also will be needed to provide educational aids 
to patients with literacy problems to help them utilize medication 
information most effectively. These programs must be diverse and 
targeted to address the particular deficiencies causing the literacy 
problem.
    Data from the recent survey ``Adult Literacy in the United States'' 
(Ref. 72) indicate that most of the individuals who perform at the 
lowest level of proficiency (from 66 to 75 percent) described 
themselves as able to read or write English ``well'' or ``very well.'' 
They did not view themselves as deficient in any substantive fashion. 
It would be inappropriate for health care professionals to withhold 
information from patients merely on the premise that they may have some 
difficulty understanding the information. Even with basic skills, 
interested patients would be able to profit to some extent from the 
documents. With additional help, the vast majority of patients would be 
able to profit from improved information.
    Of major importance to the success of improved patient information 
would be private suppliers or organizations that can help pharmacies, 
physicians' offices, and managed care organizations store, access, 
produce, and/or distribute medication information. Groups that can 
provide customized services to meet the individual needs of the vast 
array of authorized dispensers would be of great service to help this 
community meet the desired objectives. Such groups could expand the 
provision of other information, such as disease information or general 
information about using medicines safely, which would augment the 
educational benefit for patients.
    FDA welcomes comments about these topics and remains dedicated to 
forging a medicine information delivery system that encourages, and 
does not retard, the development of innovative communication systems.

X. Description of the Proposed Rule

    The proposed rule, if finalized, would require a Medication Guide 
for certain human prescription drug products, including biological 
products. The rule would require manufacturers to prepare and 
distribute, or provide the means for distributing, a Medication Guide 
that would accompany prescription drug products that patients receive 
and use on an outpatient basis without the direct supervision of a 
health care professional. Medication Guides would be distributed with 
all new prescriptions and with refills when requested by the patient.
    Under Alternative A, the provisions in the proposed rule would be 
deferred for a majority of the prescription drug and biological 
products that otherwise would be affected in order to give voluntary 
efforts an opportunity to achieve specific goals of distribution of 
useful drug information within specified timeframes. The agency will 
measure the success of the voluntary efforts by establishing 
performance standards that measure both the distribution of patient 
medication information and information usefulness. The agency will 
conduct periodic evaluations to measure whether the performance 
standards are met and will issue reports of the findings. If the 
performance standards are not met by the end of each of two specified 
timeframes, the provisions of the rule would be implemented.
    For products that pose a serious and significant public health 
concern requiring immediate distribution of patient information the 
provisions would be implemented 30 days following publication of the 
final rule.
    Under Alternative B, FDA would also give voluntary efforts an 
opportunity to achieve the goals of distribution of useful information 
within specified timeframes. The difference, however, is that under 
this option the agency does not intend to finalize immediately the 
proposed performance standards, or the sections that defer 
implementation, in the form of a regulation. Instead, the agency 
intends to use the proposed performance standards as guidance for the 
private sector. If the performance standards are not met at the 
specified times, then the agency will seek public comment on whether a 
comprehensive Medication Guide program, as described in this proposal, 
should be finalized and implemented or whether, and what, other steps 
should be taken to meet the patient information goals.
    For Alternative B, FDA, however, does intend to finalize the 
requirement for products that pose a serious and 

[[Page 44204]]
significant public health concern requiring immediate distribution of 
FDA-approved patient information. This provision would be implemented 
30 days following publication of the final rule.
    To be of value, product information must be understandable to 
patients. The use of overly technical language may deter patients from 
reading important information. Therefore, the proposed rule would 
require that the Medication Guide be written in nontechnical language, 
be nonpromotional in tone or content, be based on the professional 
labeling for the drug product, and be presented in a uniform format.
    The Medication Guide would contain a summary of the most important 
information about a drug product, including the approved uses for the 
product, circumstances under which the drug product should not be used, 
serious adverse reactions, proper use of the product, cautions related 
to proper use, and other general information.
    Parties would be permitted to request an exemption for a particular 
drug product from any of the specific requirements of the proposed 
rule. The proposed rule would also permit the agency to exempt or defer 
certain drug products from the requirement of a Medication Guide.
    The proposed rule would require manufacturers to provide directly, 
or supply the means to provide, sufficient numbers of the Medication 
Guide to the distributor or dispenser of a prescription drug product. 
The dispenser, in turn, would be required to provide the Medication 
Guide to the patient. FDA is proposing to exempt qualifying small 
retail pharmacy outlets from the requirement to dispense a Medication 
Guide, except for products packaged in unit-of-use containers and for 
products which the agency determines must be dispensed with a 
Medication Guide.
    Specific provisions of the proposed rule are as follows:

A. Scope and Implementation

    Proposed Sec. 208.1(a) would limit the Medication Guide 
requirements to human prescription drug products, including biological 
drug products, administered primarily on an outpatient basis without 
the direct supervision of a health professional. FDA is proposing this 
limitation because, as discussed earlier in this preamble, the agency 
believes that patients generally seek and are ready to receive and 
understand information about their drug products after they have 
received them. The Medication Guide would serve as an at-home reference 
for patients when they are ready to self-administer products. The 
proposed rule requires that a Medication Guide be dispensed with new 
prescriptions, and with refills if requested by the patient. The 
proposed rule would not apply to prescription drug products 
administered in licensed practitioners' offices or institutional 
settings, such as hospitals, nursing homes, or other long-term care 
facilities, because FDA believes that the continuous presence of health 
professionals in these settings gives patients the opportunity to ask 
questions about their prescription drug products. The proposed rule 
also would not apply in emergency situations because FDA believes 
distribution of the Medication Guide in such situations would be 
impractical. FDA has also provided an exemption for small retail 
pharmacy outlets. Other dispensers which meet the small business 
criteria set forth in the regulations would also qualify for such an 
exemption.
    Proposed Sec. 208.1(b) defers the implementation of the Medication 
Guide provisions for all affected drug and biologic products, except 
for the Sec. 208.1(d) products, until a determination is made by FDA 
that certain performance standards have not been met.
    Proposed Sec. 208.1(b)(1) would provide for the Medication Guide 
provisions for all but the Sec. 208.1(d) products to be deferred if 75 
percent of the patients receiving new prescription drugs or biologics 
covered under these provisions receive useful patient information 5 
years from the effective date of the final rule. If this standard is 
met, FDA would continue to monitor the voluntary efforts for 
distributing patient information. As proposed in Sec. 208.1(b)(2), if, 
after an additional 6 years, 95 percent of the patients receiving new 
prescription drugs or biologics covered under these provisions receive 
useful patient information, the Medication Guide provisions would 
continue to be deferred, except for the Sec. 208.1(d) products.
    As described in greater detail previously, the agency will evaluate 
both the distribution and usefulness of the information with regard to 
specific criteria. Proposed Sec. 208.1(c) includes the seven proposed 
components of the usefulness standard. An extensive discussion of the 
specific criteria the agency proposes to use in evaluating achievement 
of the usefulness standard is found in section VIII. of this document. 
FDA is considering whether the details of these criteria should be 
restated in the codified language, and invites comment on this issue.
    Under Alternative A, if both of the requirements in proposed 
Sec. 208.1(b) are met, the provisions of this part would be deferred 
for all products except those that the agency determines pose a serious 
and significant public health concern requiring immediate distribution 
of patient information. In addition, under Alternative A, if both of 
the requirements in proposed Sec. 208.1(b) are met, the agency intends, 
at that time, to initiate notice and comment rulemaking to revoke 
Sec. 208.1(b)(1) and (b)(2).
    As discussed previously, under Alternative B, the agency does not 
intend to finalize Sec. 208.1(b) and (c) immediately. Rather, if the 
performance standards set forth in proposed Sec. 208.1(b) and (c) are 
not met, the agency will again seek public comment on whether a 
comprehensive mandatory Medication Guide program, as described in this 
document, should be implemented or whether, and what, other steps 
should be taken to meet the goals.
    Under both alternatives, proposed Sec. 208.1(d) would allow FDA to 
require that FDA-approved Medication Guides be distributed with certain 
prescription drug products. See Section VIII. of this document for a 
discussion of the criteria that would be used to determine the types of 
products that may fall under Sec. 208.1(d).

B. Definitions

    Proposed Sec. 208.3(a) would define ``authorized dispenser'' as an 
individual who may legally dispense prescription drug products. FDA 
believes that, in most instances, the authorized dispenser will be a 
pharmacist.
    Proposed Sec. 208.3(b) would define the phrase ``dispense to 
patients'' as the act of delivering a prescription drug product to a 
patient or an agent of the patient. Because the proposed rule would 
apply only to drug products dispensed on an outpatient basis without 
the direct supervision of health care professionals, proposed 
Sec. 208.3(b) limits the scope of ``dispensing.'' For instance, the 
definition of the phrase ``dispense to patients'' does not include the 
delivery of a nonprescription drug product.
     Proposed Sec. 208.3(c) would define ``distribute'' as ``the act of 
delivering (other than by dispensing) a drug product to any person.''
    Proposed Sec. 208.3(d) would define ``distributor'' as a person who 
distributes a drug product. FDA notes that its interpretation of a 
distributor has traditionally included repackers, and would do so here. 


[[Page 44205]]

    Proposed Sec. 208.3(e) would define ``licensed practitioner'' as an 
``individual licensed, registered, or otherwise permitted by the 
jurisdiction in which the individual practices to prescribe drug 
products in the course of professional practice.''
    Proposed Sec. 208.3(f) would define ``manufacturer'' as described 
in Secs. 201.1 and 600.3(t) of this chapter.
    Proposed Sec. 208.3(g) would define ``patient'' as any individual 
with respect to whom a drug product is intended to be, or has been, 
used.

C. Content of a Medication Guide

    Proposed Sec. 208.20 would describe the content of a Medication 
Guide. As stated earlier, FDA believes that the information in a 
Medication Guide must be written in language that is easily understood 
by patients. To ensure that information in a Medication Guide provides 
a comprehensible and objective description of the drug product, 
proposed Sec. 208.20(a)(1) would require that information be written in 
English, presented in lay language, and would prohibit the use of 
promotional language.
    While FDA acknowledges that there is a significant minority of U.S. 
citizens who speak Spanish as their primary language, it hesitates to 
impose the additional burdens on manufacturers and dispensers that 
would result from requiring the availability of Medication Guides 
written in Spanish for these individuals. FDA also recognizes the many 
other population segments who do not speak English as their primary 
language. FDA requests comments concerning how it can most fairly and 
effectively communicate patient medication information to these 
populations.
    Under proposed Sec. 208.20(a)(2), the Medication Guide must be 
based on, and must not conflict with, the approved professional 
labeling for the drug product. The Medication Guide should, in general, 
provide a lay ``translation'' of those portions of the professional 
labeling that are important for effective consumer understanding and 
use of the product. This ``translation'' may include sufficient 
background information or context to facilitate consumer understanding. 
Proposed Sec. 208.20(b) lists specific types of information that must 
be included in a Medication Guide. Under proposed Sec. 208.20(b)(1), 
the Medication Guide would be required to identify the drug product 
brand name (e.g., trademark name or proprietary name), if any, and 
established name. If the product does not have an established name, the 
proposed rule would require that the drug product be designated by its 
active ingredients. In addition, the Medication Guide would include the 
phonetic spelling of the brand name or the established name, whichever 
name appears throughout the Medication Guide.
    Because many people take a number of drug products, FDA believes 
that it is important that patients be easily able to match a drug 
product with the correct Medication Guide. Information could include 
the color, shape, markings, and, if applicable, the drug product's code 
imprint. There are a number of possible ways to provide this 
information including: (1) A separate identification section, (2) 
including the information in the personalized section (this optional 
section of the Medication Guide is explained later in the preamble to 
this proposal), or (3) providing preprinted stickers that would be 
placed on the appropriate Medication Guide by the dispenser. An example 
of one way to provide product identification information is displayed 
in the sample Medication Guides in Appendix C.
    Proposed Sec. 208.20(b)(2) would require a brief section concerning 
the most important aspects of taking the drug product. This would 
include the product's approved indications, especially important 
instructions for proper use of the drug, and any significant warnings, 
precautions, contraindications, serious adverse reactions, and 
potential safety hazards.
    Proposed Sec. 208.20(b)(3) would require the Medication Guide to 
contain a statement identifying the product's indications, that is, the 
uses identified in the indications and usage section of the approved 
professional labeling. The Medication Guide may summarize indications 
or omit rarely prescribed indications.
    Proposed Sec. 208.20(b)(4) would require the Medication Guide to 
identify the conditions under which the drug product is not to be used 
for its labeled indications, i.e., contraindications to the product's 
use. In nontechnical language, the labeling would describe the 
contraindications specified in the professional labeling for the drug 
product, reminding the patient, for example, to provide the licensed 
practitioner with relevant medical history or information about other 
drugs the patient is taking that may pose a significant 
contraindication. Contraindications to use may include a previous 
allergic reaction to the product, pregnancy, the patient's use of 
certain other medications, or a particular condition that might make 
the drug product less effective or dangerous.
    Proposed Sec. 208.20(b)(4) would also require inclusion of the 
steps the patient should take to remedy the situation should any of the 
listed circumstances apply. This may include consulting with his or her 
licensed practitioner before taking the drug, discontinuing use of the 
product, etc.
    Proposed Sec. 208.20(b)(5) would require the Medication Guide to 
describe precautions related to the proper use of the drug product. 
Under proposed Sec. 208.20(b)(5)(i), these precautions would include 
activities the patient should avoid while taking the drug product, such 
as driving or sunbathing, and list other drugs, foods, or substances, 
including alcohol or tobacco products, the patient should avoid because 
they may interact with the drug product. The information would help 
patients use the drug product in a way that would promote its safety 
and effectiveness.
    Under proposed Sec. 208.20(b)(5)(ii), the Medication Guide must 
also contain a statement regarding the product's use in pregnant women. 
The statement must discuss any risks to the pregnant woman or the 
fetus. Proposed Sec. 208.20(b)(5)(iii) through (b)(5)(vi) would also 
require the Medication Guide to contain, if appropriate, precautionary 
information about risks to a nursing infant, and any information on use 
and risks for pediatric, geriatric, or other identifiable patient 
populations.
    Proposed Sec. 208.20(b)(6)(i) would require the Medication Guide to 
list and describe adverse reactions associated with the use of the drug 
product that are serious or occur frequently. This information would be 
presented in a manner that would help patients understand and remember 
it. Material presented under this provision would restate, in 
nontechnical language, the information regarding the most significant 
warnings and adverse reactions specified in the professional labeling. 
In addition, where appropriate, the Medication Guide should inform the 
patient what to do if they occur.
    Organizing and explaining adverse reaction information for 
different drug products may vary. For example, adverse reactions might 
be organized by the organ systems in which they occur, by their 
severity, by the frequency with which they occur, by a combination of 
these approaches, or by any other appropriate method that would provide 
patients with the information. In contrast to the professional 
labeling, which often contains an exhaustive list of associated adverse 
reactions, regardless of their frequency, the Medication Guide should 
only list those adverse reactions that are meaningful to 

[[Page 44206]]
the patient, in terms of seriousness, and/or frequency.
    Proposed Sec. 208.20(b)(6)(ii) would require the Medication Guide 
to discuss the risks, if any, to the patient of developing a tolerance 
to or a dependence upon the drug product.
    Proposed Sec. 208.20(b)(7) would require information concerning the 
proper use of the drug product. Studies indicate that many patients do 
not take prescription drugs properly (Refs. 3 and 4). Consequently, 
proposed Sec. 208.20(b)(7)(i) would require a statement stressing the 
importance of adhering to the dosing instructions. Under proposed 
Sec. 208.20(b)(7)(ii), the Medication Guide would also contain any 
special instructions on how to administer the drug; for example, proper 
dosing intervals, whether the drug should be taken with food, or at a 
period of time before or after eating. For products such as inhalers, 
injectables, skin patches, and so on, that have special instructions 
for administration, these instructions should be referenced in the 
Medication Guide.
    Proposed Sec. 208.20(b)(7)(iii) would require a statement of what a 
patient should do in case of an overdose, i.e., contact the local 
poison control center or hospital emergency room. Since FDA notes that 
a significant number of patients fail to adhere to the dosing regimen, 
proposed Sec. 208.20(b)(7)(iv) would require a statement of what a 
patient should do if the patient misses taking a scheduled dose.
    Proposed Sec. 208.20(b)(8) would also require the Medication Guide 
to contain general information about the safe and effective use of 
prescription drug products.
    Patients may become concerned if their Medication Guide does not 
include the purpose for which their health professional prescribed the 
product. Therefore, proposed Sec. 208.20(b)(8)(i) would require 
inclusion of the verbatim statement that ``Medicines are sometimes 
prescribed for purposes other than those listed in a Medication 
Guide.'' This statement would be juxtaposed with a statement 
encouraging the patient to discuss any questions or concerns about the 
drug product with a health professional.
    Although health professionals understand that approved products may 
be prescribed for other than FDA-approved indications, patients 
typically do not possess this knowledge. Therefore, it is appropriate 
to advise them of this fact, and that they should bring any concerns 
they may have to the attention of a health professional. FDA believes 
that these disclosures provide the necessary context to ensure that 
patients will comprehend effectively medication information. The agency 
stresses, however, that such ``contextual'' disclosure is inappropriate 
for professional labeling, which is directed at health professionals 
who are already aware of their freedom to prescribe medicines as they 
see fit, as part of the practice of their profession.
    FDA also notes that this statement is an acknowledgment about the 
use of medicines in general, not about any particular product. The 
agency will not sanction the use of this or similar statements 
concerning unapproved uses in promotional labeling and advertising for 
specific products.
    Proposed Sec. 208.20(b)(8)(i) would also require a statement noting 
that professional labeling for drug products may be available from the 
patient's authorized dispenser or licensed practitioner. Many 
individuals, including some pharmacists and licensed practitioners, 
erroneously believe that State or Federal law prohibits providing a 
drug product's professional package insert to patients. Moreover, the 
professional labeling for a drug product provides the most detailed and 
comprehensive information about prescription drug products and should 
be available to any patient upon request. Although the professional 
labeling for a drug product may be too technical for many patients to 
understand, patients should be encouraged to learn more about their 
medications and may seek to examine professional labeling. Authorized 
dispensers and licensed practitioners are able to answer questions 
about the professional labeling and thereby reduce the amount of 
confusion produced by its technical language.
    Proposed Sec. 208.20(b)(8)(ii) would require a statement informing 
the patient that the drug product has been prescribed for the sole 
purpose of treating the patient's condition and must not be used for 
other conditions or given to other persons. This statement is intended 
to caution against the dangers of self-diagnosis and lay diagnoses in 
general. A licensed practitioner prescribes a particular drug to treat 
a certain condition in a certain individual. Use of the drug by lay 
persons to treat another condition in the same individual may be, at 
best, ineffective and, at worst, directly hazardous to a patient's 
health or indirectly hazardous by delaying proper diagnosis and 
treatment. Use of the drug by another individual, without a 
professional evaluation of the individual's medical condition and 
history, could be life-threatening.
    Section 208.20(b)(8)(iii) would require the manufacturer's, 
packer's, or distributor's name and address; or the name and address of 
the dispenser of the drug product; or for biological products, the 
name, address, and license number of the manufacturer. This information 
could assist the manufacturer or distributor and FDA in tracing and, if 
necessary, recalling the drug product. Furthermore, providing names and 
addresses would enable patients to contact a manufacturer or 
distributor if they have any questions about the drug product.
    Section 208.20(b)(8)(iv) would require the date of the most recent 
revision to the Medication Guide. This will enable patients and 
authorized dispensers with multiple versions of a Medication Guide to 
determine which Medication Guide contains the most current information.
    The contents of a Medication Guide may vary based on the product's 
dosage form, bioavailability, or extent of systemic exposure, as stated 
in the product's labeling. For example, some topical prescription drug 
products that are not systemically absorbed may not require a statement 
regarding the activities, drugs, foods, or other substances that a 
patient should avoid when taking the drug product, or information on 
risks from use of the drug product during pregnancy, labor, delivery, 
or nursing. FDA encourages manufacturers, distributors, and others who 
have questions on the preparation or content of their Medication Guide 
to contact FDA.
    The Medication Guide shall be dispensed as approved by FDA without 
the inclusion of any additional information. However, authorized 
dispensers may, and are encouraged to, personalize the Medication Guide 
document by including, for example, the prescription number, the name, 
address, and/or telephone number of the authorized dispenser and/or 
licensed practitioner, and information personally identifying the 
patient and relevant demographic or medical information (that does not 
violate the patient's privacy). This information may precede or follow 
the required information in the Medication Guide, but in no instance 
should the information be more prominent or obscure any required 
information. Authorized dispensers and licensed practitioners are also 
permitted and encouraged to supply special instructions regarding the 
product's use directly before or following information in the 
Medication Guide.

D. Format for a Medication Guide

    FDA believes that the Medication Guide should have a uniform format 
so 

[[Page 44207]]
patients can become familiar with the type and location of specific 
information. The proposed rule would require the Medication Guide to 
contain identical section headings, a consistent order of information, 
the use of highlighting techniques, and a minimum type size.
    A ``shell'' of the proposed uniform format is displayed in Appendix 
A of this document. FDA chose different drugs to illustrate the uniform 
format, and these examples may be found in Appendix B of this document. 
Examples of the Medication Guide using alternative formats are 
displayed in Appendix C of this document. FDA invites comment on these 
alternative formats. These Medication Guide models were prepared solely 
by FDA for illustrative purposes and do not represent approved labeling 
by the agency.
    The proposed rule would allow the Medication Guide to reach 
consumers through a variety of methods, ranging from traditional 
preprinted inserts to state-of-the-art, computer-generated material. 
The agency recognizes that the level of information technology varies 
widely across the country. For instance, while most pharmacies are now 
equipped with computers, both the ability to access outside materials 
and the print quality of computer-generated documents can vary greatly. 
Thus, the proposed Medication Guide regulations are designed to 
accommodate these varying levels of technology and not hinder 
technological advances or improvements in the transmission of patient 
information.
    Proposed Sec. 208.22(a), would establish a minimum 10-point type 
size for the Medication Guide (1 point = 0.0138 inches). This 
requirement applies to all sections of the Medication Guide except the 
name and address of the manufacturer and the revision date. FDA 
believes that this type size is necessary to facilitate easy reading by 
elderly patients. However, as legibility is determined by additional 
graphic factors, proposed Sec. 208.22(b) would require that the print 
be legible and clearly presented.
    Additionally, FDA is proposing to amend the professional labeling 
regulation at 21 CFR 201.57, which requires the professional labeling 
to reprint, in its entirety, any patient labeling for a drug product. 
The proposed amendment would clarify that the 10-point minimum type 
size does not apply to any patient labeling or Medication Guide that is 
reprinted in the professional labeling.
    FDA recognizes that the communication of important information 
requires graphic emphasis to highlight certain portions of the text. 
The graphic emphasis selected should be appropriate to the particular 
method of printing the Medication Guide. Thus, while multiple colors 
may be used for emphasis in preprinting the Medication Guide, the use 
of dot-matrix computers would require boldfacing, underlining, or some 
other highlighting method.
    As stated earlier in the preamble, the agency acknowledges that 
there are many forms of commercially available, consumer-oriented 
medication information. To enable patients to recognize that the 
Medication Guide is the ``official'' patient labeling for a particular 
drug product, proposed Sec. 208.22(c) would require every Medication 
Guide to contain the words ``Medication Guide'' prominently at the top 
of the first page of each Medication Guide. It would also require, at 
the bottom of the Medication Guide, the verbatim statement that ``This 
Medication Guide has been approved by the U.S. Food and Drug 
Administration.'' Section 208.22(d) would require the brand and 
established name to be prominently displayed. The established name 
shall not be less than one-half the height of the brand name.
    In order to organize the information in the Medication Guide, 
proposed Sec. 208.22(e) would require that the content requirements 
listed in Sec. 208.20 be placed under specified headings. These 
headings would also be placed in a specified order so that the patient 
can easily find the information. The proposed headings are in question 
form and would include:
    (1) ``What is the most important information I should know about 
(name of drug)?;''
    (2) ``What is (name of drug)?;''
    (3) ``Who should not take (name of drug)?;''
    (4) ``How should I take (name of drug)?;''
    (5) ``What should I avoid while taking (name of drug)?;''
    (6) ``What are the possible side effects of (name of drug)?''
    The Medication Guides for certain drugs may require additional 
headings, e.g., ``How should I store (name of drug)?'' (See Ceclor for 
oral suspension draft Medication Guide in Appendix B of this document.)
    The agency invites comments on alternative headings. Examples of 
alternative headings appear in the Medication Guide models published in 
Appendix C of this document.
    In developing these model Medication Guide formats, FDA has 
reviewed the formats used in a variety of patient information leaflet 
systems and in patient information books. The agency has tentatively 
concluded that the preferred format is the one that provides consumers 
with questions about their medication and answers to these questions 
and that organizes the information in a way similar to the professional 
labeling. This will help manufacturers to prepare the Medication Guide 
and place information in a consistent section of the Medication Guide. 
Patients will obtain information that is consistent with professional 
labeling. FDA intends to evaluate this (and other possible) formats 
during the comment period for this proposal.
    FDA recognizes that there are important differences between 
labeling directed toward professionals and the Medication Guide 
directed toward patients. The format for the Medication Guide should 
help emphasize the most important information the patient needs to know 
to use the drug product properly and to communicate with his or her 
health care professional. Major sections of the professional labeling, 
such as the Clinical Pharmacology section, that are useful to health 
care professionals, are not likely to be as useful to patients 
(although conclusions from that section, such as effects of food on 
absorption, may be important). Similarly, other information, such as 
complete lists of reported adverse reactions, may overwhelm the patient 
or obscure the most important information. Thus, to facilitate the 
communication of information to patients in a meaningful fashion, the 
Medication Guide will be expected to summarize and distill the contents 
of the professional labeling into terms that are more understandable 
and useful to the layperson. On the other hand, it is not expected that 
the Medication Guide will omit serious or potentially adverse 
consequences of using the medicine that are important for patients to 
know.
    FDA will also permit the addition of ``contextual'' information, 
not included in the professional labeling, to help patients understand 
the labeling information despite their lack of background and training 
in medicine.
    FDA is aware that excessive length may discourage use of Medication 
Guides and interfere with the communication of important messages. FDA 
will therefore attempt to limit the amount of information included in 
the Medication Guide, focusing on and emphasizing the most important 
information for the patient (e.g., by changes in typeface, use of white 
space or contrast, underlining). The Medication Guide samples reprinted 
in the appendices to this document 

[[Page 44208]]
provide examples of how FDA believes a Medication Guide should be 
formatted, composed, and otherwise structured for the patient. In 
addition to inviting general comments on these formats, FDA invites 
comments on whether the Medication Guide should be printed on paper of 
a specific size and whether a page limit (e.g., two pages) is 
appropriate.

E. Distributing and Dispensing of a Medication Guide

    The proposed rule is intended to ensure that consumers receive 
patient labeling information, but permits manufacturers, distributors, 
and dispensers to provide information in addition to that required 
under the proposed rule. The agency has designed the distribution and 
dispensing requirements to be flexible and to accommodate the increased 
use of computers and other technological advances in pharmacies.
    Proposed Sec. 208.24(a) would establish distribution requirements 
for drug products in finished dosage form that are packaged in large 
volume containers. Under the proposal, a manufacturer that ships a 
large volume container of a finished dosage form to a distributor or an 
authorized dispenser would be required to provide the Medication Guide 
in sufficient numbers, or the means to produce the Medication Guide in 
sufficient numbers to enable the authorized dispenser to provide a 
Medication Guide to each patient receiving the drug product.
    The reference to the ``means to produce the Medication Guide in 
sufficient numbers'' signifies that a manufacturer is not limited to 
providing hard copies of the Medication Guide to its distributors and 
authorized dispensers. Instead, the manufacturer can satisfy its 
distribution requirements by giving distributors and authorized 
dispensers the ``means'' to produce the Medication Guide in sufficient 
numbers. For example, the manufacturer could provide computer software 
that enables the distributor or authorized dispenser to print the 
Medication Guide. However, FDA cautions that if a manufacturer elects 
to give distributors and authorized dispensers the ``means'' to produce 
the Medication Guide, it must give the individual distributor or 
authorized dispenser an effective means, including resources and 
materials, to produce the Medication Guide. In other words, FDA would 
not consider a manufacturer to have complied with its regulatory 
obligations if it gave incompatible software to a distributor or 
authorized dispenser or provided items that would require the 
distributor or authorized dispenser to purchase other machines, goods, 
or services in order to produce a Medication Guide.
    For each drug product requiring a Medication Guide, proposed 
Sec. 208.24(a)(2) would require manufacturers to place a label on each 
large volume container of finished dosage form instructing authorized 
dispensers to distribute the Medication Guide. This is necessary 
because FDA intends to phase in Medication Guide requirements, and 
authorized dispensers will need to know which drug products have 
required patient labeling and which ones do not yet have such 
requirements.
    The proposed rule would establish similar requirements for 
distributors who provide drug products to authorized dispensers.
    FDA recognizes the complexity of the drug distribution system and 
encourages the development of innovative methods to meet the 
requirements of this section. The agency intends to consult with 
interested parties so that distribution problems may be identified and 
solutions developed.
    For drugs in unit-of-use containers, proposed Sec. 208.24(c) would 
require the manufacturer and distributor to provide the Medication 
Guide with each package that is intended to be dispensed to patients. 
The agency notes that this requirement, if finalized, would be 
consistent with EC requirements on patient leaflets in unit-of-use 
packaging.
    The proposed rule, at Sec. 208.24(d), would also enable 
manufacturers and distributors to have other persons meet their 
distribution and dispensing requirements. For example, manufacturers 
could enter into a contract with a third party to provide the 
Medication Guide to distributors and dispensers. Such third party 
information systems already exist in other contexts; for example, the 
agency is aware that a third party vendor routinely collects and 
publishes drug identification information which poison control centers 
and other health organizations use to identify drug products.
    Proposed Sec. 208.24(e) would require, in the absence of an 
exemption under proposed Sec. 208.26, that an authorized dispenser 
provide a Medication Guide to the patient (or the patient's agent) at 
the time a prescription drug product is dispensed under a new 
prescription, and when requested by the patient for refill 
prescriptions.
    Section 510 of the act (21 U.S.C. 360) requires all persons engaged 
in the manufacture, preparation, propagation, compounding, or 
processing of a drug to register with FDA and provide the agency with a 
list of drug products in commercial distribution. Under section 
510(g)(1) of the act, however, pharmacies which conform to local laws, 
which are regularly engaged in dispensing prescription drugs upon 
prescriptions of licensed practitioners, and which do not manufacture, 
prepare, propagate, compound, or process drugs for sale other than in 
the regular course of dispensing drugs at retail, are exempt from the 
registration and listing requirements. The preparation and/or 
distribution of Medication Guides by a pharmacy does not diminish this 
exemption. Accordingly, under proposed Sec. 208.24(f), authorized 
dispensers are not subject to section 510 of the act solely because of 
an act performed by the authorized dispenser to comply with this 
regulation.

F. Exemptions and Deferrals

    The regulatory requirements presented in proposed Sec. 208.20 are 
intended to be exhaustive as to the content of Medication Guides. 
Nevertheless, FDA realizes that some requirements in proposed 
Sec. 208.20 may be inapplicable, unnecessary, or contrary to a 
patient's best interests for a particular drug product. Accordingly, 
proposed Sec. 208.26(a) would advise manufacturers to contact FDA if 
they believe that certain requirements are inapplicable, unnecessary, 
or contrary to the patient's best interest.
    Proposed Sec. 208.26(a) would also allow FDA to determine that 
certain information should be omitted from the Medication Guide for a 
particular drug product. This determination would occur at the time a 
Medication Guide was submitted as part of a marketing application. The 
agency may also, on its own initiative or in consultation with a 
manufacturer, determine that any or all of the Medication Guide 
requirements should be deferred or exempted for a specific drug 
product.
    The agency expects that the Medication Guide will facilitate 
communication between the health professional and patient, thereby 
enhancing the proper use of prescription drug products and helping to 
reduce the incidence of noncompliance and adverse reactions. FDA 
emphasizes, however, that the Medication Guide is not intended to 
displace or substitute for professional judgment. A practitioner may 
feel that, in certain cases, a patient may be adversely affected by the 
contents of a Medication Guide.
    Consequently, under proposed Sec. 208.26(b), the authorized 
dispenser of a prescription drug product would not 

[[Page 44209]]
be required to provide a Medication Guide to a patient if the licensed 
practitioner who prescribes the drug product directs that the 
Medication Guide be withheld. The agency believes that prescribers 
should not direct dispensers to routinely withhold a Medication Guide 
from patients but should do so only when it is in the best interests of 
the specific patient involved.
    In addition, FDA believes that authorized dispensers, as a result 
of their personal contact with a specific patient or a patient's 
family, often have information relevant to a decision to withhold a 
Medication Guide for a specific product. For example, an elderly 
patient functioning at a relatively low level of awareness of his 
cancer may have been prescribed a product that provides only palliative 
care, or a schizophrenic patient may have been prescribed a clearly 
anti-psychotic drug. Under such circumstances, the patient, and the 
course of therapy, may be adversely affected by the contents of a 
Medication Guide. Under these circumstances, where there are 
significant concerns about potential adverse effects of a Medication 
Guide, FDA would permit authorized dispensers to use their professional 
judgment in determining whether a particular patient would be best 
served by withholding the Medication Guide for a particular product. 
However, such an action should be based on the professional judgment of 
the authorized dispenser in each specific situation, and Medication 
Guides should not routinely be withheld for specific drug classes or 
specific patient characteristics. The agency invites comments on how 
best to implement this exemption.
    FDA notes that under proposed Sec. 208.26(b), the authorized 
dispenser must provide the Medication Guide to any patient who requests 
one. In addition, FDA has determined that for particular products 
patient information should be provided to all patients. Section 
208.26(b) therefore provides that this exemption does not apply if FDA 
determines that a Medication Guide for a particular product should be 
provided to all patients under all circumstances.
    Proposed Sec. 208.26(c) would permit manufacturers, distributors, 
or authorized dispensers to provide drug products without a Medication 
Guide in emergency situations and in cases where the manufacturer, 
distributor, or authorized dispenser has made a good faith effort to 
obtain a Medication Guide for the drug product, but does not have a 
Medication Guide available for the patient. The manufacturer, 
distributor, or authorized dispenser would be required to document its 
good faith effort to obtain a Medication Guide. This provision is 
intended to address those situations where the Medication Guide is 
unavailable and would not prohibit authorized dispensers from providing 
a prescription drug product to a patient. For example, if an authorized 
dispenser is utilizing computer-generated Medication Guides and the 
computer system breaks down, or if an authorized dispenser had 
exhausted its supply of the Medication Guide for a particular drug 
product and was unable to secure an additional supply of the Medication 
Guide, proposed Sec. 208.26(c) would permit the authorized dispenser to 
provide the drug product to the patient without a Medication Guide.
    Proposed Sec. 208.26(d) would exempt certain authorized dispensers 
from the requirement, in Sec. 208.24(e), to provide a Medication Guide 
directly to each patient when dispensing a prescription drug product. 
This proposed exemption would apply to retail pharmacy outlets or other 
dispensers which: (1) Dispense, on average during the previous calendar 
year, no more than 300 outpatient prescription drugs per week; (2) have 
gross annual sales of no more than $5.0 million or are part of a 
business entity (i.e., sole proprietorship, partnership, or 
corporation) that has gross annual sales of no more than $5.0 million; 
and (3) make available to patients a compilation of current Medication 
Guides for reading in the drug product dispensing area.
    FDA is proposing this exemption because it has determined, based on 
the agency's regulatory impact analysis in section XII. of this 
document, that the proposed regulation would have a significant 
economic impact on the operations of many smaller retail pharmacy 
outlets. Many larger pharmacies--members of chain drug stores and 
pharmacies in large food/drug combination stores--have computerized 
systems that can be used in dispensing Medication Guides to patients. 
Smaller pharmacies, however, will generally need to purchase computer 
equipment or they will incur costs for lost time and storage space by 
using preprinted Medication Guides.
    This proposed exemption would not apply to drugs dispensed in unit-
of-use containers. In this situation, the impact of the proposed 
regulation on smaller pharmacies would be less because the drug product 
is individually prepared for the patient by the manufacturer, and 
already includes the Medication Guide.
    In addition, the proposed exemption would not apply when the agency 
determines, for safety or other reasons, that a particular drug product 
must be dispensed with a Medication Guide. For example, FDA currently 
requires that patient labeling must be dispensed with Accutane to 
ensure its safe use, i.e., to warn patients about its association with 
birth defects.
    Exempted pharmacies must maintain a current compilation of 
Medication Guides available for consumers to consult in an accessible 
area, such as near the counter or the patient counseling area.
    This proposed exemption is intended to lessen the economic impact 
of complying with the proposed Medication Guide dispensing requirements 
for smaller pharmacies and other dispensers. FDA invites general 
comments on this exemption and specific comments on the proposed 
threshold level (300 prescriptions per week) and whether this proposed 
exemption should be permanent or merely extend the time necessary for 
smaller pharmacies to comply with the exemption, for example by 
providing a 10-year extension for small businesses to comply with the 
requirements.

G. Miscellaneous Amendments

    The proposed rule would also amend the provisions pertaining to 
NDA's, product license applications (PLA's) and abbreviated new drug 
applications (ANDA's) and abbreviated antibiotic drug applications 
(AADA's) to require applicants to include a Medication Guide as part of 
their labeling. The agency intends to review the Medication Guide along 
with the proposed professional labeling for the drug product or review 
the Medication Guide as it would review any proposed labeling change 
for a drug product that requires prior approval. Although the 
Medication Guide program would be implemented gradually if the 
performance standards are not met, its requirements would ultimately 
apply to all prescription drug products that patients primarily self-
administer without the direct supervision of a health care 
professional. Therefore, as labeling, the proposed rule would expressly 
require that the Medication Guide be submitted as part of an NDA, PLA, 
or ANDA.
    For applicants with approved products, the proposed rule would 
amend the regulations governing supplemental applications to require 
applicants to obtain prior FDA approval of any change to a Medication 
Guide. FDA is proposing to require prior approval of such changes, 
including the addition of any warning or adverse reaction, or even 
minor editorial 

[[Page 44210]]
changes. As stated earlier, the Medication Guide is directed to 
consumers who may be distracted or overwhelmed by excessive 
information. Consequently, the agency will attempt to ensure that the 
Medication Guide contains information that consumers should know and 
can understand.

XI. Legal Authority

    The act (21 U.S.C. 321 et seq.) authorizes FDA to regulate the 
marketing of drug products so that the products are safe and effective 
for their intended uses and are properly labeled. In order to carry out 
the public health protection purposes of the act, FDA: (1) Monitors 
drug manufacturers and distributors to help make certain that drug 
products are manufactured and distributed under conditions that ensure 
their identity, strength, quality, and purity; (2) approves new drugs 
for marketing only if they have been shown to be safe and effective; 
and (3) monitors drug labeling and prescription drug advertising to 
help ensure that they provide accurate information about drug products.
    A major part of FDA's efforts regarding the safe and effective use 
of drug products involves FDA's review, approval, and monitoring of 
drug labeling. Under section 502(a) of the act (21 U.S.C. 352(a)), a 
drug product is misbranded if its labeling is false or misleading in 
any particular. In addition, under section 505(d) and (e) of the act 
(21 U.S.C. 355(d) and (e)), FDA must refuse to approve an application 
and may withdraw the approval of an application if the labeling for the 
drug is false or misleading in any particular.
    Section 201 of the act (21 U.S.C. 321), the ``Definitions'' section 
of the act, describes the concept of ``misleading'' in the context of 
labeling and advertising. Section 201(n) of the act (21 U.S.C. 321(n)) 
explicitly provides that in determining whether the labeling of a drug 
is misleading, there shall be taken into account not only 
representations or suggestions made in the labeling, but also the 
extent to which the labeling fails to reveal facts that are material in 
light of such representations or material with respect to the 
consequences which may result from use of the drug product under the 
conditions of use prescribed in the labeling or under customary or 
usual conditions of use.
    These statutory provisions, combined with section 701(a) of the act 
(21 U.S.C. 371(a)), clearly authorize FDA to promulgate a regulation 
designed to ensure that patients using prescription drugs will receive 
information that is material with respect to the consequences which may 
result from the use of a drug product under its labeled conditions. 
This interpretation of the act and the agency's authority to require 
patient labeling for prescription drug products has been upheld. (See 
Pharmaceutical Manufacturers Association v. Food and Drug 
Administration, 484 F. Supp. 1179 (D. Del. 1980), aff'd per curiam, 634 
F. 2d 106 (3rd Cir. 1980)).
    For generic drug products, section 505(j)(2)(A)(v) of the act (21 
U.S.C. 355(j)(2)(A)(v)) provides additional legal authority for a 
Medication Guide. Section 505(j)(2)(A)(v) of the act requires an ANDA 
to contain information to show that the proposed generic drug product's 
labeling is the same (with some exceptions) as that of the 
corresponding reference listed drug. Thus, because a Medication Guide 
is drug labeling, FDA proposes to require generic drug product 
manufacturers to develop a Medication Guide that is the same as the one 
for the reference listed drug, except for differences attributable to 
legal or regulatory requirements (such as uses protected by patent) or 
because the generic drug product and the reference listed drug are 
produced or distributed by different manufacturers. If an ANDA or AADA 
fails to contain such information, this failure may be grounds for 
refusing to approve the ANDA or AADA under section 505(j)(3)(G) of the 
act (21 U.S.C. 355(j)(3)(G)).
    In addition, for biological products, section 351 of the Public 
Health Service Act (42 U.S.C. 262) authorizes the imposition of 
restrictions through regulations ``designed to insure the continued 
safety, purity, and potency'' (including effectiveness) of the 
products. Biological product licenses are to be ``issued, suspended, 
and revoked as prescribed by regulations'' (42 U.S.C. 262(d)(1); see 21 
CFR 601.4 through 601.6). The requirements of this proposed regulation 
on Medication Guides are designed, in part, to insure the continued 
safe and effective use of licensed biological products. Therefore, the 
agency may refuse to approve PLA's, or may revoke already approved 
licenses, for biological products that do not comply with the 
requirements of the final rule on Medication Guides.
    Based upon these authorities, the agency proposes to require 
manufacturers of prescription drug products, including biological 
products, to disclose information about their products in the form of 
patient labeling. Just as scientific standards for evaluating a drug 
product's safety and effectiveness and manufacturing practices have 
evolved since enactment of the act in 1938, standards for appropriate 
labeling for drug products must also change as data are compiled about 
the effects of labeling on patients' safe and effective use of drug 
products.

XII. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-345). 
Executive Order 12866 directs agencies to assess all costs and benefits 
of available regulatory alternatives and, when regulation is necessary, 
to select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). The agency believes that 
this proposed rule is consistent with the principles set out in the 
Executive Order.
    The distribution of useful patient information will result in 
significant consumer benefit, but may also entail costs to industry. 
Some of the regulatory alternatives examined by the agency entail 
potential regulatory costs well in excess of $100 million. Even though 
the selected option is estimated to have associated costs well below 
this amount, FDA has prepared a preliminary economic analysis in 
accordance with Executive Order 12866 and the Regulatory Flexibility 
Act.
    This preliminary economic analysis evaluates the costs and benefits 
of implementing FDA's proposal. This proposal states that in the 
absence of continued voluntary efforts to provide useful information to 
patients who purchase prescription drug or biological products, 
manufacturers of these products will be required to prepare and 
distribute patient information labeling that will accompany any new 
prescriptions. The objective of the proposed rule is to improve public 
health by allowing patients to make more informed uses of their 
medications. FDA has found that patients often fail to adhere to 
medication regimens or to recognize signs and symptoms of both 
preventable and unpreventable adverse drug reactions. These failures 
frequently prolong recovery or even contribute to additional illnesses. 
Because patients who receive understandable information about their 
drug therapies are better able to benefit from their medications, FDA 
believes that implementation of the proposed regulations will 
significantly enhance the public health. Although many programs that 
offer patient prescription drug information currently exist, this 
proposal is expected to increase the use and quality of such 
information, and provide standards for 

[[Page 44211]]
guiding and assessing the adequacy of voluntary programs.
    FDA has proposed to institute a comprehensive program of FDA-
approved patient information only if the private sector does not meet 
defined goals for the distribution and adequacy of patient information. 
These goals are both reasonable and attainable. It is FDA's hope that 
the voluntary programs will achieve the desired goals and that 
consequently a government-imposed program will not be required. 
However, this was FDA's hope in 1982 when the initial PPI regulations 
were withdrawn. To provide sufficient incentive to meet distribution 
and quality goals for written patient information, FDA is proposing two 
alternatives that could result in a comprehensive program requiring 
FDA-approved Medication Guides, but no sooner than 5 years from the 
effective date of the final rule.
    To estimate the costs of such a regulation, we have prepared a 
worst-case analysis that assumes no increase in the current state of 
distribution and quality of dispensed patient information, assumed to 
be at about 50 percent. This worst-case estimate is that the program 
would have annual gross costs of approximately $56 million, assuming 
neither inflation nor discounting. Thus, FDA estimates that the cost of 
this regulation would range from zero (if distribution and quality 
standards would have been achieved despite the promulgation of this 
rule) to $56 million (if the current state of private sector issuance 
of patient information would have remained unchanged.)
    The proposed labeling would take the form of patient information 
sheets, called Medication Guides. These sheets would accompany new 
prescriptions for outpatient human drug and biological products, and 
would also be available upon request for refill prescriptions.
    If the regulation is implemented, Medication Guides would be 
developed by drug manufacturers. They would be approved by FDA and 
would contain information designed to increase patient awareness of the 
proper use of the accompanying products. These information sheets would 
be distributed to the patient at the time the prescription is dispensed 
at the retail pharmacy (or other dispensing outlet). While 
manufacturers would be responsible for ensuring that adequate 
information is available to the dispenser, the dispenser would 
ultimately provide the information to the patient at the time the 
prescription is filled. The agency has taken the burden of small, 
retail pharmacies into account, and exempted certain low-volume outlets 
from this proposal.
    In 1980, the agency issued a similar regulatory proposal calling 
for PPI's, initially to cover 10 drugs and drug classes. That rule was 
revoked in 1982 to permit the private sector to implement information 
programs without Government intervention. In the intervening years, FDA 
has conducted periodic surveys of patients who have obtained new 
prescriptions. FDA found in the latest survey that the proportion of 
patients receiving written drug information (other than the 
prescription label on the container) had increased from 16 percent in 
1982 to 58 percent in 1994. Preliminary analyses of FDA's most recent 
survey indicate that 55 percent of patients obtain more substantial 
information than brief stickers.
    Other surveys of the pharmacy sector have also shown gains in 
distribution of written information. A 1992 survey of retail pharmacies 
conducted by the University of Mississippi showed that 77 percent of 
all pharmacies distribute printed patient counseling information (Ref. 
76). A 1994 Consumer Patient Counseling Survey conducted for the 
National Association of Boards of Pharmacy (Ref. 95) showed that 64 
percent of all patients or caregivers stated that they received printed 
materials about the medication from the pharmacy.
    The agency believes that the availability of patient information 
should continue to grow. While there is little doubt that patient 
information activities have increased since the 1980 PPI proposal, a 
sizeable proportion of the patient population remains underinformed. 
FDA believes that a regulatory process that encourages or augments 
private sector initiatives will best meet the needs of these 
underserved patients.
    OBRA '90 currently requires that pharmacists offer counseling to 
patients who receive State-assisted services. Many States have extended 
OBRA's requirements to additional patients. Required counseling under 
OBRA is limited to oral, face-to-face counseling between the patient 
and the dispensing pharmacist. Written material may be used as an 
adjunct, but cannot be substituted for oral counseling. Numerous 
studies have shown that counseling is most effective in modifying 
behavior when achieved through a combination of oral and written media. 
Thus, FDA believes that Medication Guides, or other voluntary written 
information, will complement OBRA requirements and provide more 
effective and comprehensive patient counseling.
A. Affected Sectors

    The economic effects of the proposed regulations, if implemented, 
will vary with the number of affected drug products, prescriptions, and 
retail pharmacies. The number of affected drug products will dictate 
the number of separate Medication Guides that will be developed, the 
number of prescriptions will dictate the number of Medication Guides 
that will be distributed, and the number of pharmacies will dictate the 
number of facilities that will maintain equipment to distribute 
Medication Guides. To determine an initial baseline for this analysis, 
the discussion that follows is based on the assumption that voluntary 
information programs will not meet the distribution and quality 
standards for voluntarily-supplied patient information, and that the 
Medication Guide program will therefore be fully implemented.
    Medication Guides must be available for most prescription drug and 
biological products dispensed outside of institutional environments 
(such as hospitals and nursing homes). The agency envisions an 
implementation period of 10 years, so that early resources may be spent 
developing Medication Guides for therapies that may pose public health 
concerns, as well as for new products. Over time, however, this 
analysis assumes that all prescription products that are the subject of 
approved NDA's and ANDA's will be accompanied by Medication Guides. FDA 
examined currently marketed drug products and their historical rates of 
introduction to arrive at an estimated 3,350 separate drug products 
that will require separate Medication Guides, as shown in Table 1.

BILLING CODE 4160-01-P

[[Page 44212]]
[GRAPHIC][TIFF OMITTED]TP24AU95.013


BILLING CODE 4160-01-C

[[Page 44213]]

    The 3,350 drug products will eventually require separate Medication 
Guides. To develop these, FDA estimates that companies will select 
``models'' from already existing materials. These models would be 
updated by the manufacturer. Once a manufacturer has developed a model 
it would be submitted to FDA for approval. The approved Medication 
Guide will then serve as a model for other similar drugs within the 
same therapeutic category, saving additional developmental costs. FDA 
analysis indicates that 461 guides will serve as ``innovator'' or 
``model'' Medication Guides. These can serve as models for 782 similar 
``category'' products (within narrowly-defined therapeutic categories) 
which, in turn, can be copied on a word-for-word basis for 2,107 
generic drugs.
    About 2.2 billion prescriptions were dispensed from retail 
pharmacies during 1992, according to data included in the 
``Prescription Drug Marketing Simulation Model'' developed by the NACDS 
(Ref. 75). The proposed regulation, if fully implemented, will require 
Medication Guides to accompany each new prescription, as well as be 
available upon request for refill prescriptions. For cost calculation 
purposes, FDA has assumed that prescriptions dispensed via unit-of-use 
packaging would include Medication Guides whether the prescriptions are 
new or refills. Since approximately 24 percent of all prescriptions, or 
525 million prescriptions, are issued in unit-of-use packages, an 
additional 1,661 million prescriptions would need to be prepared by a 
pharmacist. Of these, FDA estimates that approximately 55 percent, or 
914 million, would be for new prescriptions. FDA also estimates that 5 
percent of the 1,661 on-site, pharmacy- prepared prescriptions, or 83 
million, would be for patient requests for Medication Guides for refill 
prescriptions. Thus, as shown in Table 1, the agency estimates that if 
the proposal were fully implemented, Medication Guides would be issued 
for 525 million unit-of-use prescriptions, 914 million other new 
prescriptions, and 83 million refill prescriptions, for a total of 
1,522 million Medication Guides. This would cover 70 percent of all 
prescriptions.
    However, pharmacies consist of both commercial and noncommercial 
outlets. The NACDS (Ref. 75) included a distribution of pharmacy 
outlets by type. The agency has allocated these outlets into three 
categories: Independent pharmacies (up to three outlets that fill 
prescriptions), chain pharmacies (four or more outlets under the same 
management, including food outlets and mail-order companies), and 
noncommercial outlets (Health Maintenance Organizations (HMO's)), 
hospitals, ambulatory care units, and physician offices), as shown in 
Table 2. Average prescription volume by outlet type is derived from the 
NACDS survey. Independent, community pharmacies are estimated to 
average approximately 530 prescriptions per week, while an average 
chain pharmacy averages over 825 weekly prescriptions. Overall, the 
agency estimates that the typical pharmacy dispenses approximately 600 
prescriptions per week.

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B. Gross Costs of Compliance

    FDA estimated the regulatory costs of this proposed regulation by 
developing the costs for dispensing Medication Guides at a typical (600 
prescriptions per week) pharmacy. These costs were divided by the 
number of dispensed Medication Guides to derive a cost per Medication 
Guide, as well as multiplied by the number of outlets to derive a total 
cost of compliance. While this methodology may overstate unit costs for 
large outlets and understate unit costs for small outlets, due to 
economies of scale, these effects would tend to balance in the 
aggregate.
    Because voluntary efforts exist to provide patient information, and 
these efforts are expected to expand, the incremental costs of 
compliance are only those above the costs of providing patient 
information that would accrue in the absence of this proposal. The 
agency has initially assumed that 50 percent of all patients currently 
receive patient information. Thus, gross costs are reduced to account 
for current activities. If private sector initiatives continue to grow 
in the absence of this regulation, the actual incremental compliance 
costs will be even further reduced. In fact, if all affected pharmacies 
would voluntarily dispense adequate, written patient information, the 
incremental costs of this proposal would be zero. However, to develop a 
baseline for analysis, the agency has assumed that the current baseline 
of 50 percent compliance will remain constant throughout the study 
period. This strategy results in the most conservative (i.e., the 
highest possible) estimate of costs.
    Costs to manufacturers include the cost of developing Medication 
Guides and submitting them for FDA review. Costs to pharmacies include 
the cost of printing and dispensing Medication Guides with 
prescriptions.
1. Manufacturers
    The worst-case scenario would require manufacturers of new drugs to 
develop Medication Guides with no prior model or prototype, for 
example, for a newly approved drug in a new therapeutic class. 
According to Merck Pharmaceuticals, it took 6 months of calendar time 
to develop, test, and revise an FDA-approved PPI to accompany a recent 
new drug. FDA assumes that a totally new Medication Guide could be 
developed within this timeframe, and would require a total of 2 months 
of full-time effort by manufacturers. This effort would include 
scientific research associates, regulatory affairs officials, and 
legal/scientific reviewers. Assuming an annual average professional 
labor cost of $70,000, each model Medication Guide would cost industry 
between $11,000 and $12,000.
    The majority of Medication Guides (those for which there are models 
in the same therapeutic class) would be very similar to their 
applicable model guides in content. FDA expects that the cost for 
developing these ``category'' Medication Guides should be less than 
half of the model development cost, or approximately $5,000.
    Medication Guides for generic drugs should be virtually identical 
to the originator product's Medication Guide, except for the name, 
description, and patent-protected information. Therefore, FDA estimates 
that the cost of developing generic Medication Guides would be 
approximately one-tenth the cost of developing a category Medication 
Guide, or $500.
    Total industry costs of developing Medication Guides, if voluntary 
efforts do not continue to grow, are found by multiplying the 
applicable development cost by the expected number of products shown in 
Table 1. By the 10th year of implementation, all products would have 
Medication Guides at a cost to industry of approximately $10.5 million 
for development. Given the proposed phase-in plan, the agency expects 
annual development costs to equal approximately $1.3 million by year 
10. As new products continue to be marketed, FDA expects this 
equilibrium to be maintained.
    According to data developed by FDA, approximately 24 percent of all 
prescriptions are dispensed in unit-of-use packaging. These 
prescriptions would require preprinted Medication Guides that would 
likely be included in the packaging provided by the manufacturer prior 
to shipping. Thus, 525 million preprinted Medication Guides will be 
required by the 10th year of implementation.
    According to purchasers, the cost of preprinted patient information 
sheets is currently about $0.025 per page. These sheets include 
customized information such as company address, phone numbers, logo, 
and other information. A supplier of patient information sheets (USP) 
lists a price of $2.10 for a pad of 50 sheets ($0.042 per sheet), but 
the order form provides for substantial discounts for bulk orders. FDA 
has assumed a cost of $0.025 per preprinted patient information sheet, 
for a total annual printing cost of $13.1 million. The agency believes 
that current packaging technology would allow for insertion of 
Medication Guides into unit-of-use packaging with little additional 
cost.
    Prescriptions in other than unit-of-use packaging will likely be 
dispensed with Medication Guides that are generated at the retail 
pharmacy via computer. Many of the technologies for transmitting 
automated information to retail pharmacies are already in place. 
Distributor-based electronic information networks offer nationwide 
computer ties designed to influence as well as facilitate 
pharmaceutical care. According to one industry analyst, ``Nearly 95 
percent of all pharmacies in the U.S. have at least some computer link 
to a point-of-sale system that allows them to participate in these 
point-of-sale networks.'' (Ref. 73).
    Although a precise prediction of future technologies remains 
speculative, FDA believes that the current availability of computers in 
almost all pharmacies indicates that patient information would be 
available in an automated format.
    A number of possibilities would be available for the distribution 
of automated data to pharmacies. Although each individual manufacturer 
could distribute data disks to all pharmacies purchasing their drugs, 
this approach would entail routine shipments of hundreds of thousands 
of data disks and require expensive recordkeeping systems to avoid 
sending duplicate disks. It is far more likely that conventional market 
forces would lead to more rational information systems.
    Logical models for distributing computerized information data bases 
include the third parties that already accumulate and disseminate these 
data. Because the regulation will impose the initial responsibility for 
information distribution on manufacturers, yet the pharmacies will need 
to augment their computer systems, the precise outcome of these market 
forces is uncertain. However, there are several reasons to believe that 
competitive considerations would prompt manufacturers to coordinate 
with third party data bases for the distribution of Medication Guides.
    First, several vendors, such as the USP, Medi-Span, Inc., and the 
ASHP, already provide computerized drug information data bases. Thus, 
comparable systems are already in place. Second, the responsiveness of 
the private sector to the demand for Government-mandated information 
has been vividly demonstrated by the proliferation of vendors of 
chemical data bases following the promulgation of the Occupational 
Safety and Health Administration's ``Hazard Communication Standard.'' 
Finally, 

[[Page 44216]]
pharmaceutical manufacturers would vigorously support the development 
of a data distribution network that reduces the costs of printing and 
shipping large volumes of paper. The initial mechanism could reasonably 
involve manufacturer price discounts, rebates, or other like incentives 
designed to encourage pharmacies to use commercial data bases.
    For this preliminary study, the costs of disseminating computerized 
data are considered pharmacy costs, via the purchase of software and 
updates, although part of this burden may be passed back to the 
manufacturers or distributors through various incentive programs. Table 
3 indicates that the total annual gross costs to manufacturers of 
preparing Medication Guides and printing those used in unit-of-use 
packages would be expected to reach $14.4 million, if the proposed 
regulation is fully implemented.

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2. Pharmacies
    FDA has estimated the costs for a typical pharmacy that dispenses 
600 prescriptions per week to comply with the proposed regulation. 
These costs include hardware (including a computer with sufficient hard 
disk space and a dedicated printer), supplies, space, and time to 
retrieve and dispense the Medication Guide.
    a. Hardware. An estimate of the required hard disk space to operate 
a drug information network was developed from current requirements of 
the MEDTEACH program offered by ASHP, which provides 427 drug 
monographs to customers in disk form (each monograph contains 
information similar to that envisioned in a Medication Guide). The 
installation program requires two disks and quarterly updates or 
revisions are offered to all users.
    ASHP reports that the current program and data require 3.1 
megabytes of hard disk space. A program accounting for 1,000 monographs 
would require 6 megabytes. Because the proposed regulations, if 
implemented, would require 3,350 specific Medication Guides, the 
required disk space would ultimately be almost 20 megabytes. Hard disks 
exceeding 400 megabytes are now common at a price of under $1.00 per 
megabyte, and the technology is steadily advancing. FDA foresees no 
difficulty in meeting the longer term requirements for computer disk 
space, at an average amortized annual cost of only $6.
    Dedicated printers would be required to generate the large numbers 
of Medication Guides. Dot matrix printers can be purchased for about 
$300, and are assumed to have a useful life of 4 years, which results 
in an amortized cost per printer of $87 per year (at 6 percent 
interest). Laser printers are assumed to cost $1,000 and also have a 4-
year useful life, yielding an amortized annual cost of $289 per 
printer.
    FDA found that the relatively slower dot-matrix printers would be 
adequate for most outlets. The dispensing clerk or pharmacist would 
complete other filing or labeling activities while the printer was 
operating.
    b. Supplies. On the assumption that each computer-generated 
Medication Guide would fill two pages, FDA estimates that dot-matrix 
printers would require ribbon replacement every 1,250 pages, or 625 
Medication Guides. Dot-matrix ribbons are estimated to cost $8. In 
addition, office supply catalogs indicate that the cost of bulk 
computer paper ranges from less than $0.005 to $0.01 per page. This 
study uses $0.007 per page as a mid-point in this range for a cost of 
$0.014 per 2-page Medication Guide.
    A typical pharmacy is estimated to dispense 600 prescriptions per 
week. Twenty-four percent of these prescriptions (144) are dispensed in 
unit-of-use packaging, so a total of 456 prescriptions per week may 
require site-generated Medication Guides. The proposed regulation 
requires Medication Guides to accompany new prescriptions (55 percent 
of the total) as well as be available upon request. Thus, 60 percent of 
the affected prescriptions are expected to be accompanied by Medication 
Guides. This represents about 275 per week, or 14,300 per year when 
fully implemented.
    The typical pharmacy would then require 23 ribbon replacements per 
year (almost one ribbon every 2 weeks) for an annual cost of $184. In 
addition, 28,600 pages of computer paper would cost a pharmacy $200 per 
year. The gross annual cost of supplies for providing Medication Guides 
at a typical pharmacy is therefore estimated to equal $384.
    c. Software. Several companies, including the USP and ASHP, 
currently sell computerized patient information disks to pharmacies. 
Although these packages have limited coverage, and typically contain 
data for only the 200 top-selling drugs, FDA believes that such 
organizations could rapidly compile and market comprehensive Medication 
Guide data bases. Based on current costs for these software and data 
packages, this study assumes an initial cost of $400 and quarterly 
updates of $50 each. When these costs are amortized over a 4-year 
period, the resultant annual cost to the pharmacy equals $315.
    d. Storage. Using computers to print Medication Guides would also 
add costs for storage, because an additional printer and paper would 
require approximately 2 square feet within the prescription preparation 
area. For example, 1,000 sheets of paper may be stored in a stack of 
only 1.5 inches. Storage space would still be available below the 
preparation counter, so FDA assumes that potential displacement of 
equipment would be equal to 1 square foot of floor space.
    The conventional means of obtaining the economic cost of a 
productive resource is to estimate the market price of that resource. 
An annual rental charge of $7.50 per square foot of pharmacy space was 
obtained from survey data contained in the 1992 Lilly Digest (Ref. 78). 
Alternative approaches note that, in the short run, added storage 
requirements could impose additional opportunity costs if the turnover 
of goods could not be increased elsewhere in the pharmacy, which 
suggests a cost of storage based on displaced sales. FDA believes that 
this method likely overstates regulatory costs, both from a societal 
perspective (because the loss in sales to any one outlet would be 
gained by another) and an individual outlet perspective (because the 
average return per square foot of space exceeds the marginal return). 
That is, outlets would minimize any burden by displacing lower return 
items. Nevertheless, FDA has derived the value of sales per square foot 
from the 1992 Lilly Digest of independent pharmacies, and has used an 
annual cost of $104 per pharmacy per square foot to account for annual 
storage costs to the typical pharmacy. (Annual sales per square foot of 
pharmacy equal $360, and pharmacies have an average 29 percent gross 
sales margin. Thus, $360  x  .29 = $104).
    e. Time. Computerized pharmacies would incur relatively low burdens 
of time, because Medication Guides would be printed as other labeling 
and dispensing activities were occurring. However, pharmacists would 
remain responsible for ensuring that the correct Medication Guide 
accompanies each prescription. FDA has assumed that a minimum of 5 
seconds of pharmacist time would be needed to verify each selection. 
Since the annual number of Medication Guides per typical pharmacy would 
equal 14,300, a pharmacist would be expected to spend almost 20 hours 
per year verifying Medication Guides.
    The 1992 Lilly Digest reported average hourly wage rates of $30 for 
pharmacist/proprietors. Using this as a basis, the total annual cost of 
time would equal $600 for the typical pharmacy.
    Although it is possible that this patient information would cause 
returns of drugs and additional questions of pharmacists, FDA is 
unaware of any study that confirms this hypothesis. The agency's 1980 
economic analysis cited a contracted survey that indicated that no 
additional pharmacist time was required to address these concerns (Ref. 
62). FDA invites additional public comment and data on more recent 
experience.
    f. Total compliance costs to pharmacies. The sum of the annual 
costs of printers, supplies, software, storage, and time equal almost 
$1,500 for the typical pharmacy when, and if, the proposed regulations 
are fully implemented. This equals almost $0.105 per pharmacy-printed 
Medication Guide. Table 3 contains the total gross annual costs for the 
pharmacy sector.
    Total annual gross costs to the retail pharmacy sector will equal 
$106.7 

[[Page 44219]]
million if this regulation is fully implemented. This amount is found 
by multiplying the cost per pharmacy by the 71,367 universe of outlets 
shown in Table 2.
3. Total Annual Gross Costs of Developing and Dispensing Medication 
Guides
    The estimated annual gross costs of developing and issuing 
Medication Guides include the annual costs to manufacturers of 
developing Medication Guides, in general, and printing unit-of- use 
Medication Guides ($14.4 million), and the total annual cost to retail 
pharmacies of printing and dispensing Medication Guides ($106.7 
million). Thus, the total gross annual compliance cost of this proposal 
is estimated to equal $121.1 million. The estimated average cost to 
distribute one Medication Guide, whether via unit-of-use packaging or 
printed at a retail pharmacy, equals $0.08. This reflects the higher 
cost of printing Medication Guides on-site as well as the lower cost of 
including Medication Guides with unit-of-use packaging.
    This estimate does not take into account the existence of current 
voluntary patient information programs. It also assumes static 
technologies and prescription demand.

C. Incremental Compliance Costs

    As discussed earlier, the agency has assumed that current voluntary 
programs account for 50 percent of the market. Such programs include 
retail pharmacies that currently provide patient information, 
manufacturers that provide mandated patient information for certain 
individual drug products and product classes, mail-order pharmacies 
that routinely provide this information, and general unit-of-use 
packaging. Given the current state of patient information, the agency 
expects that the cost of achieving compliance with this proposal, if no 
further gains in patient information occur, would be only 50 percent of 
the total gross costs. Thus, the annual incremental cost of this 
proposal is estimated to be a maximum of $60.5 million (including those 
Medication Guides dispensed in unit-of-use packages). If private 
patient information programs continue to increase, on their own, the 
incremental cost of any regulatory plan would be even lower. In 
addition, this estimate does not account for the agency's proposal to 
allow an exemption for small-volume pharmacies. The cost implications 
of this exemption are discussed in the following section.

D. Small Pharmacy Exemption

    The Regulatory Flexibility Act requires Federal agencies to prepare 
a regulatory flexibility analysis if a proposed regulation is expected 
to have a significant impact on a substantial number of small entities. 
FDA believes that compliance with the requirements for Medication 
Guides could have a significant impact on the operations of many small, 
independent pharmacies. The agency therefore proposes to exempt from 
most of the Medication Guide requirements any retail outlet that 
dispenses an average of fewer than 300 prescriptions per week, as long 
as total company annual sales do not exceed $5.0 million.
1. Disproportionate Costs
    Although pharmacies that dispense the largest volumes of 
prescriptions would incur the greatest absolute costs, small pharmacies 
would bear a proportionally higher burden. Based on the assumptions 
previously discussed, for a typical outlet dispensing 600 prescriptions 
per week, the average gross cost to provide a Medication Guide is 
$0.105. The cost for a small outlet dispensing only 200 prescriptions 
per week would total about $0.177. This disparity reflects the ability 
of larger outlets to spread the fixed annual regulatory costs (printer, 
storage, and software) over more prescriptions.
    In some circumstances, regulatory costs can be imposed without 
inflicting noticeable change to the affected industry sectors. However, 
in recent years, independent community pharmacies have faced rapidly 
growing competitive pressure from new sources of retail prescriptions, 
especially mail-order companies and HMO's. A 1992 study prepared for 
the NACDS (Ref. 75) projected independent pharmacy's share of 
prescriptions to decrease from 41 percent to 29 percent during the 
1990's. IMS America (Ref. 77) reports that since 1990, the number of 
independent retail pharmacies decreased by 15 percent.
    In general, the profitability of retail pharmacies varies in direct 
proportion to sales volume. For example, a survey of independent 
pharmacists (Ref. 78) reports that a typical independent pharmacy 
earned income (combined pretax net store profit and proprietor/manager 
salary) of $88,000 during 1991. Figure 1 shows that very small 
independent pharmacies (fewer than 150 prescriptions per week) earned 
total pretax incomes of only 26 percent of the industry average. 
Independent pharmacies dispensing between 150 and 300 prescriptions per 
week earned total income of only 51 percent of the industry average. 
These limited profits suggest that it would be difficult for small 
outlets to finance additional regulatory costs.
    FDA is aware of the economic problems of the small retail pharmacy 
and is reluctant to impose additional economic burdens on this sector. 
Since scant public health benefits would be lost by excluding the 
smallest pharmacies from the requirement to dispense Medication Guides, 
the agency proposes exempting these pharmacies from the proposed 
regulation.

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2. Outlet Characteristics
    To estimate the number of outlets that would be eligible for a 
small business exemption, FDA constructed a distribution of retail 
pharmacy outlets by prescription volume. This distribution was 
developed by merging data from two main sources: the 1992 Lilly Digest 
of Independent Pharmacies (Ref. 78) and an earlier NACDS study (Ref. 
79). Although the Lilly Digest reported data for a self-selected sample 
of independent pharmacies, it provides the most detailed data available 
for that sector. The NACDS sampled all pharmacies with six or more 
outlets. Data are shown in Table 4.

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    Because the methodology of these studies varied, FDA standardized 
the data by adjusting and interpolating between ranges to develop an 
outlet size distribution for the entire retail sector. The three 
defined categories of retail outlets were analyzed separately:
    Independent Outlets--The 1992 Lilly Digest of independent 
pharmacies reports prescription volume in terms of prescriptions per 
day. FDA assumed that pharmacies were open an average of 12 hours a 
day, and calculated the dispensing days per week from reported weekly 
hours of operation per cohort. The establishments were then 
interpolated into cohorts of 100 weekly prescriptions.
    Chain Outlets--A distribution of chain outlets was constructed from 
a May 1990 report entitled ``An Assessment of Chain Pharmacies' Costs 
of Dispensing a Third Party Prescription'' (Ref. 79) prepared for the 
NACDS. This report sampled all pharmacies with six or more outlets 
(including food/drug combinations, general merchandisers, discounters, 
etc.) and presented a volume distribution by units of annual 
prescriptions. The agency divided annual prescriptions by 52 to arrive 
at weekly rates, and again interpolated into cohorts of 100 weekly 
prescriptions. For the purposes of this analysis, mail-order pharmacies 
were considered chain outlets.
    Other Outlets--Estimates for prescription volumes for other outlets 
were constructed separately. Hospitals and HMO's reported average 
weekly prescriptions of approximately 350 per week. Physician's offices 
and ambulatory care units averaged approximately 100 prescriptions per 
week. While outlets in this category account for 15 percent of all 
outlets, they account for less than 4 percent of all prescriptions, and 
most of these are distributed in unit-of-use packaging. The agency 
considers this sector to be minimally affected by this proposal and did 
not analyze its characteristics in detail.
    Thus, the agency considered the small business impact on the 60,608 
commercial, retail outlets that dispensed about 2.1 billion 
prescriptions per year. Approximately 54 percent of these outlets are 
independent while 46 percent are chain outlets.
    Figure 2 illustrates the relationship between prescription volume 
and volume market share, and it shows that outlets dispensing 300 or 
fewer prescriptions per week account for almost 20 percent of all 
outlets. However, their dispensed prescriptions account for fewer than 
6 percent of all prescriptions.

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3. Independent Outlets and Chain Outlets
    Independent outlets are typically smaller than chain outlets. As 
indicated in Figure 3, over 2 percent of all independent pharmacies 
dispense fewer than 100 weekly prescriptions, while only 0.9 percent of 
all chain outlets are so small. Conversely, about 7.5 percent of all 
independent outlets dispense more that 1,200 weekly prescriptions while 
almost 17 percent of all chain outlets are that large. This results in 
chain outlets accounting for 26 percent of all outlets with fewer than 
100 weekly prescriptions, but 66 percent of all outlets dispensing more 
than 1,200 weekly prescriptions.
    Moreover, chain outlets earn more store revenue on nonpharmacy 
items. An annual survey conducted by the Drug Store News (Ref. 80) 
shows that prescription sales account for only 24 percent of total 
store sales in chain outlets, but 64 percent of sales in independent 
outlets. In comparison, a typical independent outlet that dispenses 
fewer than 300 weekly prescriptions has average annual gross revenues 
of less than $300,000. A typical chain outlet that dispenses the same 
number of prescriptions will have gross revenues of over $1 million. As 
the average chain operates 47 separate outlets, these data suggest that 
very few chain outlets would be eligible for the small business 
exemption.

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[[Page 44227]]

4. Impact of Small Pharmacy Exemption
    FDA proposes to exempt small pharmacies from the Medication Guide 
requirements if three conditions are met. The first two conditions are 
based on outlet characteristics. Based on distributions of prescription 
volume, a proposed outlet size limit of 300 prescriptions per week 
would exempt about 19 percent of all commercial pharmacies. However, 
the objective of the exemption is to minimize burdens on small 
business. Thus, company size, rather than outlet size alone, must be 
considered. FDA has adopted the Small Business Administration's limit 
of $5.0 million in annual company sales as an additional criterion for 
exemption. Thus, an outlet that is a subsidiary of a company with total 
sales of more than $5.0 million, regardless of sales at the specific 
outlet, would not qualify for the exemption.
    Given these two criteria, FDA estimates that the proposed exemption 
would cover about 14 percent of all commercial outlets, primarily 
independent pharmacies. Altogether, these pharmacies dispense only 
about 4 percent of all prescriptions. Thus, although a substantial 
proportion of the smallest community pharmacies would be spared 
additional costs, the distribution of Medication Guides by outlets 
dispensing 96 percent of all prescriptions would be required. Moreover, 
since patients obtaining unit-of-use prescriptions would receive 
Medication Guides despite the small pharmacy exemption, it is likely 
that at least 97 percent of all new prescriptions would be accompanied 
by patient information.
    The third condition is that exempted outlets make available a 
compilation of Medication Guides for reading in the dispensing or 
counseling area.
    FDA calculates that this small pharmacy exemption would reduce the 
compliance costs of these proposed regulations to retail pharmacies by 
7 percent, while having virtually no effect on manufacturers' costs. 
This would reduce the expected annual incremental regulatory cost of 
compliance to $56.3 million. Figure 4 displays these estimates for 
various exemption options for the retail pharmacy sector.

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[[Page 44229]]


E. Regulatory Options

    Section VII. of this document discussed the advantages and 
disadvantages of several alternatives to the proposed regulations. The 
current section presents rough estimates of their potential costs.
    Option A, Continuation of the Status Quo, would continue current 
practice. Under this option, FDA would continue to request patient 
information on an ad hoc basis for specific drug products. Some 
pharmacies would continue to purchase private product information 
systems from a variety of vendors for patient distribution, but they 
would continue to do so voluntarily. Thus, this option would impose no 
new incremental costs.
    Option B, No Prior FDA Review, would require that patient 
information be dispensed with all drug products, but such information 
would not be approved by the agency prior to distribution. One form of 
this option reflects the proposed voluntary approach. Over time, 
compliance costs would approach those estimated for the proposed 
regulations.
    Option C-1, FDA-Approved Patient Information Available with New 
Prescriptions and Upon Request, would require that a Medication Guide 
be provided with new prescriptions and upon request for refills. This 
is the proposed regulatory option only if voluntary information efforts 
are unsuccessful. As derived above, the annual incremental costs to the 
affected sectors are estimated to reach $56.3 million by the 10th year 
after implementation, assuming a small business exemption.
    Option C-2, FDA-Approved Patient Information Available with All 
Prescriptions, would require that a Medication Guide be provided with 
both new and refill prescriptions. Although the cost per Medication 
Guide dispensed decreases slightly because fixed costs are distributed 
over more guides, the estimated annual incremental costs of compliance 
for this option are over 40 percent higher than if Medication Guides 
were only required for new prescriptions and on request for refills. 
The estimated annual incremental cost of this option is over $80 
million.
    Option D-1, Unit-of-Use Packaging, would require that all 
prescription drugs, together with Medication Guides, be dispensed in 
unit-of-use packaging. FDA does not have sufficient information to 
develop full cost estimates for this option, but believes the 
requirement would impose additional costs for both new packaging and 
increased storage space, while reducing product preparation costs. The 
following projections illustrate the potential magnitude for several of 
these categories.
    The cost to manufacturers of developing and printing the Medication 
Guides to be enclosed in each drug package would reach about $50 
million annually. In addition, the PMA estimated in 1979 that it would 
cost manufacturers between $25-$29 million to move to unit-of-use 
packaging. Updating that estimate to current dollars results in 
approximately $55 million. Moreover, there are about 67 percent more 
prescription products available today than in 1979, which would boost 
this estimate further.
    Retail pharmacies and wholesalers would need to devote more storage 
space to unit-of-use drugs. Estimates from the United Kingdom suggest 
that this type of packaging may increase storage requirements by 40 
percent (Ref. 73). A typical pharmacy uses about 500 square feet of 
floor space. If the 40 percent increment is representative, an annual 
rental fee of $7.50 per square foot would cost each pharmacy about 
$1,500. The total annual cost for retail storage would equal $107 
million. FDA assumes that wholesalers would experience additional 
storage costs.
    The reduced time for pharmacists to dispense unit-of-use products 
would offset some of these cost increases. Kaiser Permanente, for 
example, has estimated that unit-of-use packaging generates time and 
supply savings of between $0.50 to $1.00 per prescription, although 
they note that increased packaging costs offset about half of these 
savings. Other enterprises report lower savings (Ref. 73). FDA 
recognizes that strict requirements for unit-of-use packaging would 
have important consequences on these sectors and solicits additional 
public comment to allow the agency to understand better the associated 
costs and savings.
    Option D-2, Reference Book at Dispensing Site, would require only 
that a book of Medication Guides be made available at the dispensing 
site. Under this option, manufacturers would continue to bear the same 
development costs, but the burden on retail pharmacies would be 
minimal. Even if the insertion of each new or revised Medication Guide 
into looseleaf binders took only 30 seconds, 200 to 300 annual 
revisions would entail annual incremental costs to pharmacies of over 
$2.2 million.
    Option D-3, Interactive Computer Technology, would permit 
pharmacies to provide computer access to consumers in lieu of being 
handed a written Medication Guide. For example, consumers could be 
directed to a computer kiosk to retrieve automated information. If most 
consumers opted to print Medication Guides for new prescriptions, the 
annualized cost of this alternative per pharmacy might average about 
$100 for computer and printer equipment, $300 for software updates, and 
$400 for computer supplies. Further, the rental value of a 3 x 3 square 
foot cubicle in each pharmacy could add another $70 per year (or over 
$900 if displaced sales are used to value space). These assumptions 
imply a total annual incremental cost of about $38 million (about $70 
million if displaced sales are used to value space).
    Option D-4, Distribution of Books to Consumers, requires sending or 
distributing Medication Guide books to each household. The complete 
book would eventually include several thousand pages and is assumed to 
cost $5.00 to print. Consequently, if 50 percent of the nation's 95 
million households received an annually updated book, the cost of 
printing would amount to $237.5 million. If the books were distributed 
from pharmacies, there would be additional costs for storage. If they 
were annually mailed to each consumer's residence, at a per book postal 
rate of approximately $2.00, this amounts to an additional $190 
million.
    Finally, FDA considered option D-5, Telephone Counseling, which 
would require manufacturers of prescription drug and biological 
products to provide patients with a number to access counseling via 
telephone. While FDA encourages manufacturers to provide this service 
voluntarily, the agency believes that this form of oral counseling 
should be considered an adjunct, not a replacement, for written 
information. One large, mail-order company reports that about 10 
percent of its new prescription customers utilize a toll-free number. 
This percentage may be an upper-bound, however, when applied to retail 
outlets where pharmacists are available for counseling at the time of 
purchase. FDA estimates that if 5 to 10 percent of all new prescription 
purchases resulted in 3-minute telephone conversations, the annual cost 
of employing pharmacists to answer these calls would reach $82 to $164 
million. In addition, the average telephone charges may equal about 
$0.30 per minute, adding $50 to $100 million in annual costs. Thus, the 
estimated incremental costs for this option range from $65 to $132 
million. 

[[Page 44230]]


F. Benefits

    The primary objective of the proposed regulation is to enhance the 
nation's public health by allowing patients to make better use of their 
medications. FDA believes that the distribution of written prescription 
drug information to patients, when combined with licensed practitioner 
and/or pharmacist counseling, would accomplish this goal in two ways. 
First, it would reduce the incidence of therapeutic failures due to 
poor compliance with drug regimens. Second, it would decrease the 
number of preventable adverse drug reactions and preventable drug-drug 
and drug-food reactions. FDA believes that both outcomes are at least 
partly attainable with adequate patient knowledge. While there are no 
definitive studies that would allow FDA to develop precise measures of 
the present and future levels of these key health variables, this 
section presents the agency's best assessment of the expected values.
    There is substantial literature on the extent of patient 
noncompliance with prescription drugs. Although a large number of 
national programs have been initiated to improve patient information 
and education, this research continues to demonstrate that 
noncompliance with prescription drug regimens remains a public health 
concern. A 1990 NCPIE report found that about one-third of patients 
fail to take their prescribed medications (Ref. 3). An overview of 
patient compliance studies found that rates of compliance for long-term 
therapy tend to converge to 50 percent (Ref. 4). Other studies 
examining the literature on compliance rates in discrete patient 
populations suggest that pediatric nonadherence to therapeutic regimens 
exceeds 50 percent (Ref. 5), noncompliance rates for unsupervised 
psychiatric outpatients range from 25 to 50 percent (Refs. 6 and 7), 
and noncompliance in the elderly ranges from 26 to 59 percent (Ref. 8). 
Therefore, FDA has concluded that current patient noncompliance rates 
range from 30 to 50 percent.
    This research also provides evidence that patient noncompliance 
with prescribed drug regimens is directly related to therapeutic 
failure with serious health consequences, including blindness, cardiac 
arrest, and death (Refs. 9 and 10).
    A 1990 Office of the Inspector General report found that the 
process of patient education can save time by reducing calls or visits 
to the licensed practitioner or pharmacist and by reducing the number 
of hospitalizations resulting from patients' failures to follow 
prescribed drug regimens (Ref. 17).
    The economic burden to consumers and society of these preventable 
drug-related illnesses include the direct costs of additional or 
prolonged treatments by physicians or hospitals and the indirect costs 
of lost work-time, reduced productivity, and wasted expenditures on 
drugs whose efficacy is canceled or reduced by inappropriate or 
improper use. However, only a few studies have addressed the economic 
costs associated with drug noncompliance. More than 125,000 
hospitalizations, and 20 million lost work-days (with lost earnings of 
$1.5 billion in 1984) were attributed to drug noncompliance related to 
cardiovascular disease (Ref. 15). A 1990 study of 315 elderly patients 
found that hospitalization costs totaled approximately $293,000 for all 
drug-related admissions (Ref. 8) (About $224,000 was attributable to 
adverse drug reactions and $77,300 for drug noncompliance.) A recent 
report (Ref. 81) by the Task Force for Compliance, a group of 22 major 
pharmaceutical companies, estimated that the annual economic costs of 
noncompliance exceed $100 billion. They attribute these costs to added 
hospital admissions ($25 billion), prescriptions ($8 billion), nursing 
home admissions ($5 billion), and lost productivity (over $50 billion).
    The most comprehensive recent study employed a meta-analysis to 
measure the extent and direct costs of hospital admissions related to 
drug therapy noncompliance, using data on 2,942 hospital admissions 
from seven studies. Only published studies that met a strict definition 
of noncompliance (overuse, underuse, or erratic use) were included. The 
analysis found that 5.3 percent of annual hospital admissions, or 1.94 
million admissions, were due to drug noncompliance, at a cost of $8.5 
billion in 1986. The author noted that these results were similar to a 
1974 Task Force on Prescription Drugs that estimated hospital costs of 
$3 billion in 1976 dollars for all drug-related admissions (Ref. 15).
    As noted above, a precise quantitative measure of the benefits that 
would result from the increased availability of patient information is 
not possible, but FDA relied on the studies described above to develop 
an illustrative example of the potential magnitude of expected 
benefits. For its best estimate, FDA drew on the 1990 meta-analysis 
(Ref. 15) to assume that about 5 percent of the nation's 35 million 
annual hospital admissions are due to noncompliance with prescribed 
drug regimens. The average cost of each drug-related hospital admission 
is unknown, but the average cost for all inpatient hospital and 
physician services is estimated at almost $9,000 per admission (based 
on 1987 National Medical Expenditure Survey data, updated to 1993 by 
the Medical Care CPI). As shown in Table 5, the costs of these hospital 
admissions, based on an average 7-day stay, project to about $15.6 
billion per year.

BILLING CODE 4160-01-P

[[Page 44231]]
[GRAPHIC][TIFF OMITTED]TP24AU95.021



BILLING CODE 4160-01-C

[[Page 44232]]

    No comparable studies examined the nonhospital-related costs of 
drug noncompliance. However, as stated above, FDA found that from 30 to 
50 percent of all patients do not currently adhere to prescribed drug 
regimens. Because an estimated 150 million U.S. consumers use at least 
one prescription drug per year, about 60 million patients (150 
million x 40 percent) are at increased risk of added illness. FDA used 
this figure, together with an estimated incidence rate of 5 percent, to 
derive a conservative estimate of the percentage of the noncomplying 
population that would incur other direct medical costs, such as 
additional medications and physician visits. As shown, the total annual 
costs of noncompliance, including hospital admissions and other direct 
costs, are estimated to be about $15.7 billion.
    In addition, adverse drug reactions continue to be a significant 
health problem. FDA believes that appropriate information can moderate 
these incidents by warning patients about necessary precautions and 
heightening their ability to understand and respond to adverse 
reactions. A review of the relevant research in this area indicates 
that the incidence of adverse drug reactions responsible for hospital 
admissions ranges from 0.3 to 16.8 percent (Refs. 8, 11, 12, 13, and 
14). According to extrapolations from a sample of emergency rooms, 
approximately 5 percent of drug-related admissions were associated with 
adverse encounters with OTC drug products, and thus would not be 
affected by this proposal (Ref. 83). In addition, investigators have 
estimated that between 48 percent (Ref. 74) and 55 percent (Ref. 84) of 
all hospital admissions related to adverse reactions are preventable. 
Thus, using 50 percent as an estimate of preventable adverse reactions, 
the agency expects that approximately 47 percent (95 percent  x  50 
percent) of all hospital admissions associated with adverse drug 
reactions are potentially preventable by the distribution of quality 
patient information. This equals 1.4 percent of all hospital 
admissions. As shown in Table 5, these assumptions imply that the costs 
of preventable adverse drug reactions amount to about $4.4 billion per 
year. Moreover, although the incidence of adverse drug reactions in 
ambulatory patients has been reported at 20 percent (Ref. 48), FDA is 
still examining these data and has not derived estimates of the related 
costs. In sum, FDA finds that a partial tally of the direct medical 
costs associated with the additional or prolonged illnesses that result 
from both noncompliance with prescription drugs and preventable adverse 
drug reactions adds up to about $20.1 billion a year. Note that this 
estimate does not include the economic costs of lost productivity. As 
mentioned above, one pharmaceutical industry task force estimated the 
annual economic cost of noncompliance related to lost productivity as 
over $50 billion (Ref. 81).
    The realized benefits of increased patient information will depend 
on the ensuing changes in patient behavior. Several studies since 1982 
have found increases in compliance as a result of written information 
alone or in combination with oral counseling. The rate was as high as 
79 percent in the case of a comprehensive patient education program 
that included additional features (Ref. 74), although in most cases 
there were more modest increases. Of the studies involving only written 
information, one found a 30 percent increase in compliance (Ref. 48) 
and another a 50 percent increase among patients taking penicillin, but 
no significant difference among patients taking nonsteroidal anti-
inflammatory drugs (Ref. 47). Other studies using only written 
materials found no significant changes in compliance (Refs. 44 and 52). 
Two studies using both oral and written information showed increased 
compliance, with increases of 12 to 14 percent (Ref. 49) and 23 percent 
(Ref. 7). In another study, however, there was no significant effect of 
oral and written information on compliance (Ref. 66). These studies 
varied by type of patient, medication, and illness (chronic or acute), 
definition of compliance, length of therapy, and presence of noticeable 
symptoms. Such factors may explain the wide variation in the reported 
effects of written information on drug utilization behavior.
    The agency does not anticipate that required patient information 
would avert the majority of the costs associated with drug-related 
illnesses. Even with current levels of patient information, significant 
levels of noncompliance still occur. However, the above studies 
indicate that understandable information has a significant impact on 
patient compliance and awareness. Although data are not available to 
present a precise forecast of the resulting health changes, the agency 
notes that the health costs described above imply that if patient 
information was to result in even a 10 percent reduction in adverse 
outcomes, this would result in benefits of $2 billion per year. A 5-
percent improvement would produce annual benefits of $1 billion. Even a 
1 percent reduction in these health care expenditures would more than 
offset the costs of these proposed regulations.
    The agency notes that while these figures are only illustrative, it 
believes that the assumptions upon which they are based are 
conservative and that the projected range of benefits is reasonable. 
Moreover, this quantitative estimate does not account for the potential 
avoidance of catastrophic effects, such as avoidable death, permanent 
disability, or prolonged hospitalization. The costs of these more 
severe consequences, at even very low incidence rates, would be 
substantial.

G. Preliminary Conclusion

    Given the enormous benefits in cost savings and improved health 
care of this program, FDA believes that the economic costs of these 
regulations are justified. The agency expects concerns to be raised 
during the comment period about the apparent imbalance in bearing the 
direct burden of the costs of these proposed regulations, especially as 
borne by drug manufacturers and retail pharmacies should preapproved 
Medication Guides be required.
    The agency acknowledges that manufacturers would have the primary 
responsibility for providing required labeling for drug and biological 
products. FDA has recognized this concern in this proposal by requiring 
manufacturers to provide the means for the dispenser to generate a 
sufficient number of Medication Guides. However, as a practical matter, 
there is a strong possibility that the impact of the proposed patient 
labeling program, if fully implemented in the absence of satisfactory 
voluntary efforts, would place a greater share of the financial burden 
on the retail pharmacy sector rather than the manufacturer. The agency 
is soliciting guidance on how the costs of a required Medication Guide 
program could be allocated in a fair and reasonable fashion. 
Accordingly, in addition to the comments on the reasonableness of the 
estimates described above, the agency seeks comments on: (1) How 
manufacturers and pharmacies can share the costs of producing and 
dispensing Medication Guides; for example, by providing materials, 
computer support, subsidies, or in some other fashion; and (2) the role 
third-party intermediaries could play in interfacing between 
manufacturers and pharmacies, and how they could mitigate costs.

XIII. Environmental Impact

    The agency has determined under 21 CFR 25.24(a)(8) and (a)(11) that 
this action is of a type that does not 

[[Page 44233]]
individually or cumulatively have a significant effect on the human 
environment. Therefore, neither an environmental assessment nor an 
environmental impact statement is required.

XIV. Paperwork Reduction Act of 1980

    This proposed rule contains information collections which have been 
submitted for approval to the Office of Management and Budget under the 
Paperwork Reduction Act of 1980. The title, description, and respondent 
description of the information collection are shown below, with an 
estimate of the annual reporting and recordkeeping burden. Included in 
the estimate is the time for reviewing instructions, gathering and 
maintaining the data needed, and completing and reviewing the 
collection of information.
    Title: Medication Guide for Prescription Drug Products.
    Description: The information collection requirements would impose 
reporting requirements on manufacturers and a recordkeeping requirement 
on dispensers. However, until at least the year 2000, this burden would 
only be required for a small subset of products that pose a serious and 
significant public health concern requiring immediate distribution of 
FDA-approved patient information. For these products, manufacturers 
would be required to develop Medication Guides and submit them to FDA 
for approval; dispensers would be required to document a good faith 
effort to obtain Medication Guides when their supply is low or 
depleted.
    Description of Respondents: Businesses.

           Estimated Annual Reporting and Recordkeeping Burden          
------------------------------------------------------------------------
                      Annual                                     Annual 
  21 CFR section    number of      Annual     Average burden     burden 
                    responses    frequency     per response      hours  
------------------------------------------------------------------------
208.26(c)........          521           NA  30 min..........        261
314.50 (c)(2)(i),           10            1  320 hrs.........      3,200
 (d)(5)(vi)(b),                                                         
 and (e)(2)(ii);                                                        
 and 601.2(a).                                                          
314.70(b)(3)(ii).           20            1  160 hrs.........      3,200
314.94 (a)(8)(i),           10            1  16 hrs..........        160
 (a)(8)(ii),                                                            
 (a)(8)(iii), and                                                       
 (a)(8)(iv); and                                                        
 314.97.                                                                
                                            ----------------------------
      Total......  ...........  ...........                        6,821
------------------------------------------------------------------------

    The agency has submitted a copy of this proposed rule to the Office 
of Management and Budget (OMB) for its review of these information 
collections. Send comments regarding this burden estimate or any other 
aspect of this collection of information, including suggestions for 
reducing this burden, to FDA's Dockets Management Branch (address 
above) and to the Office of Information and Regulatory Affairs, OMB, 
Washington, DC 20503.

XV. Federalism

    Executive Order 12612, Federalism, is intended to ``restore the 
division of governmental responsibilities between the national 
government and the States that was intended by the Framers of the 
Constitution and to ensure that the principles of federalism 
established by the Framers guide the Executive departments and agencies 
in the formulation and implementation of policies.'' Section 3(d)(3) of 
Executive Order 12612 states that, when national standards are 
required, agencies must consult appropriate State officials and 
organizations. Section 4(d) requires agencies that foresee any possible 
conflict between State laws and federally protected interests to 
consult, to the extent practicable, appropriate officials and 
organizations representing the States to avoid such conflict.
    FDA is aware that several States have laws or regulations that 
require pharmacists to counsel patients on the use of prescription drug 
products. The agency does not believe its proposed rule on Medication 
Guides conflicts with such laws or regulations because the proposed 
rule would not affect any oral counseling requirement imposed by State 
laws or regulations. Nevertheless, the agency will continue to examine 
State laws for federalism purposes and invites comments from interested 
persons, particularly with respect to State initiatives to provide 
information on prescription drug products to patients.

XVI. References

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

1. Green, L. W., P. D. Mullen, and R. B. Friedman, ``An 
Epidemiological Approach to Targeting Drug Information,'' Patient 
Education and Counseling, 8:255-268, 1986.
2. Morris, L. A., et al., ``A Segmentational Analysis of 
Prescription Drug Information Seeking,'' Medical Care, 25:953-964, 
1987.
3. Heyduk, L. J., ``Medication Education: Increasing Patient 
Compliance,'' Journal of Psychosocial Nursing, 29:32-35, 1991.
4. Morris, L. S., and R. M. Schulz, ``Patient Compliance--An 
Overview,'' Journal of Clinical Pharmacy and Therapeutics, 17:283-
295, 1992.
5. Bartlett, E. E., ``Effective Approaches to Patient Education for 
the Busy Pediatrician,'' Pediatrics, 74:920-923, 1984.
6. Voris, J., C. Morin, and J. S. Kiel, ``Monitoring Outpatients' 
Plasma Antidepressant-Drug Concentrations as a Measure of 
Compliance,'' American Journal of Hospital Pharmacy, 40:119-120, 
1983.
7. Robinson, G. L., A. D. Gilbertson, and L. Litwack, ``The Effects 
of a Psychiatric Patient Education to Medication Program on Post-
Discharge Compliance,'' Psychiatric Quarterly, 58(2):113-118, Summer 
1986-1987.
8. Col, N., J. E. Fanale, and P. Kronholm, ``The Role of Medication 
Noncompliance and Adverse Drug Reactions in Hospitalizations of the 
Elderly,'' Archives of Internal Medicine, 150:841-845, 1990.
9. Office of the Inspector General, Office of Evaluation and 
Inspections, ``Medication Regimens: Causes of Noncompliance,'' March 
1990, citing John Urquhart, ``Drug Delivery Technology and Patient 
Compliance for New Products;'' Paper presented at The Conference on 
Advanced Therapeutics: Overcoming End User Barriers. Co-sponsored by 
the National Pharmaceutical Council and Frost and Sullivan, 
Baltimore, April 17-18, 1989.
10. Wood, A. J. J., and J. A. Oates, ``Adverse Reactions to Drugs,'' 
In Petersdorf, R., et al., ``Harrison's Principles of Internal 
Medicine,'' 12th ed. New York, McGraw-Hill; 373-379, 1991.
11. Lakshmanan, M. C., C. O. Hershey, and D. Breslau, ``Hospital 
Admissions Caused by Iatrogenic Disease,'' Archives of Internal 
Medicine, 146:1931-1934, 1986.
12. Salem, R. B., T. M. Keane, and J. G. Williams, ``Drug-Related 
Admissions to a Veterans' Administration Psychiatric Unit,'' Drug 
Intelligence and Clinical Pharmacy, 18:74-76, 1984.
13. Ives, T. I., E. J. Bentz, and R. E. Gwyther, ``Drug-Related 
Admissions to a Family Medicine Inpatient Service,'' Archives of 
Internal Medicine, 147:1117-1120, 1987.
14. Schneider, J. K., L. C. Mion, and J. D. Frengley, ``Adverse Drug 
Reactions in an 

[[Page 44234]]
Elderly Outpatient Population,'' American Journal of Hospital Pharmacy, 
49:90-96, 1992.
15. Sullivan, S. D., D. H. Kreling, and T. K. Hazlet, 
``Noncompliance with Medication Regimens and Subsequent 
Hospitalizations: A Literature Analysis and Cost of Hospitalization 
Estimate,'' Journal of Research in Pharmaceutical Economics, 
2(2):19-23, 1990.
16. Murphy, J. A., et al., ``Amiodarone: A Postmarketing Evaluation 
of Monitoring for Drug Induced Toxicity,'' DICP--Drug Intelligence 
and Clinical Pharmacy, 24:1001-1005, 1990.
17. Office of the Inspector General, Office of Evaluation and 
Inspections, ``Medication Regimens: Causes of Noncompliance,'' March 
1990.
18. National Council on Patient Information and Education, 
``Directory of Prescription Drug Information and Education Programs 
and Resources,'' Bullman, W. R., and F. Rowland (ed.), 1985.
19. Morris, L. A., E. R. Tabak, and N. J. Olins, ``A Segmentation 
Analysis of Prescription Drug Information-Seeking Motives Among the 
Elderly,'' Journal of Public Policy and Marketing, 11(2):115-125, 
1992.
20. Morris, L. A., and M. D. Tyson, ``There's More Than One Way to 
Go Direct to the Consumer,'' Perspectives, 9:5-12, 1985.
21. ``Direct to Consumer Advertising of Prescription Drugs; 
Withdrawal of Moratorium,'' Federal Register, 50 FR 36677-36678, 
September 9, 1985.
22. Morris, L. A., et al., ``Patient Receipt of Prescription Drug 
Information,'' National Technical Information Service, No. PB84-
100031, Springfield, VA.
23. Morris, L. A., et al., ``A National Survey of Prescription Drug 
Information Provided to Patients,'' National Technical Information 
Service, No. PB86-186947/XAB, 1986, Springfield, VA.
24. Morris, L. A., et al., ``Counseling Patients About Prescribed 
Medication: Ten Year Trends,'' Food and Drug Administration, 
Rockville, MD, 1993.
25. ``Public Attitudes Toward Prescription Drug Information: A 
Nationwide Study Conducted for CBS Inc.,'' Response Analysis Corp., 
Princeton, NJ, 1984.
26. Abram, M. B., ``Making Health Care Decisions: The Ethical and 
Legal Implications of Informed Consent in the Patient-Practitioner 
Relationship,'' President's Commission for the Study of Ethical 
Problems in Medicine and Biomedical and Behavioral Research, October 
1982.
27. Wiederholt, J. B., B. R. Clarridge, and B. L. Svarstad, ``Verbal 
Consultation Regarding Prescription Drugs: Findings from a Statewide 
Survey,'' Medical Care, 30:159-173, 1992.
28. Ascione, F. J., et al., ``A Survey of Patient Education 
Activities of Community Pharmacists,'' Patient Education and 
Counseling, 7:359-366, 1985.
29. McMahon, T., C. M. Clark, and G. R. Bailie, ``Who Provides 
Patients with Drug Information?'' British Medical Journal, 294:355-
356, 1987.
30. Katz, J. N., et al., ``Informed Consent and the Prescription of 
Nonsteroidal Antiinflammatory Drugs,'' Arthritis and Rheumatism, 
35:1257-1263, 1992.
31. Murphy, J. A. M., et al., ``Amiodarone: A Postmarketing 
Evaluation of Monitoring for Drug-Induced Toxicity,'' DICP, The 
Annals of Pharmacotherapy, 24:1001-1005, 1990.
32. McClellan, W., ``The Physician and Patient Education: A 
Review,'' Patient Education and Counseling, 8:151-163, 1986.
33. Gardner, M. E., et al., ``A Study of Patients' Perceived 
Importance of Medication Information Provided by Physicians in a 
Health Maintenance Organization,'' Drug Intelligence and Clinical 
Pharmacy, 22:596-598, 1988.
34. Nightingale, S. L., ``Do Physicians Tell Patients Enough About 
Prescription Drugs? Do Patients Think So?'' Postgraduate Medicine, 
74:170-175, 1983.
35. Graham, A. V., T. V. Parran, and C. R. Jaen, ``Physician Failure 
to Record Alcohol Use History When Prescribing Benzodiazepines,'' 
Journal of Substance Abuse, 4:179-185, 1992.
36. Ley, P., ``Communicating with Patients: Improving Communication, 
Satisfaction and Compliance,'' D. Marcer, ed., Croom Helm, New York, 
1988.
37. Debrovner, D., ``What Consumers Think About You,'' American 
Druggist, 24-31, 1993.
38. Weinman, J., ``Providing Written Information for Patients: 
Psychological Considerations,'' Journal of the Royal Society of 
Medicine, 83:303-305, 1990.
39. Williams-Deane, M., and L. S. Potter, ``Current Oral 
Contraceptive Use Instructions: An Analysis of Patient Package 
Inserts,'' Family Planning Perspectives, 24:111-115, 1992.
40. Casey, F. G., D. M. Fluitt, and A. L. Wiatt, ``The Patient's 
Understanding of the Oral Contraceptive Patient Package Insert,'' 
Military Medicine, 148:276-278, 1983.
41. O'Connell, M. B., and J. F. Johnson, ``Evaluation of Medication 
Knowledge in Elderly Patients,'' The Annals of Pharmacotherapy, 
26:919-921, 1992.
42. Gibbs, S., W. E. Waters, and C. F. George, ``Communicating 
Information to Patients About Medicine,'' Journal of the Royal 
Society of Medicine, 83:292-296, 1990.
43. Harvey, J. L., and R. J. Plumridge, ``Comparative Attitudes to 
Verbal and Written Medication Information Among Hospital 
Outpatients,'' DICP, The Annals of Pharmacotherapy, 25:925-928, 
1991.
44. Gibbs, S., W. E. Waters, and C. F. George, ``The Benefits of 
Prescription Information Leaflets (1),'' British Journal of Clinical 
Pharmacology, 27:723-739, 1989.
45. Van Haecht, C. H. M., R. Vander Stichele, and M. G. Bogaert, 
``Package Inserts for Antihypertensive Drugs: Use by the Patient and 
Impact on Adverse Drug Reactions,'' European Journal of Clinical 
Pharmacology, 39:551-554, 1990.
46. Sandler, D. A., et al., ``Is an Information Booklet for Patients 
Leaving Hospital Helpful and Useful?'' British Medical Journal, 
298:870-874, 1989.
47. George, C. F., W. E. Waters, and J. A. Nicholas, ``Prescription 
Information Leaflets: A Pilot Study in General Practice,'' British 
Medical Journal, 287:1193-1196, 1983.
48. Dodds, L. J., ``Effects of Information Leaflets on Compliance 
with Antibiotic Therapy,'' The Pharmaceutical Journal, 11:48-51, 
1986.
49. Myers, E. D., and E. J. Calvert, ``Information, Compliance and 
Side-Effects: A Study of Patients on Antidepressant Medication,'' 
British Journal of Clinical Pharmacology, 17:21-25, 1984.
50. Drury, V. W. M., ``Patient Information Leaflets,'' British 
Medical Journal, 288:427-428, 1984.
51. Hays, R. D., and M. R. DiMatteo, ``Key Issues and Suggestions 
for Patient Compliance Assessment: Sources of Information, Focus of 
Measures, and Nature of Response Options,'' The Journal of 
Compliance in Health Care, 2:37-53, 1987.
52. Gibbs, S., W. E. Waters, and C. F. George, ``The Benefits of 
Prescription Information Leaflets (2),'' British Journal of Clinical 
Pharmacology, 28:345-351, 1989.
53. Gibbs, S. ``Prescription Information Leaflets for Patients,'' 
European Respiratory Journal, 5:140-143, 1992.
54. Proos, M., et al., ``A Study of the Effects of Self-Medication 
on Patients' Knowledge of and Compliance with Their Medication 
Regimen,'' Journal of Nursing Care Quality, Special Report: 18-26, 
1992.
55. Schwartz-Lookinland, S., L. C. McKeever, and M. Saputo, 
``Compliance with Antibiotic Regimens in Hispanic Mothers,'' Patient 
Education and Counseling, 13:171-182 1989.
56. Haynes, R. B., E. Wang, and M. D. M. Gomes, ``A Critical Review 
of Interventions to Improve Compliance with Prescribed 
Medications,'' Patient Education and Counseling, 10:155-166 1987.
57. Prince, B. S., et al., ``Drug-Related Emergency Department 
Visits and Hospital Admissions,'' American Journal of Hospital 
Pharmacy, 49:1696-1700, 1992.
58. Wiederholt, J. B., and J. A. Kotzan, ``Effectiveness of the FDA-
Designed Patient Package Insert for Benzodiazepines,'' American 
Journal of Hospital Pharmacy, 40:828-834, 1983.
59. Morrow, N. C., ``Printed Information for Patients Receiving PUVA 
Therapy,'' Journal of Clinical and Hospital Pharmacy, 9:333-340, 
1984.
60. Hawkey, G. M., and C. J. Hawkey, ``Effect of Information 
Leaflets on Knowledge in Patients with Gastrointestinal Diseases,'' 
Gut, 30:1641-1646, 1989.
61. Dolinsky, D., et al., ``Application of Psychological Principles 
to the Design of Written Patient Information,'' American Journal of 
Hospital Pharmacy, 40:266-271, 1983.
62. Morris, L. A., and D. E. Kanouse, ``Informing Patients About 
Drug Side Effects,'' Journal of Behavioral Medicine, 5:363-373, 
1982.
63. Fisher, S., and S. G. Bryant, ``Postmarketing Surveillance: 
Accuracy of Patient Drug Attribution Judgments,'' Clinical 
Pharmacological Therapy, 48:102-107, 1990.
64. Quaid, K. A., et al., ``Informed Consent for a Prescription 
Drug: Impact of Disclosed Information on Patient 

[[Page 44235]]
Understanding and Medical Outcomes,'' Patient Education and Counseling, 
15(3):249-259, 1990.
65. Howland, S., M. G. Baker, and T. Poe, ``Does Patient Education 
Cause Side Effects? A Controlled Trial,'' The Journal of Family 
Practice, 31:62-64, 1990.
66. Brown, C. S., R. G. Wright, and D. B. Christensen, ``Association 
Between Type of Medication Instruction and Patients' Knowledge, Side 
Effects, and Compliance,'' Hospital and Community Psychiatry, 
38(1):55-60, 1987.
67. Regner, M. J., F. Hermann, and L. D. Ried, ``Effectiveness of a 
Printed Leaflet for Enabling Patients to Use Digoxin Side-Effect 
Information,'' Drug Intelligence and Clinical Pharmacy, 21:200-204, 
1987.
68. Mullen, P. D., and L. W. Green, ``Measuring Patient Drug 
Information Transfer: An Assessment of the Literature,'' 
Pharmaceutical Manufacturers Association, Washington, DC, 1983.
69. Kanouse, D. E., et al., ``Informing Patients About Drugs: 
Summary Report on Alternative Designs for Prescription Drug 
Leaflets,'' Rand Corp., Santa Monica, CA, 1981.
70. 42 U.S.C. 1396r-8(g)(2)(A)(ii)(I).
71. Council Directive 92/27/EEC, 1992 O.J. (L 113) 8-12.
72. Kirsch, I. S., et al., ``Adult Literacy in America,'' Office of 
Educational Research and Improvement, U.S. Department of Education, 
September 1993.
73. Proceedings of Conference on Unit-of-Use Packaging Contemporary 
Issues, December 13 through 15, 1992.
74. Sclar, D., et al., ``Effect of Health Education in Promoting 
Prescription Refill Compliance Among Patients with Hypertension,'' 
Clinical Therapeutics, 13:489-495, 1991.
75. National Association of Chain Drug Stores, ``Prescription Drug 
Marketplace Simulation Model,'' 1992.
76. Banahan and Garner, ``Using Pharmacy Computer Systems for Better 
Patient Care,'' Drug Topics, p. 82, January 10, 1994.
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pp. 15-16, September 6, 1993.
78. 1992 Lilly Digest, Eli and Co., 1992.
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Party Prescription,'' prepared by the Pharmaceutical Economics 
Research Center, Purdue University for the National Association of 
Chain Drug Stores, May 1990.
80. ``Annual Report of Retail Pharmacy,'' Drug Store News, April 20, 
1992, supplement.
81. Task Force for Compliance, ``Noncompliance with Medications: An 
Economic Tragedy with Important Implications for Health Care 
Reform,'' Baltimore, MD, November 1993.
82. Tabak, E. R., ``Encouraging Patient Question-Asking: A Clinical 
Trial,'' Patient Education and Counseling, 12:37-49, 1988.
83. The Drug Abuse Warning Network, Annual Emergency Room Data 1992, 
U.S. Department of Health and Human Services; Substance Abuse and 
Mental Health Services Administration, Series I, Number 12-A, p. 44.
84. Burnam, J. F., ``Preventability of Adverse Drug Reactions,'' 
Annals of Internal Medicine, 85:80-81, 1976.
85. Backinger, C. L., and P. A. Kingsley, ``Write It Right: 
Recommendations for Developing User Instructions for Medical Devices 
Used in Home Health Care,'' Department of Health and Human Services, 
Publication FDA 93-4258, 1993.
86. Doak, C. C., L. G. Doak, and J. H. Root, ``Teaching Patients 
With Low Literacy Skills,'' Philadelphia, J. B. Lippincott Co., 
1985.
87. Felker, D. B., F. Pickering, V. R. Charrow, V. M. Holland, and 
J. C. Redish, Guidelines for Document Designers, Washington, DC, 
American Institutes for Research, 1981.
88. Mettger, W. and J. Mara, ``Clear and Simple: Developing Print 
Materials for Low-literacy Readers,'' Bethesda, MD, National Cancer 
Institute, 1992.
89. Morris, L. A., M. Mazis, and E. Gordon, ``A Survey of the 
Effects of Oral Contraceptive Patient Information,'' Journal of the 
American Medical Association, 238(23):2504-2508, 1977.
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An FDA Survey,'' American Pharmacy, NS20(6):22-26, 1980.
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Patients of Potential Side Effects Without Fear of Causing Those 
Side Effects?,'' Archives of Internal Medicine, 154:2753-2756, 1994.
92. Kessler, D. A., ``Communicating With Patients About Their 
Medications,'' New England Journal of Medicine, 325:1650-1652, 1991.
93. Scheman, C. R., ``Patient Information and Education About Drugs: 
The FDA Perspective,'' Drug Information Journal, 27:1133-1136, 1993.
94. Morris, L. A., D. Brinberg, R. Klimberg, L. Millstein, and C. 
Rivera, ``Consumer Attitudes About Advertisements for Medicinal 
Drugs,'' Social Science and Medicine, 22:629-638, 1986.
95. National Association of Boards of Pharmacy, ``Consumer Patient 
Counseling Survey,'' 1994.

List of Subjects

21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.

21 CFR Part 208

    Drugs, Patient labeling, Reporting and recordkeeping requirements.

21 CFR Part 314

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

21 CFR Part 601

    Administrative practice and procedures, Biologics, Confidential 
business information.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that Chapter I of Title 21 of the Code of Federal Regulations 
be amended to read as follows:

PART 201--LABELING

    1. The authority citation for 21 CFR part 201 continues to read as 
follows:

    Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 508, 
510, 512, 530-542, 701, 704, 721 of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357, 358, 
360, 360b, 360gg-360ss, 371, 374, 379e); secs. 215, 301, 351, 361 of 
the Public Health Service Act (42 U.S.C. 216, 241, 262, 264).

    2. Section 201.57 is amended by revising paragraph (f)(2) to read 
as follows:


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

* * * * *
    (f) * * *
    (2) Information for patients: This subsection of the labeling shall 
contain information to be given to patients for safe and effective use 
of the drug, e.g., precautions concerning driving or the concomitant 
use of other substances that may have harmful additive effects. Any 
printed patient information or Medication Guide required under this 
chapter to be distributed to the patient shall be referred to under the 
``Precautions'' section of the labeling and the full text of such 
patient information or Medication Guide shall be reprinted at the end 
of the labeling. The print size requirements for patient information or 
the Medication Guide set forth in Sec. 208.22 of this chapter, however, 
do not apply to patient information or the Medication Guide that is 
reprinted in the professional labeling.
* * * * *
    3. New part 208 is added to read as follows:

PART 208--MEDICATION GUIDE FOR PRESCRIPTION DRUG PRODUCTS

Subpart A--General Provisions

Sec.
208.1  Scope and implementation.
208.3  Definitions.

Subpart B--General Requirements for a Medication Guide

208.20  Content of a Medication Guide.
208.22  Format for a Medication Guide.
208.24  Distributing and dispensing a Medication Guide.
208.26  Exemptions and deferrals.

    Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 510, 
701, 704 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 
331, 351, 352, 353, 355, 356, 357, 360, 371, 

[[Page 44236]]
374); Sec. 351 of the Public Health Service Act (42 U.S.C. 262).
Subpart A--General Provisions


Sec. 208.1  Scope and implementation.

    (a) This part sets forth requirements for patient labeling for 
human prescription drug products, including biological products. It 
applies only to those human prescription drug products administered 
primarily on an outpatient basis without direct supervision by a health 
professional. This part shall apply to new prescriptions and upon 
request by the patient for refill prescriptions. This part does not 
apply to prescription drug products administered in an institutional 
setting (such as hospitals, nursing homes, or other health care 
facilities), or in emergency situations.
    (b) Except as provided in paragraph (d) of this section, the 
provisions of this part are deferred until a determination is made by 
FDA that either of the following performance standards has not been 
met:
    (1) by (insert date 5 years from the effective date of the final 
rule), 75 percent of patients receiving new prescription drugs or 
biologics that are covered under these provisions receive useful 
patient information as described in paragraph (c) of this section, or
    (2) by (insert date 11 years from the effective date of the final 
rule), 95 percent of the patients receiving new prescription drugs or 
biologics that are covered under these provisions receive useful 
patient information as described in paragraph (c) of this section.
    (c) Determination of useful patient information will be based on 
scientific accuracy, consistency with the format in Sec. 208.22, 
nonpromotional tone and content, specificity, comprehensiveness, 
understandable language, and legibility.
    (d) This part shall apply without deferral to human prescription 
drug products and biological products that FDA determines pose a 
serious and significant public health concern requiring immediate 
distribution of FDA-approved patient information.


Sec. 208.3  Definitions.

    For purposes of this part, the following definitions shall apply:
    (a) Authorized dispenser means an individual licensed, registered, 
or otherwise permitted by the jurisdiction in which the individual 
practices to provide drug products on prescription in the course of 
professional practice.
    (b) Dispense to patients means the act of delivering a prescription 
drug product to a patient or an agent of the patient either:
    (1) By a licensed practitioner or an agent of a licensed 
practitioner, either directly or indirectly, for self- administration 
by the patient, or the patient's agent, or outside the licensed 
practitioner's direct supervision; or
    (2) By an authorized dispenser or an agent of an authorized 
dispenser under a lawful prescription of a licensed practitioner.
    (c) Distribute means the act of delivering, other than by 
dispensing, a drug product to any person.
    (d) Distributor means a person who distributes a drug product.
    (e) Licensed practitioner means an individual licensed, registered, 
or otherwise permitted by the jurisdiction in which the individual 
practices to prescribe drug products in the course of professional 
practice.
    (f) Manufacturer means the manufacturer as described in Secs. 201.1 
and 600.3(t) of this chapter.
    (g) Patient means any individual, with respect to whom a drug 
product is intended to be, or has been, used.

Subpart B--General Requirements for a Medication Guide


Sec. 208.20  Content of a Medication Guide.

    (a) A Medication Guide shall meet all of the following conditions:
    (1) The Medication Guide shall be written in English, in 
nontechnical language, and shall not be promotional in tone or content.
    (2) The Medication Guide shall be based on, and shall not conflict 
with, the approved professional labeling for the drug product under 
Sec. 201.57 of this chapter.
    (b) A Medication Guide shall contain the following:
    (1) The brand name (e.g., the trademark or proprietary name), if 
any, and established name. Those products not having an established 
name shall be designated by their active ingredients. The Medication 
Guide shall include the phonetic spelling of either the brand name or 
the established name, whichever is used throughout the Medication 
Guide.
    (2) A summary section containing the drug product's approved 
indications, critical aspects of proper use, significant warnings, 
precautions, and contraindications, serious adverse reactions, and 
potential safety hazards.
    (3) A section that identifies a drug product's indications for use. 
The Medication Guide may not identify an indication unless the 
indication is identified in the indications and usage section of the 
professional labeling for the product required under Sec. 201.57 of 
this chapter.
    (4) Information on circumstances under which the drug product 
should not be used for its labeled indication (its contraindications). 
The Medication Guide shall contain directions regarding what to do if 
any of the contraindications apply to a patient, such as contacting the 
licensed practitioner or discontinuing use of the drug product.
    (5) A statement or statements of precautions the patient should 
take to ensure proper use of the drug, including:
    (i) A statement that identifies activities (such as driving or 
sunbathing), and drugs, foods, or other substances (such as tobacco or 
alcohol) that the patient should avoid;
    (ii) A statement of the risks to the mother and fetus from the use 
of the drug during pregnancy;
    (iii) A statement of the risks of the drug product to a nursing 
infant;
    (iv) A statement of pediatric indications, if any. If the drug 
product has specific hazards associated with its use in pediatric 
patients, a statement of the risks;
    (v) A statement of geriatric indications, if any. If the drug 
product has specific hazards associated with its use in geriatric 
patients, a statement of the risks; and
    (vi) A statement of special precautions, if any, that apply to the 
safe and effective use of the drug product in other identifiable 
patient populations.
    (6)(i) A statement of the possible adverse reactions from the use 
of the drug product which are serious or occur frequently.
    (ii) A statement of the risks, if any, to the patient of developing 
a tolerance to, or dependence on, the drug product.
    (7) Information on the proper use of the drug product, including:
    (i) A statement stressing the importance of adhering to the dosing 
instructions.
    (ii) A statement describing any special instructions on how to 
administer the drug product.
    (iii) A statement of what the patient should do in case of overdose 
of the drug product.
    (iv) A statement of what the patient should do if the patient 
misses taking a scheduled dose of the drug product.
    (8) General information about the safe and effective use of 
prescription drug products, including:
    (i) The verbatim statement that ``Medicines are sometimes 
prescribed for purposes other than those listed in a Medication Guide'' 
followed by a statement that the patient should ask the health 
professional about any concerns, 

[[Page 44237]]
and a reference to the availability of professional labeling;
    (ii) A statement that the drug product not be used for other 
conditions or given to other persons;
    (iii) The name and place of business of the manufacturer, packer, 
or distributor, as required for the label of the drug product under 
Sec. 201.1 of this chapter, or the name and place of business of the 
dispenser of the drug product or for biological products, the name, 
address, and license number of the manufacturer; and
    (iv) The date, identified as such, of the most recent revision of 
the Medication Guide placed immediately after the last section.


Sec. 208.22  Format for a Medication Guide.

    A Medication Guide shall be printed in accordance with the 
following specifications:
    (a) The letter height or type size shall be no smaller than 10 
points (1 point = 0.0138 inches) for all sections of the Medication 
Guide, except the manufacturer's name and address and the revision 
date.
    (b) The Medication Guide shall be legible and clearly presented. 
Where appropriate, the Medication Guide shall also use boxes, bold or 
underlined print, or other highlighting techniques to emphasize 
specific portions of the text.
    (c) The words ``Medication Guide'' shall appear prominently at the 
top of the first page of a Medication Guide. The verbatim statement 
``This Medication Guide has been approved by the U.S. Food and Drug 
Administration'' shall appear at the bottom of a Medication Guide.
    (d) The brand and established name shall be immediately below the 
words ``Medication Guide.'' The established name shall be no less than 
one-half the height of the brand name.
    (e) The Medication Guide shall use the following headings:
    (1) ``What is the most important information I should know about 
(name of drug)?''
    (2) ``What is (name of drug)?''
    (3) ``Who should not take (name of drug)?''
    (4) ``How should I take (name of drug)?''
    (5) ``What should I avoid while taking (name of drug)?''
    (6) ``What are the possible side effects of (name of drug)?''


Sec. 208.24  Distributing and dispensing a Medication Guide.

    (a) For a large volume container of finished dosage form:
    (1) Each manufacturer shall provide to each distributor to which it 
ships a large volume container of finished dosage form either:
    (i) The Medication Guide in sufficient numbers; or
    (ii) The means to produce the Medication Guide in sufficient 
numbers to permit the distributor to comply with paragraph (b) of this 
section.
    (2) The label of each large volume container of finished dosage 
form shall instruct the authorized dispenser to provide a Medication 
Guide to each patient to whom the drug product is dispensed.
    (b) Each manufacturer or distributor shall provide to each 
authorized dispenser to which it ships the drug product either:
    (1) The Medication Guide in sufficient numbers; or
    (2) The means to produce the Medication Guide in sufficient numbers 
to permit the authorized dispenser to provide the Medication Guide to 
each patient receiving a new prescription for a drug product or 
requesting a Medication Guide.
    (c) For a drug product in a unit-of-use container, the manufacturer 
and distributor shall provide a Medication Guide with each package of 
the drug product that the manufacturer or distributor intends to be 
dispensed to patients.
    (d) The requirements of this section can be met by the manufacturer 
or distributor or by any other person acting on behalf of the 
manufacturer or distributor. Nothing in this section prohibits a 
manufacturer or distributor from meeting the requirements with a 
Medication Guide printed by the distributor or authorized dispenser.
    (e) Each authorized dispenser of a prescription drug product 
subject to this part shall, when the product is dispensed (to a patient 
or to a patient's agent), for new prescriptions and upon request by the 
patient for refill prescriptions, provide a Medication Guide directly 
to each patient (or to the patient's agent), unless an exemption 
applies under Sec. 208.26.
    (f) An authorized dispenser is not subject to section 510 of the 
Federal Food, Drug, and Cosmetic Act, which requires the registration 
of producers of drugs and the listing of drugs in commercial 
distribution solely because of an act performed by the authorized 
dispenser under part 208.


Sec. 208.26  Exemptions and deferrals.

    (a) The Food and Drug Administration (FDA) on its own initiative or 
in response to a written request from an applicant, may exempt or defer 
any or all Medication Guide requirements on the basis that the 
requirement is inapplicable, unnecessary, or contrary to the patient's 
best interests. Requests from applicants should be submitted to the 
director of the FDA division responsible for reviewing the marketing 
application for the drug product, or for a biological product, to the 
application division in the office with product responsibility.
    (b) If the licensed practitioner who prescribes a drug product, or 
the authorized dispenser who dispenses a drug product, determines that 
it is not in the patient's best interest to receive a Medication Guide 
because of significant concerns about the effect of a Medication Guide, 
the licensed practitioner may direct that the Medication Guide not be 
provided to the patient, or the authorized dispenser may withhold the 
Medication Guide. However, the authorized dispenser of a prescription 
drug product shall provide a Medication Guide to any patient who 
requests it when the drug product is dispensed regardless of any such 
direction by the licensed practitioner or the authorized dispenser. 
This exemption from providing a Medication Guide does not apply if FDA 
determines that a Medication Guide for a particular product should be 
provided to all patients under all circumstances.
    (c) A Medication Guide is not required to be dispensed to patients 
in emergency situations or where the manufacturer, distributor, or 
authorized dispenser, after documenting a good faith effort to obtain a 
Medication Guide for the patient, does not have a Medication Guide 
available for the patient.
    (d)(1) An authorized dispenser, as defined in Sec. 208.3(a), shall 
be exempt from the dispensing requirements of Sec. 208.24(e) when the 
following conditions are met:
    (i) The authorized dispenser dispensed, in the previous calendar 
year, no more than an average of 300 outpatient prescription drug 
products per week; and
    (ii) The authorized dispenser, or its business entity, has gross 
annual sales of no more than $5.0 million; and
    (iii) The authorized dispenser makes available to patients a 
compilation of current Medication Guides for reading in the dispensing 
or counseling area.
    (2) This exemption does not apply to a drug dispensed in a unit-of-
use container or a drug which the agency determines must be dispensed 
with a Medication Guide. 

[[Page 44238]]


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

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

    Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701, 
704, 721 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 
331, 351, 352, 353, 355, 356, 357, 371, 374, 379e).

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


Sec.  314.50  Content and format of an application.

    Applications and supplements to approved applications are required 
to be submitted in the form and contain the information, as appropriate 
for the particular submission, required under this section. * * * An 
application for a new chemical entity will generally contain an 
application form, an index, a summary, five or six technical sections, 
case report tabulations of patient data, case report forms, drug 
samples, and labeling, including, if applicable, any Medication Guide 
required under part 208 of this chapter. * * *
* * * * *
    (c) * * *
    (2) * * *
    (i) The proposed text of the labeling, including, if applicable, 
any Medication Guide required under part 208 of this chapter, for the 
drug, with annotations to the information in the summary and technical 
sections of the application that support the inclusion of each 
statement in the labeling, and, if the application is for a 
prescription drug, statements describing the reasons for omitting a 
section or subsection of the labeling format in Sec. 201.57 of this 
chapter.
* * * * *
    (d) * * *
    (5) * * *
    (vi) * * *
    (b) The applicant shall, under section 505(i) of the act, update 
periodically its pending application with new safety information 
learned about the drug that may reasonably affect the statement of 
contraindications, warnings, precautions, and adverse reactions in the 
draft labeling and, if appropriate, any Medication Guide required under 
part 208 of this chapter. * * *
* * * * *
    (e) * * *
    (2) * * *
    (ii) Copies of the label and all labeling for the drug product 
(including, if applicable, any Medication Guide required under part 208 
of this chapter) for the drug product (4 copies of draft labeling or 12 
copies of final printed labeling).
* * * * *
    (k) * * *
    (1) * * * Information relating to samples and labeling (including, 
if applicable, any Medication Guide required under part 208 of this 
chapter), is required to be submitted in hard copy. * * *
* * * * *
    6. Section 314.70 is amended by revising paragraph (b)(3) to read 
as follows:


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

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


Sec. 314.94  Content and format of an abbreviated application.

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

PART 601--LICENSING

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

    Authority: Secs. 201, 501, 502, 503, 505, 510, 513-516, 518-520, 
701, 704, 721, 801 of the Federal Food, Drug, and Cosmetic Act (21 
U.S.C. 321, 351, 352, 353, 355, 360, 360c-360f, 360h-360j, 371, 374, 
379e, 381); secs. 215, 301, 351, 352 of the Public Health Service 
Act (42 U.S.C. 216, 241, 262, 263); secs. 2-12 of the Fair Packaging 
and Labeling Act (15 U.S.C. 1451-1461).

    9. Section 601.2 is amended in paragraph (a) by revising the first 
sentence to read as follows:


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

    (a) General. To obtain a license for any establishment or product, 
the manufacturer shall make application to the Director, Center for 
Biologics Evaluation and Research, on forms prescribed for such 
purposes, and in the case of an application for a product license, 
shall submit data derived from nonclinical laboratory and clinical 
studies which demonstrate that the manufactured product meets 
prescribed standards of safety, purity, and potency; with respect to 
each nonclinical laboratory study, either a statement that the study 
was conducted in compliance with the requirements set forth in part 58 
of this chapter, or, if the study was not conducted in compliance with 
such regulations, a brief statement of the 

[[Page 44239]]
reason for the noncompliance; statements regarding each clinical 
investigation involving human subjects contained in the application, 
that it either was conducted in compliance with the requirements for 
institutional review set forth in part 56 of this chapter or was not 
subject to such requirements in accordance with Sec. 56.104 or 
Sec. 56.105 of this chapter, and was conducted in compliance with 
requirements for informed consent set forth in part 50 of this chapter; 
a full description of manufacturing methods; data establishing 
stability of the product through the dating period; sample(s) 
representative of the product to be sold, bartered, or exchanged or 
offered, sent, carried, or brought for sale, barter, or exchange; 
summaries of results of tests performed on the lot(s) represented by 
the submitted sample(s); and specimens of the labels, enclosures, 
containers, and, if applicable, any Medication Guide required under 
part 208 of this chapter proposed to be used for the product. * * *
* * * * *
    Dated: July 17, 1995.
David A. Kessler,
Commissioner of Food and Drugs.
Donna E. Shalala,
Secretary of Health and Human Services.
    Note: The following appendixes will not appear in the Code of 
Federal Regulations.

BILLING CODE 4160-01-P

[[Page 44240]]


APPENDIX A--A ``shell'' of the proposed uniform format

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BILLING CODE 4160-01-C

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APPENDIX B--Several sample Medication Guides using the proposed 
uniform format
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BILLING CODE 4160-01-C

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Appendix C--Several Sample Medication Guides Using Alternative 
Formats
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[FR Doc. 95-21020 Filed 8-23-95; 8:45 am]
BILLING CODE 4160-01-C