prescription drug label requirements
216, 241, 262, 263, 264; sec 122, Pub. Although our analysis did not separate administrative costs from other labeling design costs, the agency anticipated that manufacturers would require some “detailed discussions and drug-specific decisions” during the design phase of labeling (e.g., regarding exactly which adverse reactions should be listed in Highlights) (65 FR 81082 at 81106). the Federal Register. The comment asked if the combined document would satisfy the requirement to distribute the FDA-approved patient labeling to patients who have been prescribed the drug. The Supreme Court has held that certain State law requirements that parallel FDA requirements may not be preempted (Medtronic, Inc. v. Lohr, 518 U.S. 470, 495 (1996) (holding that the presence of a State law damages remedy for violations of FDA requirements does not impose an additional requirement upon medical device manufacturers but “merely provides another reason for manufacturers to comply with * * * federal law”); id. 32). Two comments stated that a bold approval date might be more informative than the inverted black triangle. (iv) Special handling and storage conditions. (See Zauderer v. Office of Disciplinary Counsel, 471 U.S. 626, 651 (1985); see also Ibanez v. Florida Dep't of Bus. Furthermore, approximately half of the affected products shown in table 14 will be new approvals that have not yet established packaging. The agency also proposed to implement by 1 year after the effective date of the final rule the requirement that in vitro or animal data related to activity or efficacy of a drug that have not been shown by adequate and well-controlled studies to be pertinent to clinical use be removed from the labeling unless a waiver is granted. U.S. Census Bureau, “Statistics of U.S. 36), sales representatives normally leave one piece of labeling for every 10 samples they distribute. (Comment 5) Several comments stated that there should be more specific criteria for selecting information for inclusion in Highlights to ensure consistency for all drug products. (Comment 31) Some comments recommended that only the manufacturer's phone number be included in prescription drug labeling, while others agreed that including the MedWatch phone number is important because manufacturers' phone numbers are subject to change. c. Costs associated with producing longer labeling accompanying drug products and drug samples (trade labeling). The comment maintained that inconsistent information about indications and dosing creates confusion and contributes to uncertainty and distrust of information in the labeling. In such cases, the agency may waive the one-half page requirement and approve the labeling with slightly longer Highlights. Unless directed otherwise by the prescribing physician, when the pharmacist dispenses a substitute generic drug, he or she must label the prescription container with the name of that drug and the name of the drug manufacturer or distributor Nov. 16, 2000). When new information comes to light that causes information in labeling to become inaccurate, manufacturers must act to change the content of their labeling, in accordance with §§ 314.70 and 601.12 (21 CFR 314.70 and 21 CFR 601.12). Practitioners who, for good reason, do not wish to reveal the name or strength of the drug prescribed to the patient shall so inform the pharmacist by a notation on the face of the prescription. (v) 8.5 Geriatric use. In most cases, frequency information is paramount, but in other cases, severity information may be more important or a combination of Start Printed Page 3950the two may be the best approach. In contrast, manufacturers submitting efficacy supplements or having existing labeling for drug products affected by the final rule will need to determine if their redesigned trade labeling fits on or within existing packaging. The agency also recognizes that there exists considerable inconsistency in how information in this section is organized and presented across different drug products. For these reasons, the agency believes the implementation as proposed is the most reasonable approach to maximizing the public health benefit and best utilizing available resources in requiring the new content and format for labeling. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. A small number of carton-enclosed products may require new packaging to accommodate longer inserts (see section XI.D.2.c and comment 124 of this document). If animal reproduction studies are also available and they fail to demonstrate a risk to the fetus, the labeling must also state: “Reproduction studies have been performed in (kinds of animal(s)) at doses up to (x) times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to (name of drug).” The labeling must also contain a description of available data on the effect of the drug on the later growth, development, and functional maturation of the child. For trade labeling, this will be a minimum type size of 6 points (see response to comment 102 for discussion of 6-point minimum type size for trade labeling for products subject to § 201.57). The agency has reconsidered its proposal to exclude from the “Clinical Pharmacology” section in vitro data for anti-infectives that are not supported by clinical data. Comments, including one by an expert in human cognition, supported Highlights as a way to improve the accessibility of the most heavily used information (see comment 2). Because the contact information is featured prominently in Highlights—bolded and set apart from other information—the agency believes that this is sufficient to make practitioners aware of the appropriate contacts to report adverse reactions and to encourage them to report suspected adverse reactions. One comment stated that pharmacists frequently access this section for information about storage conditions and that it would be more appropriate to place the section just before the “Patient Counseling Information” near the end of the labeling, where pharmacists are accustomed to finding it. (iv) For manufacturers with a Web site for voluntary reporting of adverse reactions, the Web address of the direct link to the site. (1) Boxed warning. One comment suggested that manufacturers be given the option to revise labeling for older products. State actions are not characterized by centralized expert evaluation of drug regulatory issues. Some comments expressed concern that having different labeling formats would be confusing to physicians. This information includes detailed results from controlled studies that are available to the sponsor and pertinent information from well-documented studies obtained from a literature search. (ii) Any discussion of a clinical study that relates to a risk from the use of the drug must also refer to the other sections of the labeling where the risk is identified or discussed. One comment stated that patient information typically uses larger fonts and may use color and illustrations, making it difficult and costly to reprint in the prescription drug labeling. If representative, these findings suggest that the average pharmacist in the United States seeks information from prescription drug labeling at least 257 times each year.13 To put this estimate in perspective, approximately 2.85 billion prescriptions were dispensed by retail pharmacies in 2001 (Ref. 11, p. 35). (Comment 32) Two comments stated that all adverse reactions should be reported, and not just serious adverse reactions. Authority: One comment recommended that the implementation plan also apply to all drugs that are among the 150 most frequently prescribed drugs that would not otherwise be covered by the implementation plan. Manufacturers must not speculate in labeling. On the basis of a series of national telephone surveys conducted by FDA to assess how patients receive information about their prescription medicines, the agency determined that the prescribing physician is the primary source of drug information for patients (Ref. Adding contact information where practitioners can report suspected adverse reactions will facilitate the collection of drug safety information and make it easier for the agency and manufacturers to identify significant safety concerns that can emerge after a drug is marketed and a much larger population is exposed to the product. Within a listing, adverse reactions must be categorized by body system, by severity of the reaction, or in order of decreasing frequency, or by a combination of these, as appropriate. 321(m)) and is subject to all applicable provisions of section 502 of the act (21 U.S.C. The current inflation-adjusted statutory threshold is about $115 million. documents in the last year, 67 (Comment 9) One comment requested that the sections in Highlights be reordered to lend more prominence to risk information. (3) Omit clearly inapplicable sections, subsections, or specific information. [4] (Comment 124) Some comments argued that FDA's estimate significantly underestimates increased costs for trade packaging, shipping containers, and new packaging and shipping equipment to accommodate the larger labeling that will result from the new format. The frequency of all clinically significant adverse reactions and the approximate mortality and morbidity rates for patients experiencing the reaction, if known and necessary for the safe and effective use of the drug, must be expressed as provided under paragraph (c)(7) of this section. In FDA's survey of physicians, newness of the product was the factor most often rated by physicians as “very likely” to trigger referral to prescription drug labeling (Ref. 6. Reverse type is not permitted as a form of highlighting. The agency also agrees that color printing would add cost and impose an additional burden on manufacturers that would not be offset by meaningful improvement in visual prominence. Thus, in practice, manufacturers typically consult with FDA prior to adding risk information to labeling. For example, the ways in which information will be formatted, tagged, and stored in the contemplated electronic format will permit access to labeling information in both the old and new labeling formats. The agency also considered requiring larger minimum type sizes. New Documents Thus, the agency has revised proposed § 201.57(c)(9) (designated in this final rule as § 201.57(c)(7)) to require such information in the “Adverse Reactions” section. A concise summary of the information required under paragraph (c)(9) of this section, with any appropriate subheadings. Not all of these costs to manufacturers are social costs, as the PDR publisher is presumably selling additional pages at more than its true opportunity cost. FDA believes that complete information about how to adjust dosages for various specific populations would in many cases require a great deal of space. App. Example 2—Add printed patient information to existing labeling for a product: This feature is not available for this document. There was concern that the significance of the adverse reactions discussed in the “Warnings and Precautions” section would be diluted by the inclusion of less serious adverse reactions in the section, thus undermining the value of the section. After careful consideration of the comments, FDA has revised the proposal and is issuing this final rule. Create a free website or blog at WordPress.com. Sections 201.56(d)(1), 201.57(a)(4), and (c)(1) of the final rule have been revised to remove the requirement. FDA allows each manufacturer some flexibility to determine the size and shape of a product's trade labeling and packaging. Therefore, practitioners expend time that could be spent with patients and may miss critical information about the safe and effective use of prescription drug products. FDA also proposed certain revisions to the requirements governing the content of labeling to help ensure that statements appearing in labeling related to effectiveness or dosage and administration are sufficiently supported. (Comment 15) Several comments opposed, or expressed reservations about, the use of an inverted black triangle to identify a product, indication, or dosage form that has been approved for less than 3 years. The agency estimates approximately 38 hours per product as a one-time labeling revision, totaling 3,040 hours (see row 4 of table 8b). If the final rule reduced these costs by even 1 percent, between $40 million and $48 million of the costs of hospitalization could be prevented each year. The box must briefly explain the risk and refer to more detailed information in the “Contraindications” or “Warnings and Precautions” section, accompanied by the identifying number for the section or subsection containing the detailed information. Where it is not possible to present an informative or useful statement about the recommended or usual dosage in the space available on the container label, current § 201.55 states that the requirements of § 201.100(b)(2) may be met by including the statement “See package insert for dosage information.” The agency proposed to eliminate § 201.55. Labeling changes to the FPI to add or strengthen a warning, precaution, contraindication, or adverse reaction statement are within the Start Printed Page 3969category of changes for which CBE supplements are required by FDA regulations (§§ 314.70(c)(6)(iii) and 601.12(f)(2)(i)) (see comment 5). 356b).). The agency also proposed to require in proposed § 201.57(c)(17) that any approved printed patient information or Medication Guide be referenced in the “Patient Counseling Information” section and that the full text of the approved printed patient information or Medication Guide be reprinted immediately following the section. Comments maintained that such information can be important to a practitioner's understanding of a product's clinical and safety profile, as well as to an understanding of the approved indication. The agency continues to believe strongly in the goals of the inverted black triangle—to help ensure that prescribers use a product with particular care during its initial years of marketing and to make prescribers more diligent in reporting suspected adverse reactions for newer products. The Public Inspection page FDA continuously works to evaluate the latest available scientific information to monitor the safety of products and to incorporate information into the product's labeling when appropriate. The initial U.S. approval date will alert practitioners to newer products that should be used with greater vigilance. Procedures necessary to diagnose the dependent state and the principles of treating the effects of abrupt withdrawal must be described. Some comments stated that the length restriction should be flexible enough to accommodate as many disclaimers and qualifying messages as are necessary to guide the physician to the more detailed discussion of the desired information in the FPI. The upper limit beyond which safety and effectiveness have not been established would ordinarily refer to: (1) The largest dose demonstrated to be safe and effective in controlled clinical trials, (2) the largest dose evaluated that showed an increase in effectiveness (i.e., where studied larger doses provided no additional benefit), or (3) the largest dose beyond which safety has not been established or an unacceptable risk has been demonstrated. The agency also proposed to revise certain required warning language in the labeling of drugs in pregnancy categories D and X (proposed § 201.57(c)(8)(i)(A)(4) and (c)(8)(i)(A)(5)). Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. If data that include dosage regimens other than recommended regimens are discussed in the “Clinical Studies” section, the data must be accompanied by a statement appropriately qualifying the data and indicating that those dosage regimens have not been found safe and effective by FDA, if such a statement is necessary for the labeling to be truthful and not misleading. They asserted that there is a high likelihood that Highlights would be the only part of the labeling read by practitioners. Authority: FDA proposed to permit references to be included in labeling in place of a detailed discussion of a subject that is of limited interest, but nonetheless important (proposed § 201.57(c)(16)). Over 10 years, the present value of these avoided costs would total from $240 million to $290 million with a 7 percent discount rate, and from $300 to $360 with a 3 percent discount rate (table 11). 21 U.S.C. The agency agrees that it is important for the “Adverse Reactions” section to call attention to adverse reactions for which there are clinically significant dose-response relationships. Highlights presents a succinct summary of the information in the FPI that is most crucial for safe and effective use, with cross-references to direct prescribers to more details in the FPI. (1) The following categories of prescription drug products are subject to the labeling requirements in paragraph (d) of this section and § 201.57 in accordance with the implementation schedule in paragraph (c) of this section: (i) Prescription drug products for which a new drug application (NDA), biologics license application (BLA), or efficacy supplement was approved by the Food and Drug Administration (FDA) between June 30, 2001 and June 30, 2006; (ii) Prescription drug products for which an NDA, BLA, or efficacy supplement is pending on June 30, 2006; or, (iii) Prescription drug products for which an NDA, BLA, or efficacy supplement is submitted anytime on or after June 30, 2006.Start Printed Page 3987. 38. (Comment 36) Most comments supported inclusion of an index (hereafter Contents). In contrast to trade labeling, with the new content and format requirements the length of current labeling will increase an average of about 93 percent when printed in 8-point type size. See ‘Contraindications’ section.” Under “Contraindications,” the labeling must state: “(Name of drug) may (can) cause fetal harm when administered to a pregnant woman. Although the effectiveness of the revised labeling in achieving time savings and reductions in adverse reactions is uncertain, based on the following analysis as summarized in table 9, FDA projects that the present value of the quantifiable benefits of the final rule over 10 years range from $330 million to $380 million and from $420 million to $480 million at a 7 and 3 percent discount rate, respectively. Products in the second category must file supplemental applications within 3 to 7 years of the issuance of the rule, according to the implementation plan described in the preamble (see Table 5). Whether a specific statement required by regulation must appear in Highlights will be determined by the agency. In addition, FDA also clarified that its authority under this provision must be exercised in accordance with sections 201(n) and 502(a) of the act. To mitigate this risk, manufacturers often consult with FDA before adding risk information to labeling. The labeling format required by this rule for new and more recently approved products should facilitate transition to an electronic format. They stated that these data are relied on by FDA (the Center for Devices and Radiological Health) and by manufacturers of in vitro susceptibility tests in selecting appropriate organisms for which to devise tests. Its purpose is to inform practitioners about what information is important to convey to the patient at the time of prescribing for the drug to be used safely and effectively. If the mechanism of action is not known, this subsection must contain a statement about the lack of information. FDA proposed to require that Highlights contain a “Use in Specific Populations” heading (proposed § 201.57(a)(13)). Adverse reactions important for other reasons (e.g., because they are serious or frequently lead to discontinuation or dosage adjustment) must not be repeated under this heading in Highlights if they are included elsewhere in Highlights (e.g., Warnings and Precautions, Contraindications). Other comments asked whether FDA-approved patient labeling attached to prescription drug labeling in a way that would facilitate it being torn off (e.g., along a perforation line) would satisfy these requirements. In rulemaking (initiated under section 126 of the Food and Drug Administration Modernization Act of 1997), the agency amended its regulation requiring that container labels contain the statement “Caution: Federal law prohibits dispensing without prescription” by replacing the statement with the symbol “Rx Only” (67 FR 4904, February 1, 2002). documents in the last year, 313 9. (b) Full prescribing information: Contents. The information required by § 201.80(a)(1)(i) through (a)(1)(iv) must appear in the Start Printed Page 3988“Description” section of the labeling, whether or not it also appears in a “Product Title.”. The purpose of the heading is to alert practitioners to recent substantive labeling changes. Specific requirements on content and format of labeling for human prescription drug and biological products; older drugs not described in § 201.56(b)(1). Some comments maintained that this requirement would be very burdensome for industry and the agency. State law actions also threaten FDA's statutorily prescribed role as the expert Federal agency responsible for evaluating and regulating drugs. Decrease in Costs to Treat Avoidable Adverse Reactions, 1. In some instances, a statement for a drug or class of drugs is currently required by regulation to be included in a specific section of prescription drug labeling (e.g., § 201.21). If State authorities, including judges and juries applying State law, were permitted to reach conclusions about the safety and effectiveness information disseminated with respect to drugs for which FDA has already made a series of regulatory determinations based on its considerable institutional expertise and comprehensive statutory authority, the federal system for regulation of drugs would be disrupted. The agency's proposed changes were designed to enhance the ability of health care practitioners to access, read, and use prescription drug labeling. Medication Guides are a specific category of FDA-approved patient labeling. After the seventh year, when all products approved within 5 years prior to the rule's effective date or pending on the effective date have redesigned prescription drug labeling, the costs decline to about $0.8 million per year. The agency agrees that advertising and promotional labeling regulations address product promotion issues and that this final rule is not an appropriate context for discussion of these issues. Cal. [2] Each year health care practitioners spend considerable time seeking medical knowledge about the therapeutic risks and benefits of the drugs prescribed to treat patients. Compliance primarily involves: (1) designing prescription drug labeling that conforms to the content and format requirements, and (2) once the labeling is approved by FDA, ensuring that all future printed prescription drug labeling is in the new format with the required minimum type size. The agency used focus groups, a national physician survey, a public meeting, and written comments to develop multiple prototypes and to ascertain how prescription drug labeling is used by health care practitioners, what labeling information practitioners consider most important, and how practitioners believed labeling could be improved. The proposed placement of the “How Supplied/Storage and Handling” section following the “Dosage and Administration” section was based on input from physicians who were surveyed about which information in labeling is most important and frequently referenced. This guidance, which is intended to assist manufacturers in complying with the provisions of this final rule, includes, among other things, how to determine what information from the FPI should be included in Highlights.