Bar Code Label Requirement For Human Drug Products and Blood

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Federal Register › Vol. 68 › 68 FR 12500

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DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Parts 201, 606, and 610 [Docket No. 02N-0204] RIN 0910-AC26 Bar Code Label Requirement For Human Drug Products and Blood AGENCY:

Food and Drug Administration, HHS.

ACTION:

Proposed rule.

SUMMARY:

The Food and Drug Administration (FDA) is proposing a new rule that would require certain human drug product labels and biological product labels to have bar codes. The bar code for human drug products and biological products (other than blood and blood components) would contain the National Drug Code (NDC) number in a linear bar code. The proposed rule would help reduce the number of medication errors in hospitals and other health care settings by allowing health care professionals to use bar code scanning equipment to verify that the right drug (in the right dose and right route of administration) is being given to the right patient at the right time. The proposed rule would also require the use of machine-readable information on blood and blood component container labels to help reduce medication errors.

DATES:

Submit written or electronic comments on this proposed rule by June 12, 2003. Submit written comments on the information collection requirements by April 14, 2003.

ADDRESSES:

Fax written comments to the Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Fax electronic comments to http://www.fda.gov/dockets/ecomments. Submit written comments on the information collection provisions to the Office of Information and Regulatory Affairs, Office of Management and Budget (OMB), Attn: Stuart Shapiro, Fax: (202) 395-6974.

FOR FURTHER INFORMATION CONTACT:

Philip L. Chao, Office of Policy, Planning, and Legislation (HF-23), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-827-3380.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Introduction A. What Actions Led to This Rulemaking? B. What Are Medication Errors? C

ement and Budget (OMB), Attn: Stuart Shapiro, Fax: (202) 395-6974.

FOR FURTHER INFORMATION CONTACT:

Philip L. Chao, Office of Policy, Planning, and Legislation (HF-23), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-827-3380.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Introduction A. What Actions Led to This Rulemaking? B. What Are Medication Errors? C. How Frequently Do Medication Errors Occur? What Is Their Impact? D. How Would Bar Coding Help Prevent Medical Errors? E. Can Bar Code Use Reduce the Incidence of Medication Errors? F. Is There Support for Putting Bar Codes on Drug Products? II. Description of the Proposed Rule A. Who Would Be Subject to the Bar Code Requirement? (Proposed § 201.25(a)) B. What Products Would Have to Have a Bar Code? (Proposed § 201.25(b)) C. What Would the Bar Code Contain? (Proposed § 201.25(c)(1)) D. Would the Rule Require a Specific Type of Bar Code? (Proposed § 201.25(c)(1)) E. Where on the Label Would the Bar Code Appear? (Proposed § 201.25(c)(2)) F. What Would Happen if a Bar Code Could Not Be Put on a Product? G. What Is the Proposed Implementation Plan? H. How Does This Rule Apply to Blood and Blood Components? (Proposed § 606.121(c)(13)) I. What Bar Code Requirement Would Apply to Biological Products? (Proposed § 610.67) III. Legal Authority IV. Environmental Impact V. Paperwork Reduction Act of 1995 VI. Executive Order 13132: Federalism VII. Analysis of Impacts A. Introduction B. Objective of the Proposed Rule C. Estimate of Risk/Risk Assessment D. The Proposed Rule E. Description of Affected Sectors F. Regulatory Costs of the Proposed Rule G. Other Anticipated Expenditures H. Reduction in Preventable Adverse Drug Events I. Value of Avoided ADEs J. Aggregate Benefit of Avoiding ADEs K. Other Benefits of Bar Code Technology L. Distributional Effects of Bar Code Technology M. Comparison of Costs, Expenditures, and Benefits N. Uncertainty and Sensitivity O. Small Business Analysis and Discussion of Alternatives P

ts of the Proposed Rule G. Other Anticipated Expenditures H. Reduction in Preventable Adverse Drug Events I. Value of Avoided ADEs J. Aggregate Benefit of Avoiding ADEs K. Other Benefits of Bar Code Technology L. Distributional Effects of Bar Code Technology M. Comparison of Costs, Expenditures, and Benefits N. Uncertainty and Sensitivity O. Small Business Analysis and Discussion of Alternatives P. Conclusion VIII. Request For Comments IX. References Appendix—Additional Information on Various Studies Identifying Different Types of Medication Errors I. Introduction

A. What Actions Led to This Rulemaking?

In 1999, the Institute of Medicine (IOM) issued a report entitled “To Err Is Human: Building a Safer Health System” (Ref. 1). (The IOM is a private, nonprofit organization that provides health policy advice under a congressional charter granted to the National Academy of Sciences.) The IOM report cited studies and articles to estimate that between 44,000 and 98,000 Americans may die each year due to a range of medical mistakes made by health care professionals. The IOM report estimated that, in 1993 alone, an estimated 7,000 deaths were attributable to medication errors (Ref. 1 at p. 27) and that:

• Medication errors account for 1 out of every 131 outpatient deaths, and 1 out of every 854 inpatient deaths (Ref. 1 at p. 27); and

• The death rate attributable to medication errors may be increasing. The IOM report cited a study that examined death certificates from 1983 to 1993. The study found that, in 1983, 2,876 deaths were due to medication errors (which the authors defined as accidental poisoning by drugs, medicaments, and biological products resulting from acknowledged errors by patients or health care professionals) (Ref. 1 at p. 32, Ref. A-14 of the Appendix to this document). In 1993, 7,391 deaths were attributed to medication errors, a 2.57-fold increase in the death rate (Ref. 1 at p. 32)

3, 2,876 deaths were due to medication errors (which the authors defined as accidental poisoning by drugs, medicaments, and biological products resulting from acknowledged errors by patients or health care professionals) (Ref. 1 at p. 32, Ref. A-14 of the Appendix to this document). In 1993, 7,391 deaths were attributed to medication errors, a 2.57-fold increase in the death rate (Ref. 1 at p. 32). Moreover, a comparison of outpatient death rates suggested nearly an 8-fold increase in medication error death rates (Ref. 1 at pp. 32 and 33).

The IOM report stated that deaths due to medication errors are often preventable and cited bar codes as one way to prevent them (Ref. 1 at pp. 37, 175, 188, 189, 195-196).

The IOM report generated considerable controversy. Some felt that the IOM's figures were exaggerated (Ref. 2), while others felt the figures might have been too low (Ref. 3). Some felt that the term “medical errors” was, itself, misleading (Ref. 4). Others, including FDA, suggested that the IOM report's basic message—that medical errors are a serious public health problem—should not be lost regardless of whether the annual mortality was 10,000 or 100,000 (Ref. 5)

The IOM report led to new efforts to improve patient safety. For example:

• In December 1999, President Clinton directed the HealthCare Quality Task Force to analyze the IOM report and to report back on recommendations to

• In February 2000, the Quality Interagency Coordination (QuIC) Task Force (a group composed of the Department of Health and Human Services (DHHS) and other Federal agencies) issued an action plan that highlighted steps for Federal agencies to take to reduce medical errors and to improve patient care

HealthCare Quality Task Force to analyze the IOM report and to report back on recommendations to

• In March 2001, the Agency for HealthCare Research and Quality (AHRQ) issued a report entitled “Reducing and Preventing Adverse Drug Events to Decrease Hospital Costs.” The report stated that more than 770,000 people are injured or die each year in hospitals from adverse drug events and that studies had suggested that 28 to 95 percent of adverse drug events could be prevented by reducing medication errors through the use of computerized monitoring systems, especially computerized medication ordering systems (Ref. 6).

• In April 2001, the Secretary of Health and Human Services, Tommy G. Thompson (Secretary Thompson), announced the establishment of a new Patient Safety Task Force within DHHS. Secretary Thompson named FDA as one of the Federal agencies leading this new effort (Ref. 7).

Congress also focused its attention on patient safety by holding hearings in 2000 and 2001 on patient safety and medical errors. On May 24, 2001, Secretary Thompson appeared before the Senate Committee on Health, Education, Labor, and Pensions' Subcommittee on Patient Health and stated that new technology, such as bar coding, could help save lives and money. Secretary Thompson noted that other industries used bar coding and that the same technology could be used to track drug dispensing and use and to prevent medication errors (Ref. 8)

001, Secretary Thompson appeared before the Senate Committee on Health, Education, Labor, and Pensions' Subcommittee on Patient Health and stated that new technology, such as bar coding, could help save lives and money. Secretary Thompson noted that other industries used bar coding and that the same technology could be used to track drug dispensing and use and to prevent medication errors (Ref. 8).

Shortly thereafter, the American Society for Health-System Pharmacists (ASHP) wrote to Secretary Thompson to urge that FDA “develop regulations that mandate that drug manufacturers provide a standardized machine-readable code (bar coding) on all drug product containers, including single unit containers, which are essential for hospital unit dose drug distribution systems” (Ref. 9). ASHP mentioned a June 26, 2001, recommendation by the National Coordinating Council for Medication Error Reporting and Prevention (NCCMERP) urging FDA and the United States Pharmacopeia (USP) to establish and implement a uniform bar coding program for drugs (Ref. 9 at pp. 1 and 2). Secretary Thompson later asked FDA to begin working on a bar coding proposal, thereby putting in motion the events that led to this proposed rule.

B. What Are Medication Errors?

NCCMERP 1 defines a medication error as:

1 NCCMERP is composed of over 20 national organizations (including FDA) whose objectives are to increase the reporting, understanding, and prevention of medication errors and to recommend strategies relative to systems modifications, practice standards, and guidelines, and changes in packaging, labeling, and product identity.

* * * any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the healthcare professional, patient, or consumer

understanding, and prevention of medication errors and to recommend strategies relative to systems modifications, practice standards, and guidelines, and changes in packaging, labeling, and product identity.

* * * any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the healthcare professional, patient, or consumer. Such events may be related to professional practice; healthcare products, procedures, and systems, including prescribing; order communication; product labeling, packaging, and nomenclature; compounding; dispensing; distribution; administration; education; monitoring; and use. (Ref. 10)

For purposes of this preamble, we will adopt the same definition of “medication error.” Medication errors are a part of the overall “medical errors” problem because medical errors include surgical errors, device failures, and medication errors. Medication errors can occur at several points from the time the physician selects the drug to prescribe to a patient to the time when the patient receives the drug. For example, the physician may write a prescription for the right drug, but in the wrong dose. The pharmacist might misread the prescription and provide the wrong drug, or read the prescription correctly and dispense the wrong drug. The health care professional administering the drug might give it to the wrong patient or give it to the right patient, but at the wrong time or in the wrong dose.

Articles discussing medication errors can be found dating back several decades, and refer to such errors under various names, including “preventable adverse events,” “drug misadventuring,” and “iatrogenic illness” or “iatrogenic injury.” (The word “iatrogenic” refers to “any adverse condition in a patient occurring as the result of treatment by a physician or surgeon” (see Dorland's Illustrated Medical Dictionary , 26th ed., at p

rors can be found dating back several decades, and refer to such errors under various names, including “preventable adverse events,” “drug misadventuring,” and “iatrogenic illness” or “iatrogenic injury.” (The word “iatrogenic” refers to “any adverse condition in a patient occurring as the result of treatment by a physician or surgeon” (see Dorland's Illustrated Medical Dictionary , 26th ed., at p. 647).) The articles often identify the following types of medication errors:

• Administering the wrong dose,

• Administering a drug to a patient who is known to be allergic,

• Administering the wrong drug to a patient or administering a drug to the wrong patient,

• Administering the drug incorrectly,

• Administering the drug at the wrong time or missing doses.

(See the Appendix elsewhere in this document for a description of various studies identifying different types of medication errors.)

C. How Frequently Do Medication Errors Occur? What Is Their Impact?

Studies differ as to how frequently medication errors occur. Some studies suggest that the medication error rate is under 7 percent, whereas others suggest a medication error rate at or above 20 percent. The differences may be due, in part, to different definitions of “medication error” or different research methodology that focused on fatalities, injuries, or medication orders. (See the appendix for a summary of medication error rates reported in several studies.)

Although most medication errors do not result in harm to patients, medication errors can result and have resulted in serious injury or death (Ref. 11).

errors can result and have resulted in serious injury or death (Ref. 11).

Medication errors also represent a significant economic cost to the United States. In an article published in 1995, Johnson and Bootman estimated the direct cost of preventable drug-related mortality and morbidity to be $76.6 billion annually, with drug-related hospital admissions accounting for much of the cost (Ref. 12). The authors suggested that indirect costs, such as those relating to lost productivity, might be two to three times greater than the direct costs, making the total cost of all preventable, drug-related mortality and morbidity range from $138 to $182 billion. A study by Ernst and Grizzle published in 2001 used updated figures and revised the direct cost estimate to $177.4 billion (Ref. 13). Another article estimated the cost of preventable adverse drug events in hospitalized patients to be $5,857 for each adverse drug event and the estimated annual costs for preventable adverse drug events for a 700-bed hospital to be $2.8 million (Ref. 14).

D. How Would Bar Coding Help Prevent Medication Errors?

Bar codes would be part of a system, along with bar code scanners and computerized databases, that would enable health care professionals to check whether they are giving the right drug via the right dose and right route of administration to the right patient at the right time. Under this model, the system could work as follows:

• A patient would have his or her drug regimen information entered into a computerized database.

• Each drug would have a bar code. The bar code would provide unique, identifying information about the drug that is to be dispensed to the patient.

identifying information about the drug that is to be dispensed to the patient.

• In hospitals, health-care professionals, such as pharmacists and nurses, would use bar code scanners (also called bar code readers) to read the bar code on the drug before dispensing the drug to the patient and use bar code scanners to read a bar coded wrist band on the patient before giving the drug to the patient. In an outpatient setting, the health care professional (such as a pharmacist) could scan the bar code on the drug and compare the scanned information against the patient's electronic prescription information before giving the drug to the patient.

• The bar code scanner's information would go to the computer where it would be compared against the patient's drug regimen information to check whether the right patient is receiving the right drug (including the right dose of that drug in the right route of administration). The system could also be designed to check whether the patient is receiving the drug at the right time.

• If the identity of the health care professional administering the drug was desired, each health care professional could also have a bar code. The health care professional would scan his or her own bar code before giving the drug to the patient.

Bar codes could also complement other efforts to reduce medication errors.

• In computer physician order entry (CPOE) systems, a physician enters orders into a computer instead of writing them on paper. The order can be checked against the patient's records for possible drug interactions, overdoses, and patient allergies (Ref. 26).

• The retail pharmacy community is beginning to use a bar-coded NDC number to verify that a consumer's prescription is being dispensed with the correct drug. These pharmacy-based systems compare a bar code that the pharmacy's computer prints on the consumer's prescription against the bar code on the drug's label. If the computer detects an error, the computer alerts the pharmacist to the problem

In addition, bar codes could make it easier to enter medication order entries into a patient's electronic medical records, help in inventory control and billing, and help conserve hospital or health care staff resources or free those resources so that they can be devoted to patient care.

E. Can Bar Code Use Reduce the Incidence of Medication Errors?

Published articles and other information submitted to FDA suggest that bar coding can reduce medication error rates significantly.

• One New Hampshire hospital reduced its medication error rate by 80 percent after it adopted a bar coding program (Ref. 15).

• A medical center in Colorado lowered its medication error rate by 71 percent between 1992 and 1994 (Ref. 16).

• A Department of Veterans Affairs (VA) hospital in Kansas had no medication errors when its computerized, bar coding system was used properly; the hospital estimated that the system prevented over 378,000 medication errors in a 5-year period (Ref. 17).

• Other published articles have discussed how bar coding can reduce medication errors, including missed doses, or increase drug dispensing accuracy (Refs. 18 through 23).

At a public meeting that we (FDA) held on July 26, 2002 (67 FR 41360, June 18, 2002), the VA gave a presentation on its use of bar codes at the VA Medical Center in Topeka, Kansas. The VA stated that a comparison of medication error data from 1993, the last year before the VA implemented the bar code system, to data for 2001 showed that the Topeka medical center reduced its reported medication error rate by 86.2 percent (Ref. 24)

held on July 26, 2002 (67 FR 41360, June 18, 2002), the VA gave a presentation on its use of bar codes at the VA Medical Center in Topeka, Kansas. The VA stated that a comparison of medication error data from 1993, the last year before the VA implemented the bar code system, to data for 2001 showed that the Topeka medical center reduced its reported medication error rate by 86.2 percent (Ref. 24). The improvements included:

• 75.5 percent improvement in errors caused by the wrong medication being administered to a patient;

• 93.5 percent improvement in errors caused by the incorrect dose being administered to a patient;

• 87.4 percent improvement in wrong patient errors; and

• 70.3 percent improvement in errors caused when medications scheduled for administration were not given.

(Ref. 24 at p. 14). One comment submitted in response to the public meeting indicated that a bar code scanning system, in conjunction with a robotic system for pharmaceutical distribution, reduced dispensing errors at the University of Wisconsin from 1.43 percent to 0.13 percent and that the university realized a return on its investment in 2 years (Ref. 25). The comment also stated that there was an 89 percent reduction in medication administration errors due to point-of-care bar code scanning (Ref. 25 at p. 6).

We discuss the public meeting in greater detail in section II of this document.

F. Is There Support for Putting Bar Codes on Drug Products?

In recent years, many organizations have either commented favorably on or recommended the adoption of bar coding to reduce medication errors. These organizations include the QuIC Task Force, NCCMERP, ASHP, and Premier, Inc., an alliance of not-for-profit hospital and health care systems (Refs. 27 through 29).

We also saw considerable support for bar coding at the July 26, 2002, public meeting we held to discuss a possible rule to require bar code labeling

orably on or recommended the adoption of bar coding to reduce medication errors. These organizations include the QuIC Task Force, NCCMERP, ASHP, and Premier, Inc., an alliance of not-for-profit hospital and health care systems (Refs. 27 through 29).

We also saw considerable support for bar coding at the July 26, 2002, public meeting we held to discuss a possible rule to require bar code labeling. Nearly 400 individuals attended the meeting, and they represented a broad range of interests, including:

• Nurses, including the American Academy of Nursing;

• Pharmacists, including the American Society of Health-System Pharmacists;

• Physicians, including the American Medical Association;

• Hospitals, including the American Hospital Association, the VA, which already has a bar code program in place for drugs used in VA hospitals, and the Hospital Corporation of America, Inc., which intends to have bar coding technology in place in its hospitals by the end of 2005;

• Pharmaceutical manufacturers, including the Pharmaceutical Research and Manufacturers of America (PhRMA) and the Generic Pharmaceutical Association (GPhA);

• Over-the-counter (OTC) drug manufacturers, including the Consumer HealthCare Products Association (CHPA);

• Medical device manufacturers, including the Advanced Medical Technology Association (also known as AdvaMed);

• Blood centers and blood organizations, including the American Association of Blood Banks, America's Blood Centers, and the American Red Cross;

• The Vaccine Identification Standards Initiative (VISI), a collaborative effort between public health agencies and private organizations involved in immunization practices and whose purpose is to establish voluntary, uniform guidelines for vaccine packaging and labeling and recording identifying information;

• Bar coding and other “automatic identifier” interests, including the Uniform Code Council and the Health Industry Business Communications Council (two standards development organizations that have established bar code

ions involved in immunization practices and whose purpose is to establish voluntary, uniform guidelines for vaccine packaging and labeling and recording identifying information;

• Health or medical product distributors, including McKesson

• The USP.

In addition, in response to requests to discuss bar code issues in greater detail, we met separately with PhRMA on August 19, 2002, with CHPA, GPhA, and others on September 17, 2002, and with the National Alliance for Health Information Technology on October 9, 2002.

In general, almost all individuals, companies, and organizations attending or commenting on the public meeting strongly supported the use of bar codes on human drug products to help reduce medication errors, but differed in their opinions as to the information that should go into the bar code and whether certain products, such as over-the-counter (OTC) drugs and medical devices, should have a bar code. We discuss various aspects of the public meeting throughout the remainder of this preamble to show how information from the public meeting helped shape this proposal.

II. Description of the Proposed Rule

The proposal would create a new § 201.25 entitled “Bar Code Label Requirements.” The proposal would address:

• Who is subject to these bar code requirements?

• What drugs are subject to these bar code requirements?

• What does the bar code look like?

• Where does the bar code go?

The proposed bar code requirement would also apply to biological products (other than blood and blood components). We cross-reference this requirement in the biologics regulations at new § 610.67

roposal would address:

• Who is subject to these bar code requirements?

• What drugs are subject to these bar code requirements?

• What does the bar code look like?

• Where does the bar code go?

The proposed bar code requirement would also apply to biological products (other than blood and blood components). We cross-reference this requirement in the biologics regulations at new § 610.67.

For blood and blood components, the proposal would amend part 606 (21 CFR part 606) in § 606.121(c)(13) which currently allows, but does not require, the use of machine-readable symbols, approved by the Director of the Center for Biologics Evaluation and Research (CBER), on blood and blood component container labels. The proposal would require the use of encoded, machine-readable information approved by the CBER Director on blood and blood component labels.

A. Who Would Be Subject to the Bar Code Requirement? (Proposed § 201.25(a))

In brief, under proposed § 201.25(a), manufacturers, repackers, relabelers, and private label distributors of human prescription drug products and OTC drug products regulated under the Federal Food, Drug, and Cosmetic Act (the act) or the Public Health Service Act would be subject to the bar code requirement unless they are exempt from the establishment registration and drug listing requirements in section 510 of the act (21 U.S.C. 360(g)(1)). In practice, this means that pharmacies which are exempt under section 510(g) of the act are not required to put bar codes on drugs they are dispensing. (The requirements in proposed § 201.25 would apply to biological products (other than blood and blood components) and would include a cross-reference at proposed § 610.67

d drug listing requirements in section 510 of the act (21 U.S.C. 360(g)(1)). In practice, this means that pharmacies which are exempt under section 510(g) of the act are not required to put bar codes on drugs they are dispensing. (The requirements in proposed § 201.25 would apply to biological products (other than blood and blood components) and would include a cross-reference at proposed § 610.67. For convenience, this preamble will refer only to proposed § 201.25 alone without repeated cross-references to proposed § 610.67 (see section II.I of this document).) For purposes of this proposal:

• “Manufacturer” means a person or persons who owns or operates an establishment engaged in the manufacture, preparation, propagation, compounding, or processing of a drug by chemical, physical, biological, or other manipulations of the drug. These activities include repackaging or otherwise changing the container, wrapper, or labeling of any drug package in furtherance of the drug's distribution from the original place of manufacture to the person who makes final delivery or sale to the ultimate consumer or user.

• “Repacker” means a person or persons who owns or operates an establishment that repackages and relabels a drug and does not engage in any other activities performed by a manufacturer.

• “Relabeler” means a person or persons who owns or operates an establishment that affixes or changes labels on a drug and does not engage in any other activities performed by a manufacturer.

• “Private label distributor” means a person or persons who owns or operates an establishment that commercially distributes, under its own label or trade name, any drug manufactured, prepared, propagated, compounded, or processed by a manufacturer, repacker, or relabeler.

For example, if you make a prescription drug product, you would be subject to the bar coding requirement

by a manufacturer.

For example, if you make a prescription drug product, you would be subject to the bar coding requirement. However, if you are a pharmacy operating in conformance with applicable local laws regulating the practice of pharmacy and are regularly engaged in dispensing prescription drugs upon prescriptions of practitioners licensed to administer such drugs to patients, and do not manufacture, prepare, propagate, compound, or process drugs for sale other than in the regular course of business of dispensing such drugs at retail, you would not be subject to the bar code requirements. Your pharmacy would be exempt because section 510(g)(1) of the act does not require you to comply with the establishment registration and listing requirements. We recognize that some hospitals themselves place bar codes on drugs and have reduced their medication error rates significantly. Requiring persons who manufacture, repackage, or relabel human drug products to bar code their own products should be more efficient and result in better quality bar codes. Manufacturers, repackers, and relabelers generally have sophisticated manufacturing processes and labeling machinery, and quality control systems that hospitals cannot afford. Bar coding by third parties (such as hospitals) would be more costly for the facility and would not achieve the economies of scale that larger entities could realize. Having many small entities affix bar codes could increase the possibility of a label error through the attachment of the wrong bar code and could lead to inconsistent bar code quality

ity control systems that hospitals cannot afford. Bar coding by third parties (such as hospitals) would be more costly for the facility and would not achieve the economies of scale that larger entities could realize. Having many small entities affix bar codes could increase the possibility of a label error through the attachment of the wrong bar code and could lead to inconsistent bar code quality. For example, one comment from the public meeting stated that an institution administering 2.5 million doses per year, even if operating at 99.9 percent effectiveness at applying its own bar codes, would introduce seven new errors per day from repackaging. Another comment, submitted by an entity familiar with “automatic identification” methods, stated that “on demand” bar code printing, as used in hospitals and clinics, will have a higher error rate compared to bar code printing by manufacturers and that the “use and maintenance of this type of bar code printing is historically haphazard at best.” Another comment from a bar code standards organization estimated the error rate in hospital labeling to be approximately 17 percent nationwide.

More importantly, requiring persons who manufacture, repackage, or relabel human drug products and private label distributors to bar code their own products and to use the same bar coding standard should result in a more uniform bar coding system that can be used regardless of a patient's or hospital's location in the United States (Ref. 15). Uniformity should also make it easier for health care professionals to train themselves on bar coding procedures and technique and make it easier and less expensive for hospitals to buy bar coding equipment. Uniformity should also make it easier for manufacturers, repackers, relabelers, and private label distributors to put bar codes on products, because they would not have to customize their symbols or

B. What Products Would Have to Have a Bar Code? (Proposed § 201.25(b))

lves on bar coding procedures and technique and make it easier and less expensive for hospitals to buy bar coding equipment. Uniformity should also make it easier for manufacturers, repackers, relabelers, and private label distributors to put bar codes on products, because they would not have to customize their symbols or

B. What Products Would Have to Have a Bar Code? (Proposed § 201.25(b))

1. What Did We Hear at the Public Meeting?

In the June 18, 2002, Federal Register notice (67 FR 41360 at 41361) announcing the public meeting on bar coding, we asked which medical products should have a bar code. We specifically invited comment on whether all prescription and OTC drugs should be bar coded, and we asked about blood products, vaccines, and medical devices (id.). We wanted our request for comments to help us decide which products should be covered by the proposal. For example, we sought information about OTC drugs because we did not know the costs and benefits of requiring all OTC drugs to have a bar code. For blood, we knew that an international bar coding standard (ISBT 128) existed, but did not know whether a rule requiring blood to have a bar code was necessary given that international standard. For vaccines, we were concerned that bar coding costs could have an adverse impact on vaccine manufacturers and vaccine supplies. For devices, our request for information was prompted by several letters to Secretary of DHHS Thompson, asking him to include devices in any bar coding rule (Refs. 31, 32, and 33).

The public comments we received reflected a variety of different positions. For example, almost all comments agreed that prescription drugs should have a bar code and that the bar code should extend to products at the unit dose level. However, comments from the pharmaceutical industry indicated that some products, such as samples, should not fall within a bar code regulation or that we should allow for exemptions

nts we received reflected a variety of different positions. For example, almost all comments agreed that prescription drugs should have a bar code and that the bar code should extend to products at the unit dose level. However, comments from the pharmaceutical industry indicated that some products, such as samples, should not fall within a bar code regulation or that we should allow for exemptions. The USP also supported an exemption for certain containers, such as ampules or vials under 5 milliliters (mL).

For OTC drugs, many health care professionals supported bar codes on all OTC drugs, but other comments, including a comment from a trade association representing the OTC drug industry, disagreed, stating most OTC drugs are used in consumer settings where bar codes would not add value. The trade association also stated that all OTC drug products intended for retail sale have the universal product code (UPC) on the outer container and that there could be “significant potential negative impact” if we modified the UPC bar code system on OTC drug products. In contrast, one manufacturer of OTC drugs supported requiring bar codes on the outer container, but did not favor requiring bar codes for certain categories of products that carry little or no risk of causing adverse drug events in an institutional setting. CHPA and other companies repeated their concerns about bar codes for OTC drug products during a meeting with FDA on September 17, 2002, and emphasized the potential adverse impact on retailers if we required the UPC code to contain the NDC number. Some comments supported bar codes on OTC drugs used in hospitals or in “institutional settings” or OTC drugs packaged and sold for use in institutions.

A split between health care professionals and industry also existed for vaccines

ucts during a meeting with FDA on September 17, 2002, and emphasized the potential adverse impact on retailers if we required the UPC code to contain the NDC number. Some comments supported bar codes on OTC drugs used in hospitals or in “institutional settings” or OTC drugs packaged and sold for use in institutions.

A split between health care professionals and industry also existed for vaccines. For example, the Centers for Disease Control and Prevention, which coordinates the VISI program, recommended that vaccines have bar codes so that information on vaccines could be readily captured into medical records and other forms, thereby enhancing the monitoring of immunization programs and surveillance of adverse effects. Vaccine manufacturers, including VISI members, expressed a different view, stating that even small bar codes may be difficult to place on vaccines. One industry comment added that requiring bar codes on vaccines would “increase the potential for disrupting vaccine production lines, particularly if there is a need for in-line printing” and that “[g]iven the fragile nature of vaccine supply and recent shortages of a number of vaccines, there is concern that any additional disruptions could exacerbate this situation.”

For blood, the comments generally agreed that we should require bar codes. Most comments acknowledged that an internationally standardized bar code symbology (ISBT 128) for blood exists and that the bar codes describe the blood's identification number, blood group and Rh type, product number, expiration date and time, and special testing results. However, while some comments recommended that we require blood containers to have bar codes using the ISBT 128 symbology, one comment, representing thousands of blood collection centers, blood banks, and transfusion services, opposed requiring the use of ISBT 128 through a regulation

ntification number, blood group and Rh type, product number, expiration date and time, and special testing results. However, while some comments recommended that we require blood containers to have bar codes using the ISBT 128 symbology, one comment, representing thousands of blood collection centers, blood banks, and transfusion services, opposed requiring the use of ISBT 128 through a regulation. Instead, the comment wanted us to require adoption of a United States Industry Consensus Standard for the Uniform Labeling of Blood and Blood Components or “focus on requiring electronic data interchange and the definition and use of standard data structures.”

For devices, the comments suggested another split between health care professionals and the regulated industry. Many health care professionals and hospital groups supported requiring bar codes on devices, although some would defer action on medical devices so that progress on a rule to require bar codes on drugs would not be slowed down. Others would defer action on medical devices because different device classes present different levels of risk. Device manufacturers generally opposed the inclusion of medical devices in a bar coding proposal. The device industry noted, as we did in our June 18, 2002, Federal Register notice (67 FR 41360) announcing the public meeting, that medical devices present different issues compared to drugs, biological products, and blood. For example, there are different classes of medical devices, and each class represents a different degree of risk, so, for a low-risk device (such as a bandage), a bar code might not have an impact on patient safety (67 FR 41360 at 41361). As another example, some medical devices may be reconditioned by parties other than the original manufacturer; in such situations, the original manufacturer might want to ensure that its bar code is removed or eliminated if the device is reconditioned, because the device no longer comes directly from the original manufacturer

code might not have an impact on patient safety (67 FR 41360 at 41361). As another example, some medical devices may be reconditioned by parties other than the original manufacturer; in such situations, the original manufacturer might want to ensure that its bar code is removed or eliminated if the device is reconditioned, because the device no longer comes directly from the original manufacturer. Comments from device industry interests recommended further study and a separate rulemaking for devices or the voluntary use of “automatic identifiers.” However, one device manufacturer indicated that it already uses bar codes on its devices, but it uses the bar code for reimbursement purposes and for logistical reasons rather than for safety concerns. The manufacturer also recommended that, if we wanted bar codes on devices, we should issue guidelines instead of a rule.

2. What Products Would the Rule Cover?

After careful consideration of the comments, we propose to require the following products to carry a bar code:

• All prescription drug products, including biological products (including vaccines), but excluding physician samples; and

• Over-the-counter (OTC) drugs that are dispensed pursuant to an order and are commonly used in hospitals; and

For blood and blood components, the proposal would require the use of machine-readable information.

a. Why Cover Prescription Drug Products, Including Vaccines, But Not Physician Samples ? The comments from the public meeting agreed that prescription drug products should have a bar code, although a small number of comments suggested that only prescription drug products used in institutions should be subject to a bar code requirement and that prescription drug samples should not be included.

comments suggested that only prescription drug products used in institutions should be subject to a bar code requirement and that prescription drug samples should not be included.

We decided to cover all prescription drug products, rather than limit the rule to prescription drug products used in institutions, because we are unaware of any prescription drug products that are not used in hospitals. Our primary focus is to help reduce the number of medication errors occurring in hospitals, and, as we consider “prescription drugs used in institutions” as being the same as “prescription drugs” generally, the proposal refers to “prescription drugs.”

However, with regard to prescription drug samples, we decided to omit prescription drug samples from a proposed bar code requirement because most samples are given to patients at physicians' offices, and we do not believe that physicians or patients would have or be inclined to buy bar code scanners for their own use in the immediate future. We recognize that an argument could be made for including samples. We know that some samples are donated to charitable organizations, such as free clinics, for distribution to patients without charge (Ref. 34). These samples could be subject to the same medication errors as marketed prescription drugs, and those medication errors could be prevented through the use of bar codes. In addition, Congress and FDA have been concerned about illegal sales of prescription drug samples, the potential diversion of samples to illegal drug trafficking, and the entry of counterfeit drugs into the wholesale distribution system. Requiring bar codes on samples could help identify diverted or counterfeit drug products that enter distribution through illegal channels, and this could result in benefits that are not directly related to the prevention of medication errors.

We recognize that the vast majority of prescription drug samples are usually given to patients at physicians' offices and are not administered in hospitals

Requiring bar codes on samples could help identify diverted or counterfeit drug products that enter distribution through illegal channels, and this could result in benefits that are not directly related to the prevention of medication errors.

We recognize that the vast majority of prescription drug samples are usually given to patients at physicians' offices and are not administered in hospitals. Because we have no evidence to suggest that physicians' offices are likely to be equipped with bar code scanners in the immediate future, the benefits associated with preventing medication errors through bar codes on prescription drug samples are unlikely to be realized in this health care setting. We also recognize that it is unlikely that charitable institutions, such as free clinics, would have the resources to buy bar code scanners to prevent medication errors. As a result, we have decided to omit prescription drug samples from the rule at this time. We do, however, invite comment on whether to require bar codes on prescription drug samples. Comments should address the costs and benefits associated with requiring bar codes on prescription drug samples.

The proposal would apply to vaccines. The National Childhood Vaccine Injury Act of 1986 (Public Law 99-660) (42 U.S.C. 300aa-25(a)) requires each health care provider who administers a vaccine set forth in the Vaccine Injury Table to any person to record, in that person's permanent medical record or in a permanent office log or file, the date of administration of the vaccine, the vaccine manufacturer, the vaccine's lot number, and other information. A bar code on vaccines could help ensure the accuracy of those records insofar as identification of the vaccine, its manufacturer, and date of administration are concerned, and, for those vaccines administered in health care facilities, help ensure that the right vaccine is administered to the right patient at the right time

he vaccine manufacturer, the vaccine's lot number, and other information. A bar code on vaccines could help ensure the accuracy of those records insofar as identification of the vaccine, its manufacturer, and date of administration are concerned, and, for those vaccines administered in health care facilities, help ensure that the right vaccine is administered to the right patient at the right time. However, we are sensitive to the vaccine manufacturers' concerns, particularly as they relate to possible adverse impacts on vaccine production or availability, and we invite comment on the risks and benefits of including vaccines in a bar code rule.

As for those comments that suggested an exemption for certain products or small containers, we decline to create an exemption mechanism and explain our reasons in section II.F of this document.

b. Why Cover OTC Drugs That Are Dispensed Under an Order and Commonly Used in Hospitals ? The public meeting notice asked whether we should require bar codes on all OTC drugs. After reviewing the comments, we decided against requiring all OTC drugs to carry a bar code because it is unlikely that putting bar codes on all OTC drugs would have a significant impact on reducing medication errors and offset the large costs associated with requiring bar codes on all OTC drugs. Most OTC drugs are used outside hospitals and other health care facilities and are used by consumers who purchase the OTC drugs at retail. At this point, it is unlikely that individual consumers would buy, use, or have access to bar code scanners or use such scanners before taking an OTC drug.

al consumers would buy, use, or have access to bar code scanners or use such scanners before taking an OTC drug.

We recognize, however, that some OTC drugs are administered to patients in hospitals and that bar codes would enable health care professionals to check whether they are giving the right OTC drug in the right dose and right route of administration to the right patient at the right time. In addition, we recognize that OTC drugs could interact with prescription drugs administered at that hospital or affect another drug's performance. Thus, we propose to require bar codes on OTC drugs that are dispensed pursuant to an order and are commonly used in health care facilities. For example, the bar code on an OTC drug dispensed pursuant to an order and commonly used in a hospital may allow a hospital's database to identify any potential interactions between the OTC drug and any prescription drugs prescribed for the patient, or may alert a health care professional to the patient's allergies relative to the OTC drug's ingredients. The proposal would apply to any manufacturer, repacker, relabeler, or private label distributor who sells a specific package of an OTC drug product to hospitals. It would not apply to all packages of a specific OTC drug product. An example of a specific package of an OTC drug product sold to hospitals would be an individual product, such as an aspirin tablet, packaged in a unit-of-use container.

We would interpret “commonly used in hospitals” to include OTC drugs that are sold to hospitals, packaged for institutional use, labeled for institutional use, or marketed, promoted, or sold to hospitals through drug purchasing contracts or catalogues. For example, if an OTC drug product manufacturer sends its catalogues to hospitals to solicit orders from them, the OTC drug products described in the catalogue would be “commonly used in hospitals” because the manufacturer is marketing its OTC drugs to hospitals

utional use, labeled for institutional use, or marketed, promoted, or sold to hospitals through drug purchasing contracts or catalogues. For example, if an OTC drug product manufacturer sends its catalogues to hospitals to solicit orders from them, the OTC drug products described in the catalogue would be “commonly used in hospitals” because the manufacturer is marketing its OTC drugs to hospitals. If a distributor relabeled an OTC drug “for institutional use,” then that OTC drug would be “commonly used in hospitals” because it is intended for hospital use.

We expect that manufacturers, repackers, relabelers, and private label distributors would know which of their products meet the definition of OTC drug products commonly used in hospitals. For example, we believe that when manufacturers, repackers, relabelers, and private label distributors label or package their OTC drugs for institutional use, they know that the products will likely be sold to hospitals. Manufacturers also know that their OTC drug products will be sold to hospitals when they market or promote those OTC drugs to hospital staff through detailing the products or other means, enter into hospital purchasing contracts, or sell to hospitals through catalogues.

We recognize that it is possible for a manufacturer to sell an OTC drug to a wholesaler or retailer who then re-sells the product, without making any changes to the product, directly to a hospital without the manufacturer's knowledge. We believe that, in most cases, the manufacturer would know that the product may be sold to a hospital (e.g., because of the product's labeling, packaging). However, there may be rare instances when the manufacturer may not have had reason to believe that its product would be sold to a hospital. Therefore, if the OTC drug is not packaged, labeled, marketed, promoted, or sold to a hospital as described above, we would not expect the OTC drug's manufacturer to comply with the bar code requirement

tal (e.g., because of the product's labeling, packaging). However, there may be rare instances when the manufacturer may not have had reason to believe that its product would be sold to a hospital. Therefore, if the OTC drug is not packaged, labeled, marketed, promoted, or sold to a hospital as described above, we would not expect the OTC drug's manufacturer to comply with the bar code requirement.

Proposed § 201.25(b) would also include the phrase “dispensed pursuant to an order” with regard to OTC drugs. Some products in hospitals that are traditional types of OTC drugs, such as aspirin or acetominophen, are dispensed pursuant to a physician's order. Other products that are regulated as OTC drugs are not dispensed pursuant to a physician's order. For example, a hospital might provide fluoride toothpaste or mouth rinses to a patient without a physician's order. Because these products are not likely to contribute to medication errors, the proposal would focus only on those OTC drugs used in hospitals that are dispensed pursuant to an order.

We recognize that there may be other ways to describe the types of OTC drugs that should have a bar code. For example, we considered requiring bar codes for OTC drugs “sold directly to hospitals.” If the proposal pertained to OTC drugs sold directly to hospitals, most manufacturers, repackers, relabelers, and private label distributors who sold their products directly to hospitals would be subject to the rule, but the bar code requirement could be avoided by selling the OTC drugs to distributors or other third parties for re-sale to hospitals. We considered applying the bar code requirement to OTC drugs that are labeled for use in an institutional setting. This alternative is equally difficult to administer because it is easily circumvented by relabeling the drug

hospitals would be subject to the rule, but the bar code requirement could be avoided by selling the OTC drugs to distributors or other third parties for re-sale to hospitals. We considered applying the bar code requirement to OTC drugs that are labeled for use in an institutional setting. This alternative is equally difficult to administer because it is easily circumvented by relabeling the drug. We considered requiring bar codes on OTC drugs commonly used in health care facilities (rather than hospitals), but could not determine whether clinics, nursing homes, and other facilities would invest in bar code scanning equipment.

We specifically invite comment on the terms we should use to describe OTC drugs that should be subject to the bar code requirement. Comments should also consider the following issues:

• Who should be required to apply the bar code on the OTC drugs that are subject to a bar code requirement? If the proposal refers to OTC drugs “commonly used in hospitals,” will manufacturers, repackers, and relabelers know which products require a bar code?

• Do the terms “dispensed pursuant to an order” sufficiently distinguish between those OTC drugs that are likely to be involved in medication errors from those that are not?

c. Which Blood Products Are Covered ? Current FDA regulations state that the container label on blood and blood products “may bear encoded information in the form of machine-readable symbols approved for use by the Director, Center for Biologics Evaluation and Research” (see 21 CFR 606.121(c)(13)), but they do not require the use of such symbols nor do they specify a particular symbol. Correct identification of blood is essential because transfusion errors or use of contaminated blood can have serious adverse health consequences for a patient. For example, one comment submitted in response to the public meeting stated that transfusion errors cause as many as two dozen patient deaths annually and that the number may be under reported

mbols nor do they specify a particular symbol. Correct identification of blood is essential because transfusion errors or use of contaminated blood can have serious adverse health consequences for a patient. For example, one comment submitted in response to the public meeting stated that transfusion errors cause as many as two dozen patient deaths annually and that the number may be under reported. Consequently, we propose to require that blood and blood component container labels bear “encoded information that is machine-readable” and approved for use by the Director of CBER. We address this specific requirement at proposed § 606.121(c)(13), which we discuss more fully in section II.H of this document.

d. Why Did We Omit Medical Devices From the Rule ? At this time, we are omitting medical devices from this rulemaking. We recognize that different issues arise for devices than for drugs, so further consideration is needed regarding the need for putting bar codes on medical devices. We will continue to study whether to develop a proposed rule to require bar codes on medical devices to prevent or reduce medication errors.

C. What Would the Bar Code Contain? (Proposed § 201.25(c)(1))

1. What Is the National Drug Code Number, and Why Would It Be Helpful?

Proposed § 201.25(c)(1) would require the bar code to contain, at a minimum, the drug's NDC number. The NDC number identifies each drug product that is listed under section 510 of the act. Most persons attending the public meeting agreed that a bar code should, at a minimum, contain the drug's NDC number.

To complement this proposed requirement, we intend to revise our drug establishment registration and listing regulations to redefine the NDC number and to make the NDC number unique and more useful to informational databases, whether those databases are created for purposes of preventing medication errors, obtaining the latest information about a specific drug, or tracking drug use or distribution

Please note that proposed § 201.25(c)(1) would require the bar code to contain, at a minimum, the NDC number. Several comments submitted in response to the public meeting indicated that some drug manufacturers already place bar codes on their products, but that the bar code contains a numerical identifier that contains, but is not identical to, the NDC number. For example, some comments suggested that the bar code contain the International Article Number (EAN) or the Global Trade Item Number (GTIN). We are aware that some drug companies already use a bar code containing the:

• Universal Product Code number (UPC). The UPC is usually a 12-digit number that may or may not contain the NDC number within it. For example, if the drug's NDC number were 1234567890, the UPC number might be 312345678906, where the first digit (3) signifies that the product is a drug, and the last digit is a “check digit” that helps confirm that the bar code was read correctly. However, some drugs, particularly OTC drugs, may have a UPC number that does not contain the NDC number;

• International Article Number (EAN). The EAN is a 13-digit number and also contains the NDC number within it; or

• Global Trade Item Number (GTIN). The GTIN is a 14-digit number that contains the NDC number in conjunction with a code that identifies the product's packing level. In the GTIN, the first digit signifies the packaging level

y have a UPC number that does not contain the NDC number;

• International Article Number (EAN). The EAN is a 13-digit number and also contains the NDC number within it; or

Thus, under the proposal, the bar code could contain the NDC number alone or the UPC number, EAN number, or GTIN number, as long as the NDC number is present. By making the NDC number the minimum bar code information requirement, firms could continue using various numbering systems (such as the UPC, if the UPC number contains the NDC number, EAN, or GTIN numbers) in their bar codes, thus minimizing or eliminating the need for companies to redesign or generate new bar codes and We recognize that some comments supported the use of a unique identifying number rather than the NDC number. One comment explained that the UPC code that goes on the product label does not always use the NDC number, so if we required the bar code to contain the NDC number, important label changes could go unnoticed if health care professionals relied on the bar codes instead of product labels. The comment suggested that if distributors establish the unique identifying codes and revise those codes when they make label changes, the revised code could then trigger a need for a health care professional administering the drug to read the label and to update its database accordingly. Another comment described the NDC number as a “dumb number” in OTC drugs and suggested following UCC/EAN guidelines instead to identify the product. Another comment stated that OTC drugs should use the UPC number instead of the NDC number because changing UPC bar codes to include the NDC number would result in great expense without a discernable benefit

abel and to update its database accordingly. Another comment described the NDC number as a “dumb number” in OTC drugs and suggested following UCC/EAN guidelines instead to identify the product. Another comment stated that OTC drugs should use the UPC number instead of the NDC number because changing UPC bar codes to include the NDC number would result in great expense without a discernable benefit. Additionally, during a meeting with CHPA and others, the industry representatives stated that UPC codes do not always contain NDC numbers, and retailers rely on the UPC codes, so requiring the use of NDC numbers would be disruptive to the industry and retailers. The industry representatives suggested using a unique identifier other than the NDC number.

We decline to require the use of unique identifying numbers other than the NDC number. Through the proposed drug establishment registration and listing rule, the NDC number would become a unique identifying number for listed drugs and correspond to a particular listed drug. If we allowed distributors to assign unique identifying numbers and did not coordinate the assignment of such numbers to drugs, the result could be extremely confusing as distributors could use different identification schemes (such as a mixture of letters, numbers, or other characters). Moreover, creating and maintaining databases on drug products for medication error purposes would become more difficult because identifying information would have to come from multiple sources. For example, the Federal Government might be the source for NDC number information, but firms who created unique, non-NDC identifying numbers would have to provide information on those numbers to the databases themselves if the databases are to be complete and useful

for medication error purposes would become more difficult because identifying information would have to come from multiple sources. For example, the Federal Government might be the source for NDC number information, but firms who created unique, non-NDC identifying numbers would have to provide information on those numbers to the databases themselves if the databases are to be complete and useful. Multiple information sources would increase the likelihood that some information and databases might not be updated as frequently as others, that some information might be unavailable, or that the information would be presented in different or incompatible ways. While we understand the OTC drug industry's reservations about changing UPC codes to include NDC numbers because of a possible impact on retailers, proposed § 201.25(b) would only require bar codes on OTC drugs that are dispensed pursuant to an order and are commonly used in hospitals, so most OTC drugs should not be affected.

2. Would the Bar Code Be Required to Contain the Lot Number and Expiration Date?

Many organizations and individuals have recommended that the bar code contain information regarding the drug's lot number and expiration date, and others have recommended phasing-in a requirement to have the bar code contain the lot number and expiration date.

We decline to require lot number and expiration date information in the bar code at this time. In general, while lot number and expiration date information would make it easier to identify drugs that had been recalled or were expired, we neither found nor received data to show that the benefits of bar coding lot number and expiration date information would exceed the costs of putting that information in the bar code. There is, however, limited information on the extent to which patient safety is affected by and medication errors occur as a result of taking expired or recalled drugs

drugs that had been recalled or were expired, we neither found nor received data to show that the benefits of bar coding lot number and expiration date information would exceed the costs of putting that information in the bar code. There is, however, limited information on the extent to which patient safety is affected by and medication errors occur as a result of taking expired or recalled drugs. We reviewed data from our adverse event reporting system (containing 71,546 cases) and found 90 cases where patients received an expired drug and 21 cases where patients received a recalled drug. Expired drugs may become subpotent and might not have the intended therapeutic effect. They also may contain degradation products associated with aging. Products may be recalled for a variety of reasons including no active ingredient present in the product or contamination of the product that could lead to infection.

We also tabulated data from the Office of Compliance, Center for Drug Evaluation and Research, on the reasons for and the extent to which drug products have been recalled from the market. From fiscal year 1997 through fiscal year 2002, there were 1,230 recalls, of which 97 were Class I (reasonable probability that the use or exposure to the violative product will cause serious adverse health consequences or death) and 1,133 were Class II (use or exposure of the violative product may cause temporary or medically reversible adverse health consequences or where the probability of serious adverse health consequences is remote). Despite this number of recalls for safety and health reasons, we received few reports of adverse events associated with the administration of a recalled drug, and we do not have reliable data that show how often these products were administered to patients

cause temporary or medically reversible adverse health consequences or where the probability of serious adverse health consequences is remote). Despite this number of recalls for safety and health reasons, we received few reports of adverse events associated with the administration of a recalled drug, and we do not have reliable data that show how often these products were administered to patients.

Thus, based on the data available to us, we cannot determine the magnitude of the public health problem associated with administering expired or recalled products, and we cannot quantify the patient safety benefit associated with requiring lot number and expiration date information in a bar code.

Some comments suggested that requiring lot number and expiration date information in a bar code could have benefits outside the medication error context by making it easier to track or trace products and to identify counterfeit products.

We agree that bar codes may be useful outside the medication error context, but our rule focuses on the use of bar codes to prevent medication errors.

Industry comments indicated that adding lot number and expiration date information to the bar code would adversely affect production line speed. One comment from a drug company predicted that encoding lot number and expiration date information would reduce packaging line speed by 40 percent and cost more than $4.8 million for its product lines. Another drug industry comment indicated that a requirement to encode lot number and expiration date information could cause companies to reconsider their packaging choices, or require companies to alter their printing methods.

companies to reconsider their packaging choices, or require companies to alter their printing methods.

We also note that inclusion of lot number and expiration date information might require the use of a different machine-readable format, such as a two-dimensional symbology, in addition to or as a substitute for a linear bar code, and that could affect a hospital's equipment purchasing decision. Use of nonlinear bar code formats could require the purchase of a different scanning or reading device and also increase a hospital's equipment costs.

Based on the evidence we had and our obligation under Executive Order 12866 to choose regulatory approaches that maximize net benefits, the potential burden of encoding lot number and expiration date information appeared to outweigh the potential benefit at this time. Consequently, the proposed rule

Although the proposed rule would not require the drug's lot number and expiration date to appear in the bar code, the proposed rule would not prohibit the inclusion of such information. In other words, FDA will not object if a manufacturer, repacker, relabeler, or private label distributor were to add the lot number and expiration date to its bar code or add such information in a machine-readable format provided that the lot number and expiration date information is accurate. In a meeting with PhRMA on August 19, 2002, the industry representatives suggested to us that they might add machine-readable lot number and expiration date information if a demand existed for it

el distributor were to add the lot number and expiration date to its bar code or add such information in a machine-readable format provided that the lot number and expiration date information is accurate. In a meeting with PhRMA on August 19, 2002, the industry representatives suggested to us that they might add machine-readable lot number and expiration date information if a demand existed for it. (We have placed a memorandum of this meeting in the docket for this rule, along with memoranda of meeting for other meetings we attended.) We do not know how much more such drugs would cost (compared to drugs that only had the NDC number encoded in the bar code) or whether hospitals and other health care facilities would be willing to pay more for drugs that have the NDC number, lot number, and expiration date in a bar code or machine-readable code, but the meeting raises the possibility that market forces could lead to the inclusion of lot numbers and expiration dates in bar codes or other machine-readable formats.

D. Would the Rule Require a Specific Type of Bar Code? (Proposed § 201.25(c)(1))

1. What Did We Hear from the Public Meeting?

In the public meeting notice, we asked whether we should require the use of a specific bar code symbology, such as reduced space symbology (RSS), adopt one symbology over another, or allow for “machine readable” formats (67 FR 41360 at 41361). We also asked for the “pros and cons” of each approach (id.). We had identified RSS as a possible symbology because we knew about industry-conducted pilot studies that used RSS bar codes on small vials (Ref. 35). Our reasoning was that if RSS symbology could be used on small containers, it could be used on larger containers, too.

(Ref. 35). Our reasoning was that if RSS symbology could be used on small containers, it could be used on larger containers, too.

The comments we received reflected an array of differing opinions, ranging from the adoption of a specific, non-bar code technology to prescribing no specific symbology or standard at all in order to promote innovation. Two principal, yet contradictory, themes emerged. One view advocated requiring a specific symbology or standard to promote uniformity and to create the conditions whereby hospitals could invest confidently in bar code scanning equipment, without having to buy different pieces of equipment to read different bar codes or other machine readable formats or without having to fear that any equipment purchases would soon become obsolete. Another comment declared that the bar code symbology adopted by FDA should be compatible with current scanning devices used by health care organizations. However, if the rule adopted a single symbology or standard, the rule could affect future innovation in this field, and we would have to engage in new rulemaking to adopt any newer symbology or standard.

The other view stated that we should not select any specific symbology or even require linear bar codes at all; instead, these comments said the rule should require the use of machine-readable or automatic identifier technology, thus creating the conditions under which newer, and perhaps better, technologies could be used in the future. However, the comments and our own analysis suggested that if the rule allowed for multiple symbol types or technologies, hospitals might be confronted with incompatible technologies and decide against buying multiple pieces of equipment

machine-readable or automatic identifier technology, thus creating the conditions under which newer, and perhaps better, technologies could be used in the future. However, the comments and our own analysis suggested that if the rule allowed for multiple symbol types or technologies, hospitals might be confronted with incompatible technologies and decide against buying multiple pieces of equipment. For example, if one drug used an RSS bar code, another used a radio frequency identification format, and a third used a unique, patented, automatic identification technology, a hospital would have to decide whether to buy a bar code scanner, a device to detect the radio frequency information, and a device to detect the patented identifier, or some combination of the three devices. If those costs were too great, the hospital could decide against making any equipment investments altogether, and the benefits from bar coding would not be realized.

Other comments suggested that we require the use of machine-readable codes capable of being read by “machines currently deployed” and “economically available” or use symbology that is “compatible” with “current scanners.”

Some comments suggested that we conduct research to develop time lines for adopting specific bar code symbologies, that we have USP provide bar code standards, or adopt a standard or family of symbologies. Other comments said we should form a group involving various interests to study issues further or create an “automatic identification coordinating council” to ensure that minimum information requirements are met and that the best technology is used.

ous interests to study issues further or create an “automatic identification coordinating council” to ensure that minimum information requirements are met and that the best technology is used.

Deciding whether to require a specific symbology, standard, or an unspecified “machine-readable” symbol was a very difficult decision because of the comments' competing and sometimes incompatible positions. For guidance, we examined how another Federal agency reached a decision when confronted with an analogous problem of whether to require a particular action to accomplish a specific goal or to let market forces decide the outcome. We examined how the Federal Communications Commission (FCC) decided to adopt an order to require all television receivers to include digital television (DTV) reception capability in order to move towards a 2006 target date for a transition to digital television. Congress had imposed a December 31, 2006, target date for the return of the spectrum used by broadcasters for analog channels unless 85 percent of homes in a market could not receive local digital broadcast television signals. The FCC faced a problem; the public was reluctant to buy DTV receivers until there were DTV stations offering attractive DTV programs, but broadcasters lacked the incentive to provide such DTV programming in the absence of an audience that would attract advertisers (Ref. 36 at p. 13). Moreover, because analog televisions were still being sold, each sale of an analog television set put the FCC farther from reaching the 85 percent DTV reception goal (Refs. 37 and 38). The FCC ultimately decided to adopt a plan to require DTV tuners on almost all new television sets by 2007 and established a 5-year rollout schedule to minimize costs to television manufacturers and consumers. It recognized that requiring the manufacture of DTV receivers would address “the root cause of the problem, namely the lack of television receivers capable of receiving DTV signals” (Ref. 36 at p. 13)

timately decided to adopt a plan to require DTV tuners on almost all new television sets by 2007 and established a 5-year rollout schedule to minimize costs to television manufacturers and consumers. It recognized that requiring the manufacture of DTV receivers would address “the root cause of the problem, namely the lack of television receivers capable of receiving DTV signals” (Ref. 36 at p. 13). The FCC also recognized that, without its intervention, the transition to DTV might remain stalled. The FCC's decision to require all television receivers to include digital television (DTV) reception capability is

Our case is similar to the FCC's in the sense that we have an objective (reduction of medication errors) that can be achieved through bar codes, but hospitals are reluctant to invest in equipment because of the lack of bar coded products, and manufacturers, repackers, relabelers, and private label distributors are reluctant to invest in such bar codes or other technologies in the absence of a demand by hospitals or a requirement for such bar codes. If we fail to specify a particular measure, such as a symbology or standard, progress towards medication error reduction through bar codes could remain stalled; hospitals might still be reluctant to invest in equipment because of uncertainties in the marks, symbols, or technologies used on the drug or a limited amount of resources to buy different types of equipment to read the various marks, symbols, or other technologies. Likewise, manufacturers, repackers, relabelers, and private label distributors might not invest in bar codes or other technologies because no demand would exist or because their investments in such bar codes would be wasted if hospitals declined to buy the necessary equipment to take advantage of those bar codes or other technologies.

Consequently, proposed § 201.25(c)(1) would require the bar code for drugs and biological products (other than blood and blood products) to be any linear bar code in the UCC/EAN standard

ogies because no demand would exist or because their investments in such bar codes would be wasted if hospitals declined to buy the necessary equipment to take advantage of those bar codes or other technologies.

Consequently, proposed § 201.25(c)(1) would require the bar code for drugs and biological products (other than blood and blood products) to be any linear bar code in the UCC/EAN standard. This means that the bar code can be any linear bar code symbology, such as UCC/EAN-128, RSS, or UPC (if the UPC contains the NDC number), within the UCC/EAN standard. Adopting a linear bar code in the UCC/EAN standard, as opposed to a specific bar code symbology, should give firms some flexibility in selecting the bar code symbology that best fits their needs and should also give the rule some flexibility as linear bar code symbologies change, are added, or are phased out. For example, we know that the UCC has announced a “sunrise” date of 2005 for a new EAN-13 code because the commonly-used UPC code is running out of new company prefixes for that 12-digit code (Ref. 39). So, as new linear bar codes are added to the UCC/EAN standard, those new codes would be acceptable under the proposed rule as long as those new codes include the NDC number.

The UCC/EAN standard also has the advantage of being a widely used global standard. One comment submitted on behalf of the International Working Group on Barcoding of Pharmaceuticals advocated the use of the UCC/EAN standard because it represents a “validated, testable global standard.” The comment also suggested that regulatory authorities from Europe, Japan, and Canada are actively pursuing a bar code standard for pharmaceuticals and “are watching to see what the FDA decides.” Comments from the UCC, EAN, and some pharmaceutical interests also mentioned the global applicability of the UCC/EAN standard.

We recognize that other bar code standards exist, notably those advanced by the Health Industry Business Communication Council (HIBCC)

Europe, Japan, and Canada are actively pursuing a bar code standard for pharmaceuticals and “are watching to see what the FDA decides.” Comments from the UCC, EAN, and some pharmaceutical interests also mentioned the global applicability of the UCC/EAN standard.

We recognize that other bar code standards exist, notably those advanced by the Health Industry Business Communication Council (HIBCC). HIBCC bar code symbologies include code 39 and code 128. (The UCC/EAN system also has a UCC/EAN-128 symbology that is similar, but not identical, to the HIBCC code 128.) HIBCC also has the Universal Product Number (UPN) system which is used for medical and surgical products. Comments from drug and biological product companies, however, usually referred to UCC/EAN standards if they identified any standard at all, so we presume that the use of UCC/EAN standards would be less disruptive to those industries compared to requiring the use of a different bar code standard. However, a comment from HIBCC suggested that some drugs may use HIBCC bar codes, that medical devices, in particular, are “uniquely identified by the UPN number,” and that the Department of Defense, Veterans Administration, and other organizations use the UPN numbering system. Therefore, we cannot preclude the possibility that some drug firms and organizations may use or prefer to use HIBCC bar codes, so we invite comment as to whether the rule should refer instead to linear bar codes without mentioning any particular standard or refer to UCC/EAN and HIBCC standards.

e invite comment as to whether the rule should refer instead to linear bar codes without mentioning any particular standard or refer to UCC/EAN and HIBCC standards.

Our position presumes that, by the time any final bar code rule becomes effective (assuming that we do issue a final rule), bar code scanners will be able to read different UCC/EAN linear bar code symbologies reliably and efficiently. This is a critical consideration because the proposed rule's benefits are realized only if hospitals invest in bar code scanners, and we reiterate that their willingness to make that investment may depend on the number of different bar code symbologies that will be used and the ability of bar code scanners (particularly those scanners already in use at the hospitals) to read different symbologies. Comments from the public meeting disagreed on what capabilities different bar code scanning technology had to read different symbologies. Some comments suggested that new bar code scanners can read different linear bar code symbologies, particularly those in the UCC/EAN standard. In contrast, others suggested that bar code scanners may be unable to read newer bar code symbologies or that older scanners cannot read new symbologies or composite codes. Our understanding is that scanner capability depends on how the scanner is programmed (because scanners are programmed to read individual symbologies) and whether scanners can be upgraded or modified to read new symbologies. For example, some bar code scanners might be programmed to read the most commonly used linear bar codes and might not be able to read the RSS symbology. Some scanner manufacturers may be able to upgrade or modify an existing scanner to read newer symbologies, while other scanners, due to their age or the manner in which they were made, might not be capable of being upgraded. We invite further comment on this point

bar code scanners might be programmed to read the most commonly used linear bar codes and might not be able to read the RSS symbology. Some scanner manufacturers may be able to upgrade or modify an existing scanner to read newer symbologies, while other scanners, due to their age or the manner in which they were made, might not be capable of being upgraded. We invite further comment on this point.

As for non-bar code technologies, we know that other technologies exist or are under development, but we decline to specify the use of DataMatrix or other nonlinear bar code formats or technologies, such as radio frequency identification (RFID). We realize that other technologies may be able to encode more data or be more versatile compared to linear bar codes. For example, in a meeting with the National Alliance for Health Information Technology, we heard how RFID could be used to facilitate inventory control and to track individual items because each RFID tag would have its own unique “electronic product code” (EPC) consisting of a header code, an “EPC manager” that would probably identify the product's manufacturer, an “object class” that would refer to the product type, and a “serial identifier” that would be unique to each individual item. RFID's ability to track individual items could help drug companies and public health agencies identify and eliminate counterfeit drug products. However, the costs associated with RFID tags and readers could be significant; literature provided by the Auto-ID Center conceded that current RFID tags are “fairly expensive” and that a firm might have to purchase more than one reader if multiple RFID frequencies exist (Ref. 40). A representative from the Auto-ID Center stated that the “target cost” is five cents per RFID tag, so the technology could become more available and less expensive in the future

uld be significant; literature provided by the Auto-ID Center conceded that current RFID tags are “fairly expensive” and that a firm might have to purchase more than one reader if multiple RFID frequencies exist (Ref. 40). A representative from the Auto-ID Center stated that the “target cost” is five cents per RFID tag, so the technology could become more available and less expensive in the future.

Nevertheless, we find that linear bar codes are sufficient for encoding NDC

• What other symbol, standard, or technology should we consider, either in place of a linear bar code or in addition to it? How accepted is that symbol, standard, or technology among firms that would have to affix or use that symbol, standard, or technology? For example, we know that RFID technology has great potential for encoding a lot of data and for identifying individual products, but the technology is not yet widely accepted in the pharmaceutical industry due to its novelty and costs.

• Will hospitals be able to read or use the symbol, standard, or technology, either with existing equipment or equipment under development? We reiterate that hospitals might not have the financial resources to buy multiple pieces of equipment to read multiple, incompatible formats, so hospitals must be able to make equipment purchasing decisions confidently, knowing that they will recapture their investment costs.

Insofar as drug products are concerned, we also decline to have the proposal refer to the use of machine-readable codes or symbologies that can be read by machines “currently” used. Although a reference to “machine-readable” symbols or to “current” technology might seem to make a rule more accommodating to future technological developments, words such as “machine-readable” and “current,” when used in a regulation, can create several practical difficulties

have the proposal refer to the use of machine-readable codes or symbologies that can be read by machines “currently” used. Although a reference to “machine-readable” symbols or to “current” technology might seem to make a rule more accommodating to future technological developments, words such as “machine-readable” and “current,” when used in a regulation, can create several practical difficulties. For example, in the absence of an accepted standard or process, disputes could arise as to how we or any other person or group determines what is “current.” A manufacturer who wants to use a novel bar code or symbol could get different answers depending on whom it consulted; a hospital using linear bar code readers might find the novel code incapable of being read by its “current” scanners, whereas the firm marketing a new machine to read the novel code would argue that the novel code is “machine-readable” by “current” machines. Similarly, if only a fraction of the machines used in hospitals can read a new code, a hospital might argue that the new code cannot be read by “current” machines, yet, if machines were or could be upgraded or modified, a firm that marketed the machines or upgrade service might argue that the new code can, indeed, be read by current machines, provided that upgrades or modifications are made. These and other potential problems associated with a reference to “current” machines or “machine-readable” technology lead us to avoid using such terms in this proposal. (Different considerations apply for blood and blood products, and we discuss the proposed requirement for machine-readable symbols for blood and blood product containers at section II. H of this document.)

Furthermore, we decline to establish committees or other bodies to study the issue further or to decide technological issues. Given the comments we have received thus far, we have no assurance that a committee or other body would arrive at a consensus

s, and we discuss the proposed requirement for machine-readable symbols for blood and blood product containers at section II. H of this document.)

Nevertheless, if a group comprised of the affected industries and persons who would use the bar code could agree on a standard, symbology, or technology, we would be interested in learning about such standard, symbology, or technology and its costs and benefits. We would carefully review the information and consider the information when drafting a final rule.

2. Are There Any Specific Requirements for the Bar Code?

Proposed § 201.25(c)(1)(i) and (c)(1)(ii) would require the bar code to be surrounded by sufficient blank space so that the bar code can be scanned correctly and to remain intact under normal conditions of use. These requirements would help ensure that the bar code can be read easily and accurately so that its safety benefits may be realized. We note that today some manufacturers have bar codes at locations where the bar codes are destroyed, damaged, or otherwise rendered useless. For example, some manufacturers have put bar codes on individual foil-wrapped packets, but the bar code overlaps the folds or perforations that separate the foil-wrapped packets. When one packet is separated from the others, the bar code is split into pieces, and the resulting bar code fragments can provide misleading or nonsensical information to the bar code scanner or might not be read at all by the scanner. So, the proposed rule would require the bar code to be placed in a manner so that it remains intact during normal conditions of use

parate the foil-wrapped packets. When one packet is separated from the others, the bar code is split into pieces, and the resulting bar code fragments can provide misleading or nonsensical information to the bar code scanner or might not be read at all by the scanner. So, the proposed rule would require the bar code to be placed in a manner so that it remains intact during normal conditions of use. For the foil-wrapped packet example, this would mean that the bar code would be placed away from folds or perforations so that each packet, when separated from the others, has its own intact and easily scanned bar code.

Note, too, that the proposal would include the phrase “under normal conditions of use.” Depending on the packaging and container used, the “normal conditions of use” may or may not require the bar code to remain intact at all times. For example, assume that you have a tablet in a blister package and that the bar code is printed on the flat side of the blister package. If the bar code is scanned before the tablet is pushed through the flat side, the bar code would not remain “intact” after the tablet has been dispensed, and this would be acceptable because, under “normal conditions of use,” the bar code would have already served its purpose by being scanned before the drug was dispensed. In contrast, assume that you have a bottle that contains multiple tablets. The bar code on the bottle, under proposed § 201.25(c)(1)(ii), would have to remain intact throughout the bottle's use so that the bar code could be scanned each time a tablet is dispensed from that bottle.

One comment said we should audit bar code quality, help industry build a bar code information infrastructure, publish our results, and support mandatory testing and verification of bar codes.

comment said we should audit bar code quality, help industry build a bar code information infrastructure, publish our results, and support mandatory testing and verification of bar codes.

We decline to adopt the comment's suggestions. The bar code would be part of the drug's label, so issues concerning its quality and verification would be subject to current good manufacturing practices (GMP's). In general, persons who would be subject to the bar code requirement would be responsible for having written procedures for the receipt, identification, storage, handling, sampling, examination, and/or testing of labeling and packaging materials, for exercising control over labeling materials and label operations, and for ensuring that correct labels are used (see 21 CFR 211.122, 211.125, 211.130). Failure to meet GMP's will cause a drug to be considered adulterated under section 502(a)(2)(B) of the act.

We also note that there are various standards relating to bar codes already. For example, the American Society for

The bar code can also be used to access the medication information found in the professional labeling of a specific drug product. We are currently working on a collaborative initiative with the National Library of Medicine and the Department of Veterans Affairs to create a collection of up to date, computer readable electronic labels for marketed drug products called the “DailyMed.” By linking the NDC to the appropriate label in the DailyMed, people will be able to use computer systems to access important medication information simply by scanning the bar code found on the drug package. This could help locate proper dosage instructions, identify drug interactions, and find other information necessary for the safe use of medications.

E. Where on the Label Would the Bar Code Appear? (Proposed § 201.25(c)(2))

In the public meeting notice, we asked where the bar code should be placed

ccess important medication information simply by scanning the bar code found on the drug package. This could help locate proper dosage instructions, identify drug interactions, and find other information necessary for the safe use of medications.

E. Where on the Label Would the Bar Code Appear? (Proposed § 201.25(c)(2))

In the public meeting notice, we asked where the bar code should be placed. We asked if there were benefits to placing bar codes on immediate containers and if there was a way to distinguish whether certain containers with a bar code would have a more significant effect on preventing medication errors than other containers (67 FR 41360 at 41361).

Some comments suggested that the bar code go on every package level down to the unit-of-use or unit dose. Other comments recommended placing the bar code on the “immediate container” or unit dose or unit-of-use package only.

In contrast, one comment expressed surprise that we would even consider putting bar codes on unit dose or unit-of-use packages because of the potential impact on manufacturers.

Several comments also disagreed as to whether we should specify where a bar code should appear on a particular package. For example, one comment recommended that we draft guidelines for bar code placement; the guidelines would consider ergonomics, scanner types, symbologies, and packaging. Another comment would require the bar code to be placed where “the typical user of the scanning device can reliably and consistently scan it.”

In contrast, other comments stated that we should not restrict the bar code's placement on a package because differences relating to package size, shape, and material demand flexibility as to the bar code's placement.

Proposed § 201.25(c)(2) would require the bar code to appear on the drug's label

be placed where “the typical user of the scanning device can reliably and consistently scan it.”

Proposed § 201.25(c)(2) would require the bar code to appear on the drug's label. Section 201(k) of the act defines “label” as “a display of written, printed, or graphic matter upon the immediate container of any article; and a requirement made by or under authority of this act that any word, statement, or other information appear on the label shall not be considered to be complied with unless such word, statement, or other information also appears on the outside container or wrapper, if any there be, of the retail package of such article, or is easily legible through the outside container or wrapper.” Thus, by requiring the bar code to be on the drug's label, proposed § 201.25(c)(2) would result in bar codes on the drug's immediate container label as well as the outside container or wrapper, unless the bar code is easily legible and machine-readable through the outside container or wrapper.

We decline to adopt the comments' positions to require bar codes on all packages or only on immediate containers because that would either result in too many products being bar coded or too few. For example, if we required every package to bear a bar code, then arguably a shipping container of drugs would have a bar code, even though no hospital would dispense a drug directly from a shipping container to a patient, and a bar code on the shipping container would have no impact on medication errors

containers because that would either result in too many products being bar coded or too few. For example, if we required every package to bear a bar code, then arguably a shipping container of drugs would have a bar code, even though no hospital would dispense a drug directly from a shipping container to a patient, and a bar code on the shipping container would have no impact on medication errors. (The bar code could help with inventory control and tracking, but such matters are outside the scope of this proposed rule.) If we required only the immediate container (which is the container that is in direct contact with the drug at all times) to have a bar code, then patients receiving multiple-unit containers (such as a box holding blister packed tablets) would be vulnerable to medication errors because the multiple-unit container would not have a bar code.

As the previous paragraph suggests, there may be more than one bar code on a product depending on the package and whether it has a unique NDC number. For example, assume that you make drug tablets that are individually packaged in a plastic blister pack and then boxed in a cardboard container. If the individually packaged tablets have a unique NDC number, then each individual blister pack would have a bar code. The cardboard container holding the blister pack would have to have a bar code, too, because the cardboard container would be an “outer container” within the statutory definition of “label.”

Although proposed § 201.25(c)(2) would not require the bar code to appear at a specific location on a product, proposed § 201.25(c)(1)(ii) would require the bar code to remain intact under normal conditions of use. The latter requirement may influence the bar code's location.

F. What Would Happen if a Bar Code Could Not Be Put on a Product?

The proposed rule would not contain an exemption provision. We are aware of industry-conducted pilot studies that have placed RSS bar codes on small vials (Ref. 35)

proposed § 201.25(c)(1)(ii) would require the bar code to remain intact under normal conditions of use. The latter requirement may influence the bar code's location.

F. What Would Happen if a Bar Code Could Not Be Put on a Product?

The proposed rule would not contain an exemption provision. We are aware of industry-conducted pilot studies that have placed RSS bar codes on small vials (Ref. 35). These pilot studies suggest that almost all products are capable of bearing a bar code. However, some comments from the public meeting suggested that small products might not be capable of bearing a bar code and recommended that we allow for exemptions.

We decline to create an exemption provision because we believe that almost all products are capable of bearing a bar code. In addition, exemption provisions sometimes create unintended administrative problems and consume agency resources as some individuals or firms may be tempted to submit exemption requests notwithstanding their ability to comply with a particular regulatory requirement. For example, if we were to create a general exemption provision, a firm whose drug product was packaged in a small vial might seek an exemption even though it could use a RSS linear bar code on that vial. If we tried to impose a limitation on the exemption, such as allowing for possible exemptions if it would not be technologically feasible to affix a bar code on the label, a firm might argue over whether economic or other considerations determined whether a bar code was technologically feasible. In the end, we could be obliged to devote resources to reviewing, deciding, and perhaps re-examining exemption requests, and we can avoid that potential drain on FDA resources by not creating an exemption provision. We invite comment as to whether any specific product or class of products should be exempt from a bar code requirement and the reasons why such an exemption is considered to be necessary. We also invite comment on

o devote resources to reviewing, deciding, and perhaps re-examining exemption requests, and we can avoid that potential drain on FDA resources by not creating an exemption provision. We invite comment as to whether any specific product or class of products should be exempt from a bar code requirement and the reasons why such an exemption is considered to be necessary. We also invite comment on

G. What Is the Proposed Implementation Plan?

If we issue a final rule to require bar coding, we would require bar codes on human prescription drugs and OTC drugs dispensed under an order and commonly used in hospitals within three years after we publish the final rule in the Federal Register . The 3-year period would give affected parties time to obtain NDC numbers, if necessary, exhaust supplies of existing labels, and make new labels that contain the bar code or machine-readable information.

Additionally, because the bar code's addition to a label would be a ministerial act that would not require us to exercise any judgment as to the information being presented, we intend to have firms whose drug products are already approved or marketed notify us about the addition of the bar code to their product labels through an annual report (see § 314.81(b)(2)(iii) (21 CFR 314.81(b)(2)(iii) and 601.12(d)). For marketed OTC drugs, there is no comparable, routine reporting requirement if the drug is not the subject of an approved new drug application, and we do not intend to impose any reporting obligation relating to bar codes on OTC drugs.

We recognize that the bar codes' ability to prevent medication errors depends on many external factors outside this rule, such as the availability of bar code scanners, computer software that can process the bar code information and compare it against patient information, training health care professionals to use scanning equipment, and the willingness of hospitals to invest in bar code scanning equipment

nize that the bar codes' ability to prevent medication errors depends on many external factors outside this rule, such as the availability of bar code scanners, computer software that can process the bar code information and compare it against patient information, training health care professionals to use scanning equipment, and the willingness of hospitals to invest in bar code scanning equipment. However, requiring bar coding on human drugs is a necessary “first step” for promoting the use of technology to combat medication errors (Ref. 42).

We also acknowledge the various comments from the public meeting suggested different implementation periods for this rule. In general, some comments suggested short implementation dates measured in months whereas other comments suggested implementation dates measured in years. A few comments suggested different implementation dates for different products or would have the implementation date depend on the product's potential for harm. Several comments recommended requiring bar codes to contain the NDC number first, and require the lot number and expiration date at some future date.

We decided on the 3-year implementation date to give affected firms time to redesign their labels and exhaust pre-existing label stocks and to give hospitals time to decide which scanning devices or systems to develop or purchase. Additionally, as we suggested earlier, we want to give hospitals more time to decide whether they would be willing to work with pharmaceutical firms to have other information (such as lot number and expiration date) encoded. While we believe the 3-year implementation date is appropriate, we invite comment on whether the implementation period can and should be shortened.

We decline to create a “phased-in” implementation system whereby we would require the NDC number first, and then require inclusion of lot numbers and expiration dates at a future time

ther information (such as lot number and expiration date) encoded. While we believe the 3-year implementation date is appropriate, we invite comment on whether the implementation period can and should be shortened.

We decline to create a “phased-in” implementation system whereby we would require the NDC number first, and then require inclusion of lot numbers and expiration dates at a future time. As we explained earlier in section II.C.2 of this document, we lack data that would support requiring lot numbers and expiration dates on bar codes at this time. While we will not object if firms volunteer to encode such information (assuming that they encode the correct information), we will not require or specify any implementation period for the encoding of lot number and expiration date information.

H. How Does This Rule Apply to Blood and Blood Components? (Proposed § 606.121(c)(13))

Like medication errors, errors involving blood transfusions can result in serious injury or death. For example, one study examined reported transfusion errors occurring between January 1, 1990, and December 31, 1999, from approximately 256 transfusion services in New York (Ref. 43). The study focused on reports involving the administration of a unit of blood to someone other than the intended patient or the issuance of incorrect blood because of a blood bank or phlebotomy error. During the study period, nine million red blood cell and whole-blood units were transfused, and 659 cases of erroneous administration were observed, for a frequency of 1 error per 14,000 transfusions. Five cases resulted in fatalities, at a rate of 1 per 1,800,000 units. In cases where the patient received an incompatible unit, nearly half (47 percent) suffered no ill effects, but 41 percent of the cases resulted in an acute hemolytic reaction, and 2 percent resulted in fatalities (id.) The most common error outside blood banks was administering properly labeled blood to a patient other than the one for whom the unit was intended (37 percent)

per 1,800,000 units. In cases where the patient received an incompatible unit, nearly half (47 percent) suffered no ill effects, but 41 percent of the cases resulted in an acute hemolytic reaction, and 2 percent resulted in fatalities (id.) The most common error outside blood banks was administering properly labeled blood to a patient other than the one for whom the unit was intended (37 percent). In blood banks, the study identified issuance of the wrong unit (4 percent) and testing errors (7 percent) as some common errors (id.).

Current FDA regulations, at 21 CFR 606.121(c)(13), state that the container label for blood and blood components “may bear encoded information in the form of machine-readable symbols approved for use by the Director, Center for Biologics Evaluation and Research.” The reference to “machine-readable symbols” in § 606.121(c)(13) was intended to be flexible and accommodate changes in machine-readable technologies. For example, FDA recognized the use of Codabar (a specific bar code symbology) in 1985, and, in 2000, approved the use of ISBT 128, version 1.2.0 (Ref. 44).

Unlike the situation for other prescription drugs, there is already substantial use of bar codes for blood and blood products. Most blood establishments currently use machine-readable symbols or “ABC Codabar” on their blood and blood component labels. In August, 1989, the International Society for Blood Transfusion (ISBT), an organization established to promote and maintain a high level of ethical, medical, and scientific standards in blood transfusion medicine and science throughout the world, recognized that ABC Codabar, the first bar coding system adopted by the health care industry, was becoming outdated and initiated the design of a new system using the bar code symbology which eventually became known as ISBT 128

organization established to promote and maintain a high level of ethical, medical, and scientific standards in blood transfusion medicine and science throughout the world, recognized that ABC Codabar, the first bar coding system adopted by the health care industry, was becoming outdated and initiated the design of a new system using the bar code symbology which eventually became known as ISBT 128.

In December, 1996, the International Council for Commonality in Blood Bank Automation (ICCBBA) held an ISBT 128 Consensus Conference in Washington, DC, to provide an opportunity for dialogue among the affected industry groups and FDA. Although there was a consensus for use of ISBT 128, some participants expressed concerns regarding implementation time frames and costs of implementation to hospital transfusion services. However, ISBT 128 has numerous advantages over the ABC Codabar. For example, ISBT 128 is more secure, allows more flexibility in coding highly variable information, uses double-density coding to allow more information to be encoded in a limited space, and can be interpreted by the same bar code readers used with ABC Codabar.

The ISBT 128 bar code system established by ISBT is similar, but not identical to, Code 128. ISBT 128 is a copyrighted symbology. The ability to read, store, interpret, transfer, print, or otherwise manipulate ISBT 128 data structures requires registration with the ICCBBA and payment of an annual

ility to read, store, interpret, transfer, print, or otherwise manipulate ISBT 128 data structures requires registration with the ICCBBA and payment of an annual

Despite the international convention and guidance document, comments submitted in response to the public meeting suggest that § 606.121(c)(13) has not resulted in a uniform, international bar coding system for blood in the United States. While some comments described ISBT 128 in favorable terms, stating, for example, that it allows more information to be encoded or is more accurate than Codabar or that ISBT 128 represents an internationally-accepted standard for blood, at least one comment indicated that licensing fees associated with ISBT 128 may deter hospitals from using the ICCBBA system. Comments were also divided as to whether to require the use of ISBT 128 or simply require the use of “machine readable” symbols.

We considered whether the proposal should specify the use of ABC Codabar, ISBT 128, a different symbology or standard, or simply require the use of “machine-readable information” approved by the CBER Director. Each approach has its advantages and disadvantages. For example, requiring the use of ISBT 128 would help ensure a uniform bar coding standard for blood and blood components and be consistent with the international standard, but requiring ISBT 128 would mean that we would have to institute new rulemaking if a new symbology, standard, or technology was adopted. Requiring “machine-readable” information approved by the Director of CBER would allow CBER to consider new technologies in the future, but could result in some blood establishments adopting one system and others using a different system, thereby defeating the goal of creating a uniform system for identifying blood and blood components

making if a new symbology, standard, or technology was adopted. Requiring “machine-readable” information approved by the Director of CBER would allow CBER to consider new technologies in the future, but could result in some blood establishments adopting one system and others using a different system, thereby defeating the goal of creating a uniform system for identifying blood and blood components. Therefore, we invite comment as to whether we should require the use of ISBT 128, require the use of a symbology consistent with that required for drugs in proposed § 201.25, or require “machine-readable information” as approved by the Director of CBER or some other standard or symbology.

In developing this proposal, we recognize that the blood industry currently uses a machine-readable code that does not meet UCC/EAN standards. Some comments at the public meeting stated that the scanners are capable of reading multiple systems (e.g., UCC/EAN and ISBT). Based on our understanding of the state of the industry and the ability of scanners to read more than one symbology, we decided to propose a rule that would permit the existing coding to continue. We invite comments on whether this proposal is feasible or whether we should require the use of UCC/EAN standards for blood and blood components.

The proposal would require that the machine-readable information meet certain minimum requirements and be approved by the Director of CBER. These minimum requirements would move us closer to the goal of increasing patient safety. We anticipate that the industry will standardize encoded machine-readable information and readers, using our minimum requirements to minimize, to the greatest extent possible, the need for “country-specific” software and the high cost associated with software development and maintenance.

Thus, we propose to amend § 606.121(c)(13) to require the use of “machine-readable information” approved by the Director of CBER

the industry will standardize encoded machine-readable information and readers, using our minimum requirements to minimize, to the greatest extent possible, the need for “country-specific” software and the high cost associated with software development and maintenance.

Thus, we propose to amend § 606.121(c)(13) to require the use of “machine-readable information” approved by the Director of CBER. The Director will review the machine-readable information technology to ensure that the minimum requirements are met regarding the accuracy of the required labeling information, spacing, and conditions of use.

Proposed § 606.121(c)(13) also would:

• Explain that all blood establishments that manufacture, process, repackage, or relabel blood or blood components intended for transfusion and regulated under the act or the Public Health Service Act are subject to the machine-readable information requirement. This would be consistent with the pre-existing requirement at § 606.121(a) and (b).

• State that blood and blood components intended for transfusion are subject to the machine-readable information requirement. This would be consistent with the pre-existing requirement at § 606.121(a) that describes the purpose behind container label requirements.

• Describe the minimum contents of the machine-readable information as a unique facility identifier, lot number relating to the donor, product code, and the donor's ABO blood group and Rh type. This would reflect the pre-existing requirement at § 606.121(c)(1), (c)(2), (c)(3), (c)(10), and (c)(12).

• Specify that the machine-readable information must be unique to the blood or blood component, be surrounded by sufficient blank space so that the machine-readable information can be read correctly, and remain intact under normal conditions of use. This would be consistent with the pre-existing requirement at § 606.120(c) that requires labeling to be clear and legible

(3), (c)(10), and (c)(12).

• State that the machine-readable information must appear on the label of the blood or blood component which is or can be transfused to a patient or from which the blood or blood component can be taken and transfused to a patient. The proposal would not specify where the machine-readable information must appear on the label. To illustrate how this would work, the proposal's reference to any blood or blood component would include a unit of whole blood, packed red blood cells, plasma, platelets, and cryoprecipitate AHF. The unit of blood or blood component label would contain the machine-readable information if the blood or blood component has any possibility of being transfused to a patient, whether or not the unit is actually transfused. Additionally, the phrase, “from which the blood or blood component can be taken and transfused to a patient” would include the circumstance where blood or a blood component is extracted or aspirated with a syringe from the container of blood or blood component in order to transfuse to a patient. This technique might be used when transfusing neonates or under other medically necessitated circumstances. In this case, the blood or blood component from which the aspirate is taken must have affixed to it a label containing the required machine-readable information. This would be consistent with the pre-existing requirement at § 606.121(c)(8)(iii) that requires specific statements if a product is intended for transfusion.

We also invite comment on how the proposed rule might affect hospitals where patients receive blood or blood components

from which the aspirate is taken must have affixed to it a label containing the required machine-readable information. This would be consistent with the pre-existing requirement at § 606.121(c)(8)(iii) that requires specific statements if a product is intended for transfusion.

We also invite comment on how the proposed rule might affect hospitals where patients receive blood or blood components. Specifically, we want to hear how the proposal might affect a hospital's decision to purchase a machine reader (e.g., scanner) that properly identifies the intended recipient of the blood or blood component. To prevent medical errors, this machine reader would need to be compatible with the machine readable information encoded on the blood or blood component label, yet a hospital's purchasing decision might also be influenced by the bar codes appearing

We intend to make a machine-readable information requirement effective for blood and blood components 3 years after we publish a final rule in the Federal Register . Changes to existing blood and blood component labels would require the submission of an annual report as described in 21 CFR 601.12(f)(3).

I. What Bar Code Requirement Would Apply to Biological Products? (Proposed § 610.67)

The proposal would create a new § 610.67 that describes a new labeling requirement for biological products (other than blood and blood products, which would be covered by proposed § 606.121(c)(13)). Proposed § 610.67 would simply state that biological products must be labeled in accordance with the bar code requirements at § 201.25. In addition to the separate authority provided by section 351(j) of the Public Health Service Act, the Federal Food, Drug, and Cosmetic Act also applies to a biological product that is regulated under section 351 of the Public Health Service Act.

The proposal would not apply to biological products that are regulated as devices for the reasons we stated earlier in section II.B.2.d of this document.

III

ion to the separate authority provided by section 351(j) of the Public Health Service Act, the Federal Food, Drug, and Cosmetic Act also applies to a biological product that is regulated under section 351 of the Public Health Service Act.

The proposal would not apply to biological products that are regulated as devices for the reasons we stated earlier in section II.B.2.d of this document.

III. Legal Authority

We believe we have the authority to impose a bar coding requirement for the efficient enforcement of various sections of the act. These include sections 201(n), 201(p), 501, 502, 503, 505, and 701(a)) (21 U.S.C. 321(n), 321(p), 351, 352, 353, 355, and 371(a)) of the act, and sections 351 and 361 of the Public Health Services Act.

A bar coding requirement for drugs would permit the efficient enforcement of the misbranding provisions in section 502(a) and (f) of the act, as well as the safety and effectiveness provisions of sections 201(p) and 505 of the act. Bar coding is expected to significantly advance: (1) The provision of adequate directions for use to persons prescribing, dispensing, and administering the drug; (2) the provision of adequate warnings against use by patients where a drug's use may be dangerous to health; and (3) the prevention of unsafe use of prescription drugs.

Section 502(a) of the act prohibits false or misleading labeling of drugs. This prohibition includes, under section 201(n) of the act, failure to reveal material facts relating to potential consequences under customary conditions of use. Information in a database that could be readily accessed through the use of a bar code, such as the drug strength, dosage form, route of administration, and active ingredient and drug interactions is material with respect to consequences which might result from use of the drug under such conditions of use

o reveal material facts relating to potential consequences under customary conditions of use. Information in a database that could be readily accessed through the use of a bar code, such as the drug strength, dosage form, route of administration, and active ingredient and drug interactions is material with respect to consequences which might result from use of the drug under such conditions of use. Because all the drugs (prescription drugs and the subset of covered OTC drugs) covered by this proposal may be used in the hospital setting, such use in hospitals can be considered the “conditions of use as are customary or usual.” As is made clear in section I of this document, bar coding can be expected to reduce the incidence of the following types of medication errors:

• Administering the wrong dose to a patient;

• Administering a drug to a patient who is known to be allergic;

• Administering the wrong drug to a patient or administering a drug to the wrong patient;

• Administering the drug incorrectly;

• Administering the drug at the wrong time; and

• Missing or duplicating doses.

Because information accessed through use of the bar code will reveal material facts relating to potential consequences under customary conditions of use, the bar code requirements are justified under section 502(a) of the act.

Section 502(f) of the act requires drug labeling to have adequate directions for use, adequate warnings against use by patients where its use may be dangerous to health, as well as adequate warnings against unsafe dosage or methods or duration of administration, in such manner and form, as necessary to protect users. The bar code would make it easier for the person administering the drug to have full access to all of the drug's labeling information, including directions for use, warnings and contraindications

e by patients where its use may be dangerous to health, as well as adequate warnings against unsafe dosage or methods or duration of administration, in such manner and form, as necessary to protect users. The bar code would make it easier for the person administering the drug to have full access to all of the drug's labeling information, including directions for use, warnings and contraindications. Moreover, because the bar code's information would go to the computer where it could be compared against the patient's drug regimen and medical record, the person administering the drug will be able to determine whether the right patient is receiving the right drug (including the right dose of that drug in the right route of administration) at the right time. The person administering the drug will also be able to avoid giving products to a patient who might be allergic to, or otherwise unable to take, a particular drug. Because the bar code will facilitate access to information including adequate directions for use and adequate warnings, the bar code requirements are justified under section 502(f) of the act.

In addition to the misbranding provisions, the premarket approval provisions of the act authorize FDA to require that prescription drug labeling provide the practitioner with adequate information to permit safe and effective use of the drug product. Under section 505 of the act, we will approve a new drug application (NDA) only if the drug is shown to be safe and effective for its intended use under the conditions set forth in the drug's labeling. Bar coding will ensure the safe and effective use of drugs by reducing the number of medication errors in hospitals and other health care settings. Such coding would allow health care professionals to use bar code scanning equipment to verify that the right drug (in the right dose and right route of administration) is given to the right patient at the right time

s set forth in the drug's labeling. Bar coding will ensure the safe and effective use of drugs by reducing the number of medication errors in hospitals and other health care settings. Such coding would allow health care professionals to use bar code scanning equipment to verify that the right drug (in the right dose and right route of administration) is given to the right patient at the right time.

Section 505(b)(1)(D) of the act requires a new drug application to contain a full description of the methods used in, and the facilities and controls used for, the manufacture, processing, and packing of such drug. The same requirement exists for abbreviated new drug applications (see section 505(j)(2)(A)(vi) of the act) and for biological products (see section 351(a)(2)(B)(i)(II) of the Public Health Service Act). Information in the bar code would reflect the facilities and controls used to manufacture the product. As described in section II.C.1 of this document, the NDC number would identify the manufacturer, product, and package.

A bar coding requirement also would permit the efficient enforcement of the adulteration provisions of the act. A regulation requiring the bar coding of products should avert unintentional mix up and mislabeling of drugs during labeling, packaging, relabeling, and repackaging. A bar coding requirement therefore prevents adulteration under section 501(a)(2)(B) of the act. It is a manufacturing method or control necessary to ensure that a drug product has the identity and strength its labeling represents it to have, and meets the quality and purity characteristics which the drug purports or is represented to possess.

Requiring that the bar code be surrounded by sufficient blank space, and remain intact under normal conditions of use, would also further the efficient enforcement of section 502(c) of the act

essary to ensure that a drug product has the identity and strength its labeling represents it to have, and meets the quality and purity characteristics which the drug purports or is represented to possess.

Requiring that the bar code be surrounded by sufficient blank space, and remain intact under normal conditions of use, would also further the efficient enforcement of section 502(c) of the act. Section 502(c) of the act provides that a drug product is misbranded if: Any word, statement, or other information required by or under authority of this Act to appear on the label or labeling is not prominently placed thereon with such conspicuousness (as compared with

Because biological products, including blood, are also prescription drug products, the sections of the act discussed elsewhere in this legal authority section provide ample legal authority for promulgating a regulation requiring bar coding for such biological products. There is, however, additional legal authority for the rule's requirements as to biological products. Section 351 of the Public Health Service Act authorizes the imposition of restrictions through regulations “designed to insure the continued safety, purity, and potency” (including effectiveness) of the products. Biological product licenses are to be “issued, suspended, and revoked as prescribed by regulations” (42 U.S.C. 262(d)(1); see §§ 601.4 through 601.6). The bar code requirement for biological drugs, and the machine-readable information requirement for blood and blood products, is designed to insure the continued safe and effective use of licensed biological products. Therefore, if this rule were finalized, we may refuse to approve biologics license applications (BLAs), or may revoke already approved licenses, for biological drug products that do not have such codes.

Additionally, section 361 of the Public Health Service Act authorizes regulations necessary to prevent the introduction, transmission, or spread of communicable diseases

nsed biological products. Therefore, if this rule were finalized, we may refuse to approve biologics license applications (BLAs), or may revoke already approved licenses, for biological drug products that do not have such codes.

Additionally, section 361 of the Public Health Service Act authorizes regulations necessary to prevent the introduction, transmission, or spread of communicable diseases. With specific regard to blood and blood products, the requirement for machine readable information will aid in the recall, quarantine and retrieval of units that are at risk of spreading communicable diseases.

After the effective date of any final rule, if a product required by the final rule to bear a bar code does not have such a bar code, the product may be considered adulterated or misbranded under the act and would be subject to regulatory action. Our enforcement actions under the act include seizure, injunction, and prosecution, and violation may result in withdrawal of an NDA or BLA.

IV. Environmental Impact

We have determined under 21 CFR 25.30(h) and 25.30(k) that this action is of a type that does not individually or cumulatively have a significant effect on the human environment. Therefore, neither an environmental assessment nor an environmental impact statement is required.

V. Paperwork Reduction Act of 1995

This proposed rule contains information collection requirements that are subject to public comment and review by the Office of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). We describe the provisions in this section of the document with an estimate of the annual reporting burden. Our estimate includes the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing each collection of information

e of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). We describe the provisions in this section of the document with an estimate of the annual reporting burden. Our estimate includes the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing each collection of information.

We invite comments on: (1) Whether the collection of information is necessary for the proper performance of FDA's functions, including whether the information will have practical utility; (2) the accuracy of FDA's estimate of the burden of the proposed collection of information, including the validity of the methodology and assumptions used; (3) ways to enhance the quality, utility, and clarity of the information to be collected; and (4) ways to minimize the burden of the collection of information on respondents, including through the use of automated collection techniques, when appropriate, and other forms of information technology.

Title : Bar Code Label Requirement for Human Drug Products and Blood.

Description : We are proposing a new rule that would require human drug product and biological product labels to have bar codes. The proposed rule would require bar codes on human prescription drug products and OTC drug products that are dispensed pursuant to an order and commonly used in hospitals and would require machine-readable information on blood and blood components. For human prescription drug products and OTC drug products that are dispensed pursuant to an order and commonly used in hospitals, the bar code would contain the National Drug Code for the product. For blood and blood components, the proposed rule would specify the minimum contents of the machine-readable information approved by the Director of the Center for Biologics Evaluation and Research as blood centers have generally agreed upon the information to be encoded on the label

uant to an order and commonly used in hospitals, the bar code would contain the National Drug Code for the product. For blood and blood components, the proposed rule would specify the minimum contents of the machine-readable information approved by the Director of the Center for Biologics Evaluation and Research as blood centers have generally agreed upon the information to be encoded on the label. The proposed rule would help reduce the number of medication errors in hospitals and other health care settings by allowing health care professionals to use bar code scanning equipment to verify that the right drug (in the right dose and right route of administration) is being given to the right patient at the right time.

Because the Center for Drug Evaluation and Research would have bar code information for drugs subject to a new drug application or abbreviated new drug application to be reported through an annual report, this proposed rule affects the reporting burden associated with § 314.81(b)(2)(iii) (21 CFR 314.81(b)(2)(iii)). Section 314.81(b)(2)(iii) requires the submission of an annual report containing a representative sample of package labels and a summary of labeling changes (or, if no changes have been made, a statement to that effect) since the previous report. Here, the bar code would result in a labeling change. We have previously estimated the reporting burden for submitting labels as currently required under § 314.81(b)(2)(iii), and OMB has approved the collection of information until March 31, 2005 under OMB control number 0910-0001. We are not re-estimating these approved burdens in this rulemaking; we are only estimating the additional reporting burdens associated with the submission of label changes under § 314.81(b)(2)(iii).

urdens in this rulemaking; we are only estimating the additional reporting burdens associated with the submission of label changes under § 314.81(b)(2)(iii).

Minor label changes for blood and blood products may be reported as part of an annual report, as described in 21 CFR 601.12(f)(3), and we would consider the machine-readable information on blood and blood product labels to be a minor change. We have previously estimated the reporting burden for submitting labels as currently required under § 601.12(f)(3), and OMB has approved the collection of information until August 31, 2005 under OMB control number 0910-3338. We are not re-estimating these approved burdens in this rulemaking; we are only estimating the additional reporting burdens associated with the submission of label changes under § 601.12(f)(3).

Description of Respondents : Persons who manufacture, repackage, or relabel prescription drug products or OTC drugs that are dispensed pursuant to an order and commonly used in hospitals, and blood establishments.

We estimate the burden of this collection of information as follows:

Table 1.— Estimated Annual Reporting Burden 1 21 CFR Section No. of Respondents Frequency of Responses Total Annual Responses Hours per Response Total Hours § 201.25, § 610.67 1,447 31.1 45,000 24 hrs. 1,080,000 § 314.81(b)(2)(iii) 1,447 5.9 8,576 10.5 min. 1,497 § 601.12(f)(3) 211 1 211 1 min. 3.5 § 606.121(c)(13) 981 42,507.7 41.7 million 1 min. 695,000 Total 1,776,590.5 1 There are no capital costs or operating and maintenance costs associated with this collection of information. Our estimates are based on the following assumptions.

are based on the following assumptions.

• For prescription drugs (including prescription biologics and vaccines) and OTC drugs subject to the bar code requirement, information from our own records indicates that there are 1,447 establishments that would be affected by a bar code requirement, and there are approximately 89,800 separate, identifiable product packages subject to this proposed rule. We expect that half of the packages (45,000) would need redesigned labels to comply with a bar code requirement because they do not currently use coded NDC numbers. This means that the annual frequency of reports, under proposed § 201.25 (and proposed § 610.67 for biological products not regulated as devices), would be 31.1 (45,000 package labels requiring a bar code/1,447 establishments = 31.09 packages per establishment, which we have rounded up to 31.1). Consultations with industry sources suggest that the number of hours per response to redesign a package label to include bar coded information to comply with this regulation is approximately 24 hours. Therefore, the total burden hours for proposed § 201.25 and § 610.67 would be 1,080,000 hours (45,000 packages x 24 hours per package label = 1,080,000 hours).

• For prescription drugs whose label changes would be reported in an annual report under § 314.81 or under § 601.12(f)(3) for biological products), there are approximately 1,447 registered establishments that would be reporting. Information on listed drugs indicates there are 89,800 separate, identifiable product packages that will comply with the proposed bar code requirement. These packages account for 8,576 separate and distinct products (each product is marketed in an average of 10.47 packaging variations). This means that the annual frequency of reports would be 5.9 (8,576 products subject to annual reports/1,453 registered establishments = 5.92 products per registered establishment, which we have rounded down to 5.9)

l comply with the proposed bar code requirement. These packages account for 8,576 separate and distinct products (each product is marketed in an average of 10.47 packaging variations). This means that the annual frequency of reports would be 5.9 (8,576 products subject to annual reports/1,453 registered establishments = 5.92 products per registered establishment, which we have rounded down to 5.9). Section 314.81(b)(2)(iii) requires firms to submit an annual report that includes a summary of any changes in labeling since the last annual report. Similarly, § 601.12(f)(3)(I)(A) requires manufacturers of biologics to include in their annual reports editorial or similar minor labeling changes. We expect that the addition of a bar code to a label would necessitate a simple statement in the annual report declaring that the bar code has been added, so we have assigned an estimate of one minute for such statements per label. Each product's annual report would include labels for all packaging variations. Thus, the total reporting burden would be 1,496.67 hours ((8,576 reports x 10.47 labels (or one label per packaging variation) per report x 1 minute per report)/60 minutes per hour = 1,496.67 hours), which we have rounded up to 1,497 hours.

• For minor labeling changes for blood and blood components included in an annual report under § 601.12(f)(3)(i)(A), FDA's database indicates there are 211 licensed blood and blood component manufacturers. We expect that the addition of machine-readable information to the label of blood and blood components would necessitate a simple statement in the annual report declaring that the machine-readable information has been added, so we have assigned an estimate of one minute for such statements. Thus, the total reporting burden would be 3.5 hours ((211 reports x 1 minute per report)/60 minutes per hour = 3.516 hours), which we have rounded down to 3.5 hours

ion to the label of blood and blood components would necessitate a simple statement in the annual report declaring that the machine-readable information has been added, so we have assigned an estimate of one minute for such statements. Thus, the total reporting burden would be 3.5 hours ((211 reports x 1 minute per report)/60 minutes per hour = 3.516 hours), which we have rounded down to 3.5 hours.

• For the requirement in proposed § 601.121(c)(13) to include machine-readable information on blood and blood components, FDA's registration database indicates there are 981 blood and plasma establishments. The American Association of Blood Banks estimates that approximately 13.9 million blood donations are collected annually. We estimate that each blood donation yields approximately three blood components. This means that the frequency of responses is approximately 41.7 million occurrences (13.9 million blood donations x three blood components per donation) divided by 981 establishments or 42,507.645 occurrences per establishment, which we have rounded up to 42,507.7. We estimate that it takes 1 minute to apply a machine-readable code manually; if a blood collection facility uses an on-demand printer, the time would range between 15 to 30 seconds. For purposes of this estimate, we adopt the larger time estimate of 1 minute per machine-readable information for blood, thus resulting in an annual reporting burden of 695,000 hours ((41.7 million reports x one minute per report) /60 minutes per hour = 695,000 hours). However, we reiterate that facilities using on-demand printers would face lower burdens. In addition, blood collection centers are currently allowed and encouraged to apply machine readable information to collections. This burden estimate accounts for requiring an activity that is currently voluntary and does not reflect an additional activity.

In compliance with the Paperwork Reduction Act of 1995 (44 U.S.C

eiterate that facilities using on-demand printers would face lower burdens. In addition, blood collection centers are currently allowed and encouraged to apply machine readable information to collections. This burden estimate accounts for requiring an activity that is currently voluntary and does not reflect an additional activity.

In compliance with the Paperwork Reduction Act of 1995 (44 U.S.C. 3507(d)), we have submitted the information collection requirements of this rule to OMB for review. Interested persons are requested to fax comments regarding information collection by April 14, 2003, to the Office of Information and Regulatory Affairs, OMB (see ADDRESSES ).

VI. Executive Order 13132: Federalism

We have analyzed this proposed rule in accordance with the principles set forth in Executive Order 13132. We have determined that the rule does not contain policies that have substantial direct effects on the States, on the relationship between National Government and the States, or on the distribution of power and responsibilities among the various levels of government. Accordingly, we have concluded that the rule does not contain policies that have federalism implications as defined in the order and, consequently, a federalism summary impact statement is not required.

VII. Analysis of Impacts

A. Introduction

We have examined the proposed rule under Executive Order 12866, the Regulatory Flexibility Act as amended by the Small Business Regulatory Enforcement Fairness Act, the Unfunded Mandates Reform Act, and the Congressional Review Act. Executive Order 12866 directs agencies to assess all costs and benefits of available regulatory alternatives and, when regulation is necessary, to select regulatory approaches that maximize net benefits (including potential economic, environmental, public health and safety, distributive impacts and equity)

nforcement Fairness Act, the Unfunded Mandates Reform Act, and the Congressional Review Act. Executive Order 12866 directs agencies to assess all costs and benefits of available regulatory alternatives and, when regulation is necessary, to select regulatory approaches that maximize net benefits (including potential economic, environmental, public health and safety, distributive impacts and equity). Under the Regulatory Flexibility Act (as amended by the Small Business Regulatory Enforcement Fairness Act), if a regulation has a significant economic impact on a substantial number of small entities, we must analyze regulatory options that would minimize the impact on small entities. Section 202(a) of the Unfunded Mandates Reform Act requires that agencies prepare a written statement of anticipated costs and benefits before proposing any regulation that may result in expenditure by State, local, and tribal governments, or by the private sector of $100 million in any one year (adjusted annually for inflation). Currently, such a statement is required if costs exceed about $110 million for any one year. The Congressional Review Act requires that regulations determined to be major must be submitted to Congress before taking effect.

The proposed rule is consistent with the principles set forth in Executive Order 12866 and the three statutes. We have identified the proposed rule as an economically significant regulatory action, as defined in Executive Order 12866. We believe the proposed rule is unlikely to have a significant impact on a substantial number of small entities. The expected cost of this proposed rule is greater than $110 million in a single year and therefore is considered a major regulatory action as defined by the Unfunded Mandates Reform Act. The Office of Information and Regulatory Affairs (OIRA) in the Office of Management and Budget (OMB) has determined this proposed rule to be major under the Congressional Review Act.

We contracted with the Eastern Research Group, Inc

is proposed rule is greater than $110 million in a single year and therefore is considered a major regulatory action as defined by the Unfunded Mandates Reform Act. The Office of Information and Regulatory Affairs (OIRA) in the Office of Management and Budget (OMB) has determined this proposed rule to be major under the Congressional Review Act.

We contracted with the Eastern Research Group, Inc. (ERG), to collect data, interview industry experts, and analyze the costs and benefits of the proposed rule. The detailed analyses and references in support of the impacts summarized in Table 2 are included in the docket as Reference 46.

Table 2.— Estimated Impacts of the Proposed Rule (in Millions of Dollars) (Over 20-Year Period at 7-Percent Discount Rate) Impacts Regulatory Costs Anticipated Hospital Costs 1 Societal Benefits 2 Potential Hospital Efficiencies 3 Net Benefits (benefits minus costs) 4 Present Value $53.1 $7,204.3 $41,381.3 $4,783.3-$7,643.0 $34,123.9 Annualized $5.1 $680.0 $3,906.1 $451.5-$721.5 $3,221.0 1 Costs due to voluntary accelerated purchase and utilization of bar coding systems. 2 Benefits to public health due to avoidance of adverse drug events. 3 Potential efficiencies in reports, records, inventory, and other hospital activities. 4 Net benefits include only public health benefits of increased patient safety. Table 2 presents the total expected regulatory costs to manufacturers, repackers, relabelers, retail outlets, and FDA. Most of these costs will occur during the first several years after implementation. Table 2 also shows the estimated opportunity costs of the expected accelerated investment in bar coding systems by the health care sector. These investment expenditures are necessary to achieve the societal benefits expected from the proposed rule. Table 2 also shows our estimated range of possible efficiencies in hospital activities associated with accelerated adoption of technology

plementation. Table 2 also shows the estimated opportunity costs of the expected accelerated investment in bar coding systems by the health care sector. These investment expenditures are necessary to achieve the societal benefits expected from the proposed rule. Table 2 also shows our estimated range of possible efficiencies in hospital activities associated with accelerated adoption of technology. Both anticipated hospital costs and societal benefits would occur after hospitals purchase and install the necessary equipment to take advantage of bar codes. The net benefit figure is the societal benefit minus the induced expenditures minus the regulatory costs. This estimate, however, accounts for neither potential hospital efficiencies, nor income transfers to hospitals following fewer awards for medical malpractice.

B. Objective of the Proposed Rule

The objective of the proposed rule is to enable the health care sector to utilize technological solutions to reduce preventable adverse drug events (ADEs) 2 associated with medication errors 3 in hospitals. 4

2 For this analysis, an adverse drug event (ADE) is an injury from a medicine (or a lack of an intended medicine). (source: American Society of Hospital Pharmacists, 1998)

3 For this analysis, a medication error is a preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the health care professional, patient, or consumer. (source: NCCMERP, 2002)

4 For this analysis, a hospital is a facility that provides medical, diagnostic, and treatment services that include physician, nursing, and other health services to inpatients and the specialized accommodation services required by inpatients. (source: NAICS, 2002)

C. Estimate of Risk/Risk Assessment

In 1999, the Institute of Medicine (IOM) issued a report that drew public attention to the number of deaths that occur each year in the United States from preventable medication errors in hospitals

that include physician, nursing, and other health services to inpatients and the specialized accommodation services required by inpatients. (source: NAICS, 2002)

C. Estimate of Risk/Risk Assessment

In 1999, the Institute of Medicine (IOM) issued a report that drew public attention to the number of deaths that occur each year in the United States from preventable medication errors in hospitals. A significant proportion of the reported deaths, as well as the additional illnesses and morbidities, were associated with errors involving FDA-regulated products, especially medications. This section briefly describes the agency's efforts to estimate the current number of preventable ADEs.

The public health literature includes many attempts to determine the rate of preventable ADEs in United States hospitals, although these studies typically employed varying methodologies and definitions. Our methodology begins by multiplying estimated hospital admissions by reported rates of ADEs per admission. We combined the resulting number of ADEs per hospital per year with the reported ratio of preventable to total ADEs to estimate the number of preventable ADEs per hospital per year. We first developed these calculations for various hospital size classes and then aggregated the data to present national estimates. We relied on published literature to derive ADE rates for each major stage of the medication process in hospitals.

ERG identified four comparable published studies that reported rates of ADEs per hospital admissions (Bates et al., 1995, Classen et al., 1997, Jha et al., 5 are either intercepted before reaching the patient or do not cause an injury. According to projected increases in hospital expenditures and population demographics that imply future increases in hospital admissions, the annual number of ADEs could triple within 20 years.

5 A potential ADE is a medication error that could have caused an ADE, but did not. Potential ADEs include medication errors that were intercepted before reaching the patient

nt or do not cause an injury. According to projected increases in hospital expenditures and population demographics that imply future increases in hospital admissions, the annual number of ADEs could triple within 20 years.

5 A potential ADE is a medication error that could have caused an ADE, but did not. Potential ADEs include medication errors that were intercepted before reaching the patient. Potential ADEs include any errors that do not involve patients.

ERG searched the public health literature to identify stages in the hospital medication process in which errors occur and concluded that the medication stages of prescribing, transcribing, dispensing, and administration provide a useful analytic structure. The m

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