Prescription Drug Product Labeling; Medication Guide Requirements

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

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presentations to assist hospital and retail pharmacists in providing

drug information to patients; (4) the United States Pharmacopeial

Convention, Inc. (USP), published several consumer guides to

prescription drugs; (5) the American Association of Retired Persons

(AARP) provided package inserts with prescriptions filled by its mail-

order pharmacy service; (6) Doubleday, Inc., published a consumer's

compendium of drug therapy, which included tear-out sheets about

specific diseases; and (7) many retail pharmacies provided pamphlets,

posters, and books on prescription drugs to pharmacy customers (47 FR

39147 at 39151). Some of these programs and others are discussed in

detail below.

In the preamble to the final rule FDA stated:

*** Although the agency realizes that consumer groups generally

supported the PPI pilot program, it believes that as the voluntary

systems emerge, consumers will receive not only an adequate supply

of prescription drug information from a variety of sources, but

should receive more information about more drugs than would have

resulted from a mandatory system. FDA also believes that the current

regulatory environment demands that these various private sector

efforts be given the opportunity to demonstrate that they can meet

consumers' needs as well, if not better than, a government program.

(47 FR 39147 at 39153).

FDA indicated that, although it was revoking the 1980 regulation,

it intended to work closely with the private sector and with other

public sector agencies to identify and implement methods of providing

information about prescription drugs to consumers, to promote patient

education, to monitor changes in patient awareness of drug information,

and to develop and evaluate the effectiveness of information

dissemination activities. As mentioned above, FDA announced that it was

forming a Committee on Patient Education to coordinate efforts to

educate consumers about prescription drugs and to serve as a catalyst

for private sector initiatives. Specifically, the committee was

established to: (1) Evaluate existing patient information systems as

well as new ones; (2) encourage the formation of, and serve as a

liaison for, outside organizations that are or want to become active in

patient information systems; (3) provide guidance and serve as a

clearinghouse for firms that want to draft prescription drug

information; (4) alert consumers and health professionals to the

usefulness and availability of prescription drug information; and (5)

identify the need for patient information in the use of other FDA-

regulated products. FDA also indicated that it would be conducting

surveys of consumers and health care professionals to evaluate the

availability of adequate patient information on a nationwide basis. FDA

stated that it will assess this information ``over the next several

years.'' FDA also noted: ``The agency believes it would be

counterproductive to the development of private initiatives for it to

develop and publicly announce a course of action it might take should

these private initiatives not materialize'' (47 FR 39147 at 39152).

III. The Continuing Need for Prescription Drug Information

A. Continuing Problems of Lack of Adherence and Preventable Adverse

Drug Reactions

FDA's proposal and final rule extensively reviewed the literature

relating to patient adherence (also known as compliance) with

medication regimens. FDA cited two literature reviews, and completed

its own review of 50 studies, and concluded that noncompliance rates

averaged from 30 percent to 50 percent. FDA also concluded that

improved communication could contribute to improving compliance rates.

Written information was necessary not only to improve adherence rates,

but to inform patients about precautions, contraindications, and

adverse drug reactions, leading to better knowledge about: (1) Using

drugs properly, (2) monitoring reactions to medications for signs of

possible problems, and (3) raising issues with licensed practitioners

and other health professionals to improve communications about

medication. (The term ``licensed practitioner'' in this document refers

to individuals licensed, registered, or otherwise permitted to

prescribe drug products in the course of their professional practice.)

The literature published since 1982 continues to support the

conclusion that patient education can contribute to the prevention of

disease, successful results in treatment, and reduction in medical

costs. However, the need for drug information, education, and

counseling exceeds the current supply, both in quantity and quality,

and much of the available information fails to reach patients who need

it, when they need it, and in the form they need it (Ref. 1). Although

there is a wide variety of sources, the information that actually

reaches most patients is focused primarily on how to use the

medication, with little precautionary or adverse drug information

obtained by most patients (Ref. 2). FDA believes that standard drug

information, when combined with counseling from a prescribing

practitioner, pharmacist, or other health professional should

significantly increase patients' knowledge about the prescription drugs

they are taking, and thereby make prescription drugs safer and more

effective for consumer use.

The literature on patient compliance since 1982 continues to

demonstrate a significant lack of medication adherence. For example, a

1990 report by NCPIE found that about one-third of patients fail to

take their prescribed medications (Ref. 3). An overview of patient

compliance studies reveals that about one-half of prescribed

medications fail to produce the intended therapeutic effect because of

improper use (Ref. 4). Studies examining compliance rates in specific

patient populations suggest that parental noncompliance with drug

therapy prescribed for their children exceeds 50 percent (Ref. 5) and

noncompliance in the elderly ranges from 26 percent to 59 percent (Ref.

8).

Patient noncompliance with prescribed drug regimens can be directly

related to therapeutic failure. For example, missed doses of

antiglaucoma medications may lead to optic nerve damage and blindness.

Missed doses of antiarrhythmic medications may lead to arrhythmia and

cardiac arrest. Missed doses of antihypertensive drug products may lead

to rebound hypertension that is sometimes worse than if no medication

was taken at all. Missed doses of antibiotics may lead to recurrent

infection and also may contribute to the emergence of antibiotic-

resistant microorganisms (Ref. 9).

In addition to addressing problems of adherence, patient

information is also necessary to improve drug use by forewarning

patients about precautions to take to avoid adverse drug reactions.

Further, forewarning is necessary to improve the patient's ability to

monitor reactions to treatment to ensure both that the drug is working

and that it is not causing adverse reactions.

A 1990 report by the Office of the Inspector General found that the

process of patient education can save time by reducing calls or visits

to the licensed practitioner or pharmacist and reducing the number of

hospitalizations that are due to a patient's failure to follow his or

her prescribed drug regimen (Ref. 17). For example, increased visits to

the licensed practitioner may be required if the patient's condition

does not improve because of noncompliance with his or her drug regimen.

If the licensed practitioner is unaware of the

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noncompliance, he or she may increase the patient's dosage or prescribe

additional medicine that may be unnecessary and possibly dangerous. Or

if the patient's condition fails to improve, the licensed practitioner

may order additional diagnostic tests or unnecessary treatments.

Adverse drug reactions also are a continuing problem for the health

care system. Adverse drug reactions occur in 20 percent of ambulatory

patients (Ref. 10), and 2 percent to 5 percent of hospital admissions

are attributed to drug-related illness (Ref. 10). The case/fatality

rate from drug-induced disease in hospitalized patients is 2 percent to

12 percent (Ref. 10). Iatrogenic admissions to medical wards continue

to be a costly result of improper use of prescription drugs.

At a psychiatric service of a Veterans' Administration hospital, 41

admissions over a 4-month period were reviewed for drug-related

problems (Ref. 12). Two percent of admissions were determined to be due

to drug side effects.

Charts of 293 patients admitted over the course of 1 year to a

family medicine inpatient service were reviewed, showing 15.4 percent

of admissions to be drug related (Ref. 13). Six percent of admissions

for the most frequent type of drug-related admissions were for adverse

drug reactions.

Adverse drug reactions among older Americans are even more

frequent. In one study, researchers analyzed 463 charts of geriatric

outpatients (Ref. 14), revealing 107 notations of adverse drug

reactions in the charts of 97 patients (21 percent). Twelve patients

were hospitalized as a direct result of an adverse drug reaction. In

another study (Ref. 8) of 315 geriatric hospitalizations, 16.8 percent

of admissions were determined to be related to adverse drug reactions.

The hospital charge for these admissions was $224,542.

Some proportion of adverse drug reactions will occur regardless of

how carefully patients follow their therapeutic regimens. Although it

is difficult to estimate the proportion of adverse drug reactions and

associated health care costs that can be attributed to nonoptimal

patient adherence, there are some data relevant to this issue. In one

study, 834 admissions to a hospital medical service were reviewed for

iatrogenic disease, and 4 percent were determined to be drug-related

(Ref. 11). Of these, 54 percent were classified as potentially

avoidable, including, for example, overdoses and adverse reactions that

evolved slowly enough that had the problems been reported earlier,

treatment alterations could have been made in ambulatory care settings.

In an earlier study of a sample of 1,000 patients in a community

practice, it was determined that 55 percent of the adverse drug

reactions experienced were unnecessary and potentially preventable

(Ref. 84).

In addition, a 1990 meta-analysis of seven studies that looked at

the association between hospital costs and admissions for problems

specifically caused by noncompliance (strictly defined as overuse,

underuse, or erratic use) indicates that adverse drug reactions caused

by noncompliance constitute costly consequences for the health care

system. This analysis estimated that 5.3 percent of annual hospital

admissions, costing $8.5 billion in 1986, were a direct result of drug

treatment noncompliance (Ref. 15).

B. The Benefits of Patient Information

1. Written Information Increases Patient Knowledge and Satisfaction

Patients who receive written information about their medications

derive increased personal benefits from the information. The most

widely documented of these is increased knowledge.

Industry experts, practitioners, and consumers agree that patients

must have some basic information about prescription drugs to adhere

successfully to their prescribed drug therapy. Many studies have tested

whether the dissemination of written material increases patient

knowledge and understanding. For example, a 1983 study of FDA's PPI for

benzodiazepines concluded that the PPI effectively conveyed written

drug information to patients, and that knowledge and comprehension

varies according to the patient's age, years of education, and reading

environment (Ref. 58). In this study, patients who received written

patient information scored higher on a knowledge and comprehension test

than those who received no written information, and those who completed

the test at home scored higher than those who completed it at the

pharmacy.

It is clear that patients who receive written materials about

medications have increased knowledge about the use and effects of the

medications (Refs. 38, 42, 44, 47, 48, 52, 53, and 59 through 61). In

particular, patients who receive written information show more

knowledge about side effects (Refs. 46, 47, 48, 52, and 58), and are

better able to attribute adverse reactions to the medications they are

taking (Ref. 62). They can more easily discriminate adverse reactions

attributable to the medication from other clinical events (Ref. 63).

Patients who receive written information about their medications

are more likely to make healthy lifestyle changes (Ref. 60). They are

also more satisfied with their treatment (Refs. 33, 42, 47, and 53). In

a review of the literature, one author suggests that provision of

written materials may help patients cope with illnesses over time, as

their modes of coping evolve and the corresponding need for information

changes (Ref. 38).

When presented with written information about their medications,

the vast majority of patients read it, particularly if it is the

initial prescription (Refs. 38, 40, and 44). Reading may be thorough or

superficial (Ref. 45). Patients report reading the printed information

when receiving the first prescription and refills (Ref. 40), and they

may read the materials more than once (Ref. 46).

2. Written Materials About Medications Can Increase Patient Compliance

Even more critical to the health care system, studies of the

effects of providing written medication information to patients

demonstrate that the result can be increased compliance with the

treatment regimen (Refs. 38, 47, and 48). For example, in one study,

outpatients who received a patient information leaflet along with their

penicillin prescription were tested against patients who received no

information at all. Researchers found that a significantly lower

proportion of patients who received the patient information omitted

doses than those who did not receive the information (Ref. 47).

Similarly, researchers concluded that providing written information to

patients with antibiotic prescriptions resulted in significant

improvement in drug taking behavior and in knowledge about the therapy

prescribed (Ref. 48). In a study of psychiatric patients, those

receiving written information were more compliant in their medication

regimens than those not receiving it, and patients receiving both

written and oral information were the most compliant (Ref. 7). In

another study, patients receiving both written and oral information

about their medications were more compliant than those given no

information (Ref. 49). Providing written information has also resulted

in fewer patients stopping treatment (Ref. 50). The results of

increased compliance may be fewer deaths and lower overall costs of

treatment, due to fewer requirements for hospitalizations and

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nursing home admissions (Refs. 4 and 57).

In a broad review of the effects of written information, Ley (Ref.

36) concluded that most of the studies examined found positive effects

resulting from the provision of written information to patients. Out of

32 studies examining effects on knowledge, 97 percent found increases;

of the 25 studies examining compliance, 60 percent found increases; and

in 7 studies examining therapeutic benefit, 57 percent found increases.

It should be noted that ``compliance'' represents a broad range of

behaviors that are difficult to measure (Ref. 51). Several studies that

have sought to measure the effects of written information have failed

to find compliance improved by written information (Ref. 44, 52 through

55). However, in a critical review of the methodologically rigorous

studies of interventions to improve compliance, Haynes et al. (Ref. 56)

concluded that compliance with short-term treatments can be improved by

clear instructions, including written information, as well as by other

interventions. Compliance with long-term treatments is more difficult

to achieve; no single intervention has been shown to be effective on

its own. Rather, improved compliance with long-term regimens requires a

combination of interventions, including clear instructions enhanced by

written information.

3. Written Patient Information Does Not Have Negative Consequences

There has been speculation about the potential adverse effects of

providing information about medications to patients. However, the

studies suggest that written information does not increase reports of

adverse events (Refs. 38, 42, 44, 45, 48, 52, 53, 62 and 91), nor does

oral information (Ref. 65). Two studies that appear to indicate the

opposite are flawed. In one case, the authors admit that the written

information given to patients was inadequate (Ref. 52) and, in the

other, statistical analyses were performed by combining control and

experimental groups inappropriately (Ref. 50). A study of psychiatric

patients was inconclusive on this point (Ref. 66).

Studies do not show evidence of decreased compliance as a result of

written information (Refs. 52 and 66) or evidence of increased anxiety

levels (Ref. 60).

4. Relative Effectiveness of Oral and Written Patient Information

Studies examining the relative effectiveness of printed and oral

medication information are scarce. However, one study shows that

provision of printed information is more effective in increasing

patients' knowledge than oral information, and that a combination of

the two is best. The authors believe that written materials,

particularly those containing information about side effects, may be

more effective and timely and less alarming to patients than oral

information because most side effects do not occur until after the

medication has been taken for a while (Ref. 67). One author suggests

that written information should be used to supplement oral instructions

that should be tailored to meet the particular beliefs, concerns, and

expectations of the individual patient (Ref. 38).

One meta-analysis of the literature, published in 1983 by the

Pharmaceutical Manufacturers Association (PMA) (Ref. 68), merits

special attention because it purports to demonstrate that PPI's about

drugs have almost no effect in improving knowledge or compliance. After

careful review of this analysis, FDA has concluded that the methodology

was flawed and should not be relied upon with regard to the effects of

written drug information on compliance. The details of the study and

FDA's analysis of its methodology follow.

In 1983, PMA funded a grant to assess the literature regarding

mechanisms for improving patients' knowledge and use of prescription

drugs. The authors performed a meta-analysis of studies selected from

the patient education/compliance literature. They examined eight

different strategies to improve patient knowledge and use of

prescription drugs: Counseling, group education, behavior modification,

counseling plus materials, materials alone, memory aids, counseling

plus memory aids, and PPI's. The authors concluded that seven of the

strategies improved patient knowledge and use by 24 percent to 72

percent; however, PPI's had practically no effect in improving patient

knowledge or compliance. They concluded that PPI's were an ineffective

tool to improve patients' knowledge about or use of medication.

FDA staff reviewed the meta-analysis and found its conclusions to

be unsupported by the analysis performed by its authors. There are

major definitional and methodological problems with the authors'

analysis.

First, the inclusion criteria used were not rigorously followed.

Following Kanouse, et al. (Ref. 69), the authors of the meta-analysis

defined PPI's as ``standardized leaflets which accompany a prescription

drug as it is dispensed to the patient and which are designed to inform

patients about a drug's actions, indications, and proper use, and to

alert them about risks, necessary precautions, and possible side

effects.'' However, as a practical matter, the authors sorted studies

meeting this definition into two analytical groups (``materials'' and

``PPI's''). They placed studies in the PPI category if the authors of

that study called the leaflets ``PPI's'' as opposed to ``written''

information. The ``materials'' group included studies that did not

designate the written materials as PPI's.

Second, the PMA authors used a different analytical procedure for

the PPI section of their analysis than for the remaining sections.

Selecting test and control groups for the meta-analysis is a vital

aspect of this type of analysis because it seeks to estimate the effect

size of the difference between these groups. For all but a few studies

examined in the meta-analysis, a group of subjects that received an

intervention (e.g., counseling) was compared to a group that did not

receive the intervention (e.g., no counseling). However, for the PPI

analysis in 27 of the 28 studies examined, the test group was compared

to a group that received an alternative version of that PPI. Thus, for

PPI's, the authors compared intervention to intervention rather than

intervention to control.

The 27 PPI studies included in the meta-analysis were from FDA-

funded studies that had been conducted by the Rand Corp. These Rand

studies examined 12 different formats for communicating information to

patients for each of three drugs: erythromycin (an antibiotic),

flurazepam (a sleeping pill), and estrogens (for postmenopausal

symptoms). The Rand studies included no-intervention control groups for

erythromycin and flurazepam. For estrogens, the Rand study included a

control group composed of patients receiving the FDA-approved PPI for

estrogens. Citing incompatibility of the data offered by Rand with

meta-analytical procedures, the authors of the PMA-funded study

selected the intervention group that they believed should have

performed worst (i.e., was less sound educationally) to serve as the

control group.

The authors of the Rand studies concluded that PPI's lead to

reliable gains in drug knowledge. This conclusion directly contradicts

the PMA meta-analysis conclusion that was based primarily on Rand study

results. The Rand studies were designed only to compare the effects of

variations in style of information presentation within PPI's. Each of

the PPI's studied by Rand

[[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 presc

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