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Among the goals of the Department of Health and Human Services and the Food and Drug Administration (FDA) is to improve written communication to patients about their prescription medicines. Bristol-Myers Squibb Company recognizes the need for patients to receive high-quality information regarding their therapeutic options. The company has initiated a program to prepare patient-oriented labeling for certain prescription products for which such material is appropriate, using the FDA's proposed Medication Guide as a basis for content and format.

Key Words: Food and Drug Administration; Patient labeling; Consumer labeling; Patient package insert; Medication Guide, Healthy People 2000, Action Plan for the Provision of Useful Prescription Medicine Information

INTRODUCTION

THE CONCEPT OF patient-oriented labeling for prescription drugs in the United States is not a new one, nor is the idea that such labeling be subject to regulatory oversight. Since 1968 the Food and Drug Administration has required that patient information be distributed with certain prescription products when such a measure would enhance the safe use of the drug or alert the patient to particular safety issues. This information is written and produced by the sponsor and reviewed by the FDA. The first class of drugs to be subject to a mandatory requirement for patient labeling was the isoproterenol inhalation products (1), followed by oral contraceptives (2), estrogens (3), and progestational drugs (4). FDA has also imposed the requirement for patient-oriented labeling on certain individual products as a condition for approval or postapproval when there was a concern for safe use either generally or in a specific population. At present, FDA requires that more than 40 prescription medicines be accompanied by consumer-oriented written information (5). In addition, approximately 70 drugs have patient labeling of some type that has been submitted voluntarily by the manufacturer to FDA for review.

In 1979 FDA issued a proposed rule to set a requirement for "patient package inserts" (PPIs) for all prescription products, based on its research into the utility of such written information for consumers (6). This rule was finalized the following year, with FDA declaring that there was "ample evidence that PPIs can significantly improve the quality of health care obtainable from using prescription drugs" (7). FDA then issued draft guidelines for patient labeling for 10 drugs or drug classes (ampicillin, benzodiazepines, cimetidine, clofibrate, digoxin, methoxsalen, phenytoin, propoxyphene, thiazide, and warfarin), intending to implement these over a three-year period, after which the agency would evaluate the results of this pilot program before applying the requirement to all prescription drug products. The program was suspended in 1981 as a result of an Executive Order requiring federal agencies to adhere to certain principles in promulgating new regulations and reviewing existing ones (8,9). On the basis of such a review, which raised questions about the implementation costs of patient labeling as well as optimal style and format requirements, the rule was revoked in 1982 (10). At that time, the onus for preparing and distributing patient information shifted to the private sector. Several organizations were identified as sources of leadership in preparing and disseminating patient drug information, including the National Council on Patient Information and Education, American Medical Association, United States Pharmacopeial Convention, and American Association of Retired Persons, among others. FDA's role after the PPI rule was rescinded was to monitor the situation and to regularly assess the effectiveness of the voluntary private-sector initiative before proceeding with a mandatory program.

After about a decade of closely monitoring the progress of voluntary programs, FDA concluded in 1995 that, although the quantity of written information provided to patients had increased significantly, the quality of such information was "uneven" and that "in the interests of . . . improving the value of the information to patients. . . standard-setting activities. . . are appropriate and necessary." Therefore, in August 1995 FDA published a proposed rule that specified standards for the distribution and quality of useful drug information. The proposed regulations described a program whereby manufacturers would prepare FDA-approved patient labeling (Medication Guides) for their prescription drug products, following specified requirements for format and content. The Medication Guide program was to be mandated only for products that pose a serious and significant public health concern requiring immediate distribution of FDA-approved patient information. On the other hand, the proposed regulations encouraged voluntary, private-sector efforts to ensure that useful drug information was made available to all patients receiving new prescriptions. If private-sector efforts failed, the FDA proposed two alternative approaches:

1. Implement a comprehensive, mandatory program of patient-oriented labeling, or

2. Seek public comment on whether such a program should be implemented or whether and what other measures should be taken (11).

On August 6, 1996, enactment of section 601 of the Agriculture Rural Development, Food and Drug Administration and Related Agencies Appropriations Act of 1997 (Public Law 104-180) placed the proposed rule, as it related to a voluntary program, in abeyance (12). Public Law HR 104-180 in many respects mirrors the Department of Health and Human Services' initiative known as "Healthy People 2000" (now updated to "Healthy People 2010"), which set objectives for the distribution of "useful" written patient information to 75% of patients receiving new prescriptions by the year 2000. In addition, for the year 2006, the FDA proposed that the distribution goal be set at 95% (13). The law "required the Secretary of Health and Human Services (HHS) to organize a committee of diverse interests to develop a long-range, comprehensive action plan to improve oral and written communication to patients about their prescription medicines" (14). The resultant steering committee, comprising participants from professional organizations, consumer groups, health agencies, and the pharmaceutical industry, among other interest groups, issued its "Action Plan for the Provision of Useful Prescription Medicine Information" in December 1996. The action plan identified mechanisms for the achievement of the goals of the HHS initiative for consumer drug information such as improving verbal advice given to patients and establishing specific criteria for what constitutes "useful" written drug information. The Action Plan parallels the FDA's 1995 proposed rule, presenting several format options for printed drug information leaflets, one of which is nearly identical to the Medication Guide prototype. The FDA was called on in HR 104-180 to monitor and report on the progress of the private sector in meeting the goals of the Action Plan.

On December 1, 1998 FDA issued a Final Rule establishing requirements for the distribution of Medication Guides for selected prescription drugs and biologics used primarily on an outpatient basis. The regulation, which becomes effective June 1, 1999, will mandate the distribution of Medication Guides for certain products that pose a serious and significant public health concern. These will be requested by FDA if one or more of the following conditions hold:

1. Patient labeling could help prevent serious adverse effects,

2. The product has serious risks (relative to benefits) about which patients should be made aware, because this information may affect their decision to use the product, or

3. The product is important to health, and strict adherence to directions is crucial to its effectiveness (15).

The term "Medication Guide" can be used for patient labeling formally required by FDA for products fulfilling these criteria. In all other cases, a substitute term, such as "patient information," must be used.

The pharmaceutical industry recognizes the role of patients in making decisions about their own health care. Yet, the industry, including Bristol-Myers Squibb Company (BMS), also appreciates the role of physicians, as learned intermediaries, to provide their patients with the benefit of their medical expertise regarding the therapies they are prescribing. It is the difficulty in reconciling these two sometimes competing needs that has made the process of developing userfriendly information for patients a difficult matter for all elements of society to resolve. While mandatory standardized Medication Guides may not be the most appropriate mechanism for transmitting prescription drug information to all patients in all circumstances, BMS does recognize the need for patients to receive high-quality information regarding their therapeutic options for many pharmaceuticals. Patient-oriented labeling may help meet that need and be a valuable tool for the dissemination of such information. BMS is undertaking a thorough review of its prescription pharmaceuticals to determine for which products patient labeling may be appropriate for addressing these societal goals.

METHODS

A cross-disciplinary, nonproduct-specific task force was assembled that included representatives from regulatory, legal, marketing, medical, safety, and packaging areas. This group evaluated the concept of patient-oriented labeling. It reviewed the potential liability implications associated with material produced and disseminated by third parties for BMS products and acknowledged the opportunities for using patient-oriented labeling in direct-to-consumer advertisements and patient education programs. Through informal conversations with representatives of other companies and industry associations, the task force assessed industry-wide activity in the development and distribution of labeling for consumers. BMS appears to be in the forefront of proactively addressing these issues.

The task force concluded that patient-oriented labeling represents an important opportunity for BMS to ensure that current, complete, and accurate information about many of its prescription products is disseminated to the public. The group agreed, however, that such labeling may not be necessary or appropriate for all products, depending on the nature of the product or disease state for which it is prescribed. Finally, it was decided that the FDA's proposed Medication Guide format should be used, given that agency research had evaluated its effectiveness in extensive consumer-based studies; moreover, it was thought that conforming to a format suggested by the FDA would facilitate the approval process for the planned submissions.

The task force was then reassembled along product-specific lines to identify products for which patient labeling may be considered appropriate and to prioritize these activities. For each identified product, distribution mechanisms and additional uses also were discussed.

The labeling group of the regulatory department was assigned the task of coordinating the production of patient labeling for identified products following development of a prioritized schedule. The labeling group begins the process by creating a first draft for internal review. This document is based on the current professional package insert for the product, although existing patientoriented literature is an additional resource. The draft patient labeling is initially reviewed by a small group of key people from medical, marketing, and regulatory areas, who not only review the accuracy and comprehensiveness but also confirm that the information is presented with the mandated nontechnical language at the appropriate reading level. Once their comments are incorporated, the patient labeling is presented to a cross-disciplinary committee consisting of representatives of regulatory, legal, marketing, medical, and safety areas. This committee's charge is to produce an accurate and understandable document. The patient labeling would thereafter be submitted to the FDA for review and approval.

RESULTS

The first patient labeling approved by the FDA since the inception of this program at BMS was patient labeling for DROXIA(R) (hydroxyurea). DROXIA(R) patient labeling is distributed as a perforated attachment to the professional package insert, as negotiated with FDA before implementation. Terms of these negotiations specifically provide that, for this product, direct attachment of the patient labeling to the professional labeling obviates the requirement for repetition of the full text of the patient labeling at the end of the package insert which can be viewed on the Bristol-Myers Squibb Company website, www. bms. com.

No optimal standard of packaging and distribution has been established for all products for which patient labeling is planned. The company is putting substantial thought into establishing effective distribution mechanisms for patient labeling, considering among other options the use of shelf packs (several units of a product, each containing a patient leaflet, packaged in a shelf carton with one professional package insert). Considerations that will be part of all decisions regarding distribution and packaging of patient labeling include the constraint of FDA's recommended minimum font size (10 point) and the expansion of the professional insert when the text of patient labeling is appended. Choice of distribution mechanism is also driven by the nature of the product they accompany and the ultimate purpose of the literature. For example, patient-oriented leaflets for products administered in a clinical setting by a medical professional, such as oncology products, may not be distributed in the same manner as those for drugs to be self-administered.

DISCUSSION

The need for consumer information about prescription drugs continues to be identified as a public health imperative and as such remains the subject of activity by the FDA and the private sector. Labeling that targets the medication end-user has demonstrated utility in contributing to patient knowledge and in improving compliance with complicated regimens (16-22). For example, the potential for written drug information to reduce the rate of medication errors was noted in a FDA seminar in January 1998 (23).

Patient-oriented labeling has been mandated since 1992 for prescription products sold in the European Union (EU), but it has yet to be authorized as a broad regulatory requirement in the United States. In fact, questions were raised by health professional organizations and the pharmaceutical industry when FDA published its proposed Medication Guide program in 1995. FDA's December 1, 1998 rule finalizing the requirements for Medication Guides for a limited number of drug products, however, appears to indicate a continuing interest in establishing a comprehensive, regulated program for the provision of useful written drug information in the United States.

While the key function of patient-oriented labeling is to improve compliance and alert consumers to a drug's risk/benefit profile, effectively designed ("useful") patient information also can be used in consumer education programs and direct-to-consumer advertising. In direct-to-consumer advertising, patient-oriented labeling can serve as the summary of critical information, replacing the technically daunting professional labeling.

Despite the evidence pointing to the value of:

1. Providing consumer-oriented labeling with prescription drugs,

2. Preparing such labeling based on a wellresearched model of effectiveness, and

3. Submitting it for regulatory review and approval,

it appears that few pharmaceutical companies have moved quickly to implement this process for disseminating patient information. Our experience suggests that BMS is in the vanguard of companies proactively addressing the need to develop and deliver to consumers useful written drug information. Whatever the results of the current voluntary initiative, FDA has imposed regulatory requirements in some measure and is likely to expand its oversight of consumer-oriented materials in the coming years. Therefore, BMS's activities in this regard may anticipate the possibility of a broader formal regulatory requirement.

An issue yet to be addressed by the BMS program and other initiatives in this area is measuring the utility of written patient information. Leaflets that are prepared, reviewed, and approved by medically sophisticated professionals may not be useful for a general audience, for reasons of readability, understandability, or even difficulty locating information. The importance of assessing the actual consumer utility of patient-oriented materials is well recognized. For example, when a product is a candidate for a switch from prescription to over-the-counter status, the sponsor is required to show label usability through field-testing. The guideline for development of the Australian version of patient labeling (known as Consumer Medicines Information), a regulatory requirement for marketing pharmaceutical products in that country, devotes considerable space to recommendations for consumer testing of these leaflets (24). FDA does not require sponsors to test their patient-oriented labeling, but is certainly encouraging it. BMS realizes the need to assess the usefulness of patient information and, in its later phases, the patient labeling program will address this issue.

The patient labeling program at BMS was initiated as an additional method-when appropriate-of providing useful information to consumers about the use of certain pharmaceutical products. BMS anticipates that patient labeling will serve as written references supplementing, but not supplanting, information provided by health professionals. Plans are to continue this effort for the United States market and to integrate this domestic initiative into a general approach to patient labeling that addresses consumer and regulatory needs worldwide. A goal is to create "core" patient-oriented profiles to serve as the basis for consumer labeling in those markets where it is required and for those products for which it is appropriate.

Acknowledgments-The authors wish to acknowledge the key role played by Marianne F Kammer, MBA, Director, U.S. Labeling, Bristol-Myers Squibb Company, Wallingford, CT in the initiation and development of this patient labeling program.

REFERENCES

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CATHLEEN A. O'CONNELL, RPH, MS, PHD

Director, U.S. and Export Labeling, Bristol-Myers Squibb Company, Princeton, New Jersey

REBECCA SKINNER

Senior U.S. Labeling Associate, Bristol-Myers Squibb Company, Wallingford, Connecticut

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