98-31242. Dissemination of Information on Unapproved/New Uses for Marketed Drugs, Biologics, and Devices  

  • [Federal Register Volume 63, Number 224 (Friday, November 20, 1998)]
    [Rules and Regulations]
    [Pages 64556-64588]
    From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
    [FR Doc No: 98-31242]
    
    
    
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    Part IV
    
    
    
    
    
    Department of Health and Human Services
    
    
    
    
    
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    Food and Drug Administration
    
    
    
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    21 CFR Parts 16 and 99
    
    
    
    Dissemination of Information on Unapproved/New Uses for Marketed Drugs, 
    Biologics, and Devices; Final Rule
    
    Federal Register / Vol. 63, No. 224 / Friday, November 20, 1998 / 
    Rules and Regulations
    
    [[Page 64556]]
    
    
    
    DEPARTMENT OF HEALTH AND HUMAN SERVICES
    
    Food and Drug Administration
    
    21 CFR Parts 16 and 99
    
    [Docket No. 98N-0222]
    RIN 0910-AB23
    
    
    Dissemination of Information on Unapproved/New Uses for Marketed 
    Drugs, Biologics, and Devices
    
    AGENCY: Food and Drug Administration, HHS.
    
    ACTION: Final rule.
    
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    SUMMARY: The Food and Drug Administration (FDA) is issuing final 
    regulations pertaining to the dissemination of information on 
    unapproved uses (also referred to as ``new uses'' and ``off-label 
    uses'') for marketed drugs, including biologics, and devices. The final 
    rule describes the new use information that a manufacturer may 
    disseminate and describes the content of and establishes procedures for 
    a manufacturer's submission to FDA before it may begin disseminating 
    information on the new use. The final rule also describes how 
    manufacturers seeking to disseminate information on a new use must 
    agree to submit a supplemental application for that use within a 
    specified period of time, unless a supplemental application already has 
    been submitted or FDA has exempted the manufacturer from the 
    requirement to submit a supplement. The final rule provides for 
    requests to extend the time period for submitting a supplemental 
    application for a new use and describes how a manufacturer can seek an 
    exemption from the requirement to submit a supplemental application for 
    the new use. Additionally, the final rule discusses FDA actions in 
    response to manufacturers' submissions, corrective actions that FDA may 
    take or require, and recordkeeping and reporting requirements. The 
    final rule implements sections 551 through 557 of the Federal Food, 
    Drug, and Cosmetic Act (the act) (21 U.S.C. 360aaa through 360aaa-6) as 
    amended by section 401 of the Food and Drug Administration 
    Modernization Act of 1997 (FDAMA).
    
    DATES: The final rule is effective November 20, 1998. Written comments 
    on the information collection requirements should be submitted by 
    January 19, 1999.
    ADDRESSES: Submit written comments on the information collection 
    requirements to the Dockets Management Branch (HFA-305), Food and Drug 
    Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    
    FOR FURTHER INFORMATION CONTACT:
        Regarding biological products and devices regulated by the Center 
    for Biologics Evaluation and Research: Toni M. Stifano, Center for 
    Biologics Evaluation and Research (HFM-602), Food and Drug 
    Administration, 1401 Rockville Pike, Rockville, MD 20852, 301-827-3028;
        Regarding human drug products: Laurie B. Burke, Center for Drug 
    Evaluation and Research (HFD-40), Food and Drug Administration, 5600 
    Fishers Lane, Rockville, MD 20857, 301-827-2828;
        Regarding medical devices: Byron L. Tart, Center for Devices and 
    Radiological Health (HFZ-302), Food and Drug Administration, 2098 
    Gaither Rd., Rockville, MD 20850, 301-594-4639.
    
    SUPPLEMENTARY INFORMATION:
    
    I. Introduction
    
        In the Federal Register of June 8, 1998 (63 FR 31143), FDA 
    published a proposed rule that would add to title 21 of the Code of 
    Federal Regulations (CFR) a new part 99 entitled, ``Dissemination of 
    Information on Unapproved/New Uses for Marketed Drugs, Biologics, and 
    Devices.''
        The proposed rule was intended to implement section 401 of FDAMA. 
    In brief, section 401 of FDAMA amended the act to permit drug, 
    biologic, and device manufacturers to disseminate certain written 
    information concerning the safety, effectiveness, or benefits of a use 
    that is not described in the product's approved labeling to health care 
    practitioners, pharmacy benefit managers, health insurance issuers, 
    group health plans, and Federal and State Government agencies, provided 
    that the manufacturer complies with certain statutory requirements. For 
    example, the information that is to be disseminated must be about a 
    drug or device that is being legally marketed; it must be in the form 
    of an unabridged reprint or copy of a peer-reviewed journal article or 
    reference publication; and it must not be derived from another 
    manufacturer's clinical research, unless that other manufacturer has 
    given its permission for the dissemination. The information must be 
    accompanied by certain information, including a prominently displayed 
    statement that the information discusses a use or uses that have not 
    been approved or cleared by FDA. Additionally, 60 days prior to the 
    dissemination, the manufacturer must submit to FDA a copy of the 
    information to be disseminated and any other clinical trial information 
    that the manufacturer has relating to the safety or effectiveness of 
    the new use, any reports of clinical experience that pertain to the 
    safety of the new use, and a summary of such information.
        A detailed description of section 401 of FDAMA appeared in the 
    preamble to the proposed rule (see 63 FR 31143 at 31144 and 31145).
    
    II. Highlights of the Final Rule
    
        Although the statute is very detailed, and the final rule closely 
    tracks its provisions, there are some places where the regulation fills 
    in the details of the statutory requirements. For example, the final 
    rule defines terms that were not defined in the legislation (e.g., 
    ``supplemental application'' and ``clinical investigation,'' and it 
    explains concepts that required additional explanation (e.g., what is 
    meant by the term ``unabridged''). The final rule also sets forth the 
    more detailed procedures for how to submit the required information to 
    FDA before disseminating any new use information (e.g., where the 
    information should be submitted and how many copies are required). 
    Finally, the final rule defines what is meant by the basic criteria 
    that the statute sets forth for granting an exemption from the 
    requirement to submit a supplement application on the basis that it 
    would be unethical or economically prohibitive to conduct the studies 
    needed to submit a supplemental application.
        The final rule has been revised in response to comments received on 
    the proposal. For example, Sec. 99.3 was revised to add a definition 
    for pharmacy benefit manger, which is not included in the statute. The 
    definition of ``clinical investigation'' in Sec. 99.3 also was revised. 
    Section 99.101 was revised to reflect FDA's position that most journal 
    articles and reference texts (as those terms are defined in the 
    regulation) would be considered to be scientifically sound and to 
    describe specific instances (e.g., letters to the editor, Phase 1 
    trials in healthy individuals) when that would not be the case.
        Section 99.103 revised the mandatory statement that the 
    disseminated information has not been approved or cleared by FDA. That 
    section also was revised to ensure that the financial disclosures 
    required under this part would be consistent with FDA's final rule on 
    financial disclosures by clinical investigators.
        Sections 99.201(a)(4)(i)(B) and (a)(4)(ii)(B), 99.203(b), and 
    99.401(b) were revised to clarify that for purposes of computing time 
    periods that begin on the date of initial dissemination, FDA will look 
    to the date that dissemination can begin. This clarification was
    
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    necessary because FDA will not know when a manufacturer actually begins 
    to disseminate materials.
        Sections 99.203 and 99.303 were revised to clarify that there are 
    two different ways that FDA can extend the time period for completing 
    the studies needed to submit a supplemental application for a new use: 
    One before any studies have begun and one after the studies have begun. 
    FDA also revised the standard for granting an exemption from the 
    requirement to submit a supplemental application on the basis that it 
    would be economically prohibitive. The focus is now on the revenue from 
    the new use rather than the revenue from the product.
        In Sec. 99.301, FDA clarified when it would require a manufacturer 
    to keep records identifying the individual recipients of new use 
    information as opposed to just the categories of such recipients. 
    Finally, the final rule was revised to ensure that a decision on a new 
    use submission would be made within 60 days.
    
    III. Responses to Comments on the Proposed Rule
    
        FDA received over 50 written comments on the proposed rule. In 
    addition, on July 8, 1998, FDA held a public meeting on the proposed 
    rule. Thirteen speakers commented on the proposal. In general, the 
    comments expressed a diverse range of opinions, both favoring and 
    opposing the proposed rule, and were submitted by health professionals, 
    medical organizations, consumer groups, patient groups, a medical 
    journal, members of Congress, trade associations, and manufacturers.
    
    A. General Comments
    
        Several comments addressed the concept of disseminating information 
    on unapproved or new uses rather than the proposed rule itself. Other 
    comments sought further restrictions on the dissemination of 
    information on unapproved or new uses, while still other comments 
    sought to expand the rule to cover more products.
        1. A number of comments expressed concern that the proposed rule 
    could result in harm to patients. One comment expressed concern over 
    the self-policing aspects of the rule. Another comment cited several 
    examples where drugs were administered for unapproved uses and proved 
    to be harmful. The comment stated that dissemination of information on 
    unapproved uses for approved drugs would further encourage the use of 
    ``untested'' drugs and discourage clinical trials that would show 
    whether the drugs are safe and effective for their intended uses. The 
    comment asked FDA to ``revise or abandon these regulations so as to 
    continue to protect consumers from untested and potentially dangerous 
    drugs.'' One comment argued that the new rule was not ``warranted'' 
    because the disseminated information may be inappropriate and would 
    pose a significant risk to public health. The comment further argued 
    that current practices in this area are the best way to handle 
    information on unapproved uses. Finally, a number of comments expressed 
    concern that FDA does not have sufficient resources to implement the 
    regulation in a manner that can adequately protect the public health. 
    Such comments urged FDA to direct adequate resources to implementation.
        Section 401(c) of FDAMA required FDA to issue regulations to 
    implement sections 551 through 557 of the act by November 21, 1998. The 
    final rule, which closely tracks the statutory language, represents 
    FDA's effort to comply with that requirement. FDA is committed to 
    implementing this new statutory authority consistent with its 
    obligation to protect the public health.
        2. Several comments claimed that dissemination of information on 
    unapproved or new uses of drugs for which pediatric labeling is not 
    available would be contrary to section 505A of the act (21 U.S.C. 355A) 
    as it pertains to pediatric studies of drugs because it would impede 
    the development of pediatric data. Several comments said that 
    dissemination of information on unapproved uses for pediatric therapy 
    should be limited to drugs that have ``sufficient labeling in the ages 
    of the children addressed by the information disseminated.'' Another 
    comment noted that dissemination of information for an unapproved use 
    of a drug in children when the drug's approved use has not been tested 
    for safety in pediatric patients may pose even more risk than 
    unapproved uses generally. Others said that for drugs without labeling 
    for pediatric populations or specific age populations, drug 
    manufacturers should not be able to disseminate unapproved use 
    information about pediatric populations or about specific age 
    populations not specified in the label, unless such information is 
    specifically requested by the physician.
        FDA declines to amend the rule as suggested by the comments. It is 
    FDA's hope that the statutory scheme set forth in section 401 of FDAMA 
    and implemented by this part will actually stimulate research and the 
    development of data on new uses, including pediatric uses. Moreover, 
    nothing in section 401 of FDAMA or its legislative history suggests 
    that Congress intended to exclude pediatric uses from section 551 of 
    the act or to further limit how information on such uses can be 
    disseminated. Finally, the act does not require that the disseminated 
    information be specifically requested by a physician in order to be 
    disseminated.
        Although FDA is not amending the codified language in any way, it 
    does recognize that the potential dangers of unapproved uses in 
    children may be greater than for adults because few drugs have been 
    tested in children. The agency will take this into account in making a 
    determination as to whether a proposed dissemination of information on 
    a new use poses a significant risk to public health such that the 
    dissemination under this part should not be permitted.
        3. One comment would revise the rule to exclude drugs that may be 
    covered by orphan drug exclusivity. The comment explained that a 
    manufacturer may obtain orphan drug exclusivity for a particular use of 
    a drug, but that other manufacturers could be marketing the same drug 
    for non-orphan indications. The comment stated that such other 
    manufacturers could disseminate information on the orphan indication, 
    thereby undermining the value of orphan drug exclusivity.
        There is no indication in section 401 of FDAMA or its legislative 
    history that Congress intended the dissemination of information on 
    unapproved uses of drugs and devices to undermine patent protection or 
    exclusivity granted to a product under the Orphan Drug Act, the Waxman-
    Hatch Amendments, or the pediatric exclusivity provisions in section 
    111 of FDAMA. Therefore, an indication that is not included in a 
    particular sponsor's approved product labeling because the indication 
    is protected by patent or exclusivity is not eligible for dissemination 
    under part 99.
        4. Several comments urged FDA to broaden the proposal to include 
    over-the-counter (OTC) drug products being marketed under an OTC 
    monograph.
        Section 401 of FDAMA requires that in the case of a drug, there be 
    in effect for the drug an application filed under section 505(b) or (j) 
    of the act. OTC drugs being marketed under an OTC monograph do not have 
    an application filed under section 505(b) or (j) of the act in effect. 
    Therefore, FDA declines to revise the rule as suggested in these 
    comments.
        5. One comment stated that companies sometimes assist physicians 
    and patients in obtaining reimbursement from Medicare, Medicaid, and 
    private insurers by furnishing copies of journal articles and reference 
    publications on unapproved
    
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    uses to the insurer or government agency when reimbursement is denied 
    on the ground that use of the product is experimental. The comment 
    concluded that this practice appeared to be legal prior to the passage 
    of section 401 of FDAMA and asked FDA to clarify that it did not become 
    illegal as a result of FDAMA.
        Prior to passage of FDAMA, the practice described in this comment 
    was not permissible unless the unapproved use information was provided 
    in response to an unsolicited request for such information. FDA's 
    policy, which allows manufacturers to provide unapproved use 
    information in response to an unsolicited request, was not affected by 
    FDAMA (see section 557(a) of the act). Accordingly, manufacturers who 
    wish to furnish unapproved use information as described in the comment 
    may do so if it is in response to an unsolicited request. Otherwise, 
    they must comply with the requirements set forth in section 401 of 
    FDAMA and this part.
        6. One comment asserted that the proposal should recognize the 
    specific legal authorization for manufacturers to provide off-label 
    information to health care practitioners in response to an unsolicited 
    request.
        Section 401 of FDAMA added a new section 557(a) of the act, which 
    provides that nothing in section 551 of the act shall be construed as 
    prohibiting a manufacturer from disseminating information in response 
    to an unsolicited request from a health care practitioner. Although FDA 
    does not construe section 557(a) of the act as a specific legal 
    authorization for manufacturers to provide off-label use information to 
    health care practitioners in response to an unsolicited request, 
    Sec. 99.1(b) of the final rule recognizes this statutory provision.
        7. One comment stated that FDA should exempt manufacturers from the 
    ``pre-approval and reporting requirements'' when the primary focus of a 
    publication is on the approved uses of the product.
        Section 401 of FDAMA and this part do not cover publications 
    regarding approved uses. FDA intends to permit manufacturers to 
    disseminate certain information that focuses primarily on approved uses 
    and that report the results of studies that have been relied on by FDA 
    in its approval or clearance of a drug or device without meeting all of 
    the requirements set forth in this part. (Cf. Guidance to Industry on 
    Dissemination of Reprints of Certain Published Original Data (61 FR 
    52800, October 8, 1996). The agency was enjoined from applying this 
    guidance document in Washington Legal Foundation v. Friedman, CA No. 
    1:94CV1306 (D.D.C. July 30, 1998) (hereinafter referred to as WLF v. 
    Friedman). FDA sought clarification on the scope of the order through a 
    motion to amend the judgment in that case.) FDA plans to issue guidance 
    on this issue at some time in the future pending clarification by the 
    court.
        8. One comment suggested that FDA exempt manufacturers from the 
    requirements set forth in this part if the new use that is the subject 
    of the information being disseminated has been accepted as standard 
    medical practice (i.e., indications listed in the United States 
    Pharmacopoeia Drug Information for the Health Care Professional (USP 
    DI) or American Hospital Formulary Service, etc.).
        FDA declines to create an exemption from the entire rule as 
    suggested by the comment. Regardless of whether the unapproved use is 
    listed in the USP DI or American Hospital Formulary Service, the 
    statutory requirements in sections 551 through 557 of the act apply to 
    a manufacturer who intends to disseminate information on the unapproved 
    use for an approved product to health care practitioners, pharmacy 
    benefit managers, health insurance issuers, group health plans, or 
    Federal or State governmental agencies. Evidence that the unapproved 
    use represents standard medical care may, however, enable the 
    manufacturer to seek an exemption from the requirement to submit a 
    supplemental application for the unapproved use if the manufacturer can 
    demonstrate that it would be unethical to conduct the studies necessary 
    for a supplemental application for the new use. A discussion of the 
    ``unethical'' exemption appears later in section III of this document.
        9. Some comments stated that the proposal properly reflects the 
    intent of Congress and achieves the important goals of assuring the 
    public health and encouraging the dissemination of information. Others 
    argued that the proposal is contrary to congressional intent, 
    paternalistic and cumbersome, and would restrict, rather than 
    facilitate, access to information about new uses.
        Although FDA drafted the proposed rule to reflect congressional 
    intent, the agency has revised the rule in response to specific 
    comments. These revisions are meant to ensure that the final rule more 
    accurately reflects congressional intent.
    
    B. Comments on Specific Provisions
    
    1. Subpart A--General Information
        a. Scope (Sec. 99.1). Proposed Sec. 99.1 described the scope of 
    part 99, explaining that the part applies to the dissemination of 
    information on human drugs, including biologics, and devices where the 
    information to be disseminated pertains to the safety, effectiveness, 
    or benefit of a use that is not included in the approved labeling for 
    an approved drug or device or in the statement of intended use for a 
    cleared device and the information is to be disseminated to a health 
    care practitioner, pharmacy benefit manager, health insurance issuer, 
    group health plan, or Federal or State Government agency.
        10. Several comments urged FDA to add pharmacists to the list of 
    recipients of information under this part.
        Section 401 of FDAMA specifically lists who can receive the new use 
    information under this provision and proposed Sec. 99.1 tracked that 
    statutory provision. Therefore, FDA declines to amend the regulation as 
    requested. However, to the extent that pharmacists fall within the 
    definitions of ``health care practitioner,'' ``pharmacy benefit 
    manager,'' health insurance issuer,'' or ``group health plan'' (see 
    Sec. 99.3) they will be included as recipients of this information.
        b. Definitions (Sec. 99.3). Proposed Sec. 99.3 defined various 
    terms, such as ``clinical investigation'' (proposed Sec. 99.3(b)), 
    ``health care practitioner'' (proposed Sec. 99.3(d)), ``new use'' 
    (proposed Sec. 99.3(g)), ``scientific or medical journal'' (proposed 
    Sec. 99.3(i)), and supplemental application (proposed Sec. 99.3(j)).
        11. One comment urged FDA to include a definition for ``pharmacy 
    benefit manager'' and to include pharmacists in that definition.
        Although the statute defines the other recipients of information 
    under this provision (i.e., health care practitioner, health insurance 
    issuer, and group health plan), it does not define pharmacy benefit 
    manager. FDA has revised the rule to define a ``pharmacy benefit 
    manager'' (PBM) as ``a person or entity that has, as its principal 
    focus, the implementation of one or more device and/or prescription 
    drug benefit programs.'' PBM's, which generally include pharmacists, 
    typically provide claims processing services for devices and/or 
    prescription drugs; negotiate device and/or prescription drug prices; 
    negotiate volume purchase agreements with medical device and/or 
    pharmaceutical manufacturers, develop formularies, and institute 
    formulary
    
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    compliance programs (e.g., mandatory generic substitution programs). 
    The new definition is in Sec. 99.3(h) and the agency has redesignated 
    the remaining definitions accordingly.
        12. Proposed Sec. 99.3(b) defined a ``clinical investigation'' as 
    an ``investigation in humans that is prospectively planned to test a 
    specific clinical hypothesis.'' Several comments argued that FDA should 
    delete the proposed definition of ``clinical investigation.'' They 
    argued that restricting clinical investigations to those that are 
    prospectively planned is not part of the statute, that it would 
    preclude the use of retrospective studies, modeling studies, open label 
    studies, metanalysis, reference articles, and consensus standards, 
    which these comments assert may be useful, and that Congress never 
    intended for the definition to be limited in this manner. One comment 
    argued that the prospective planning criteria should not have to meet 
    the criteria for investigational new drug applications (IND's).
        FDA believes that many of these comments misconstrued what the 
    agency meant by the phrase ``prospectively planned.'' FDA does not 
    consider modeling studies, which are not actual studies, but rather 
    extrapolations of information or data that are used to predict how a 
    study might come out, to be clinical investigations. Moreover, FDA does 
    not consider consensus standards and reference articles to contain 
    adequate detail about ``clinical investigations'' as defined by this 
    rule. However, it was the agency's intent that the definition could 
    include historically controlled studies, retrospective analyses, open 
    label studies, and metanalyses if they are testing a specific clinical 
    hypothesis. To avoid any confusion, FDA is eliminating the phrase 
    ``prospectively planned'' from the definition of ``clinical 
    investigation.'' In the final rule, FDA has defined a clinical 
    investigation to mean ``an investigation in humans that tests a 
    specific clinical hypothesis.''
        13. Several comments urged FDA to revise the definition of ``health 
    care practitioner'' in Sec. 99.3(d) to include pharmacists.
        Section 556(1) of the act (21 U.S.C. 360aaa-5(1)) defines the term 
    ``health care practitioner'' to mean a physician, or other individual 
    who is a provider of health care, who is licensed under the law of a 
    State to prescribe drugs or devices.'' FDA's proposed regulation 
    tracked this statutory definition. FDA declines to revise the 
    definition. To the extent that pharmacists fall within this definition, 
    they will be eligible to receive information disseminated under this 
    part.
        14. Proposed Sec. 99.3(g) defined ``new use'' to mean a use that is 
    not included in the approved labeling of an approved drug or device, or 
    a use that is not included in the statement of intended use for a 
    cleared device. The preamble to the proposed rule explained that a new 
    use is one that would require approval or clearance of a supplemental 
    application in order for it to be included in the product labeling.
        The preamble to the proposed rule explained that ``new uses,'' 
    include, but are not limited to: A completely different indication; 
    modification of an existing indication to include a new dose, a new 
    dosing schedule, a new route of administration, a different duration of 
    usage, a new age group (e.g., unique safety or effectiveness in the 
    elderly), another patient subgroup not explicitly identified in the 
    current labeling, a different stage of the disease, a different 
    intended outcome (e.g., long-term survival benefit, improved quality of 
    life, disease amelioration), effectiveness for a sign or symptom of the 
    disease not in the current labeling; and comparative claims to other 
    agents for treatment of the same condition (see 63 FR 31143 at 31145).
        A number of comments supported FDA's definition of new use. 
    However, others disagreed with the specific examples set forth in the 
    preamble as too broad. Most of the latter comments objected to the 
    inclusion of patient subgroups and comparative claims for approved 
    indications. They argued that their inclusion in the definition is 
    inconsistent with the agency's prescription drug advertising 
    regulations, which permit companies to promote patient subgroups and 
    comparative claims if certain conditions are met. Several comments 
    disagreed with the inclusion of a new age group--specifically 
    children--in the definition of new use. One comment argued that 
    children should not be considered a ``use,'' but a ``user.'' One 
    comment stated that the definition should focus only on information 
    that differs from the current labeling; it should not include 
    information that is consistent with, but more detailed than what is 
    described in the approved labeling. Finally, one comment disagreed with 
    the agency's characterization of a different intended outcome as an 
    off-label use.
        FDA agrees with the comments discussed previously, which note that 
    FDA's prescription drug advertising regulations permit companies to 
    make comparative claims about two approved uses, without getting the 
    claims on the approved label if the companies have on file, substantial 
    evidence or substantial clinical experience to support such claims. 
    (See Sec. 202.1(e) (21 CFR 202.1(e)).) FDA did not intend to change the 
    provision found in its prescription drug advertising regulations. In 
    addition, FDA agrees that as long as the comparison is between two 
    approved claims, there technically is not a new ``use'' involved. 
    Therefore, FDA is deleting comparative claims about approved uses from 
    its interpretation of ``new use.'' Manufacturers who want to make such 
    claims for a drug, must submit a labeling supplement or must meet the 
    requirements set forth in FDA's drug advertising regulations. (See 
    Sec. 202.1(e).) Manufacturers who want to make such claims for a 
    medical device must meet the requirements set forth in 
    Secs. 807.81(a)(3)(ii) or 814.39 (21 CFR 807.81(a)(3)(ii) or 814.39).
        With respect to claims of efficacy in a new patient subgroup, 
    including a new age group, claims that are more detailed than the 
    approved labeling, and claims that relate to different intended 
    outcomes (as well as with respect to some of the other types of new use 
    claims listed in the preamble to the proposed rule), FDA's prescription 
    drug advertising regulations may permit companies to make such claims 
    about prescription drugs in certain circumstances, without submitting a 
    supplement, provided they have on file the required evidence to support 
    the claim. (See Sec. 202.1(e).) However, FDA does consider such claims, 
    including claims regarding children, to be new uses in some cases. In 
    cases where such claims constitute new uses, manufacturers also can use 
    the procedures set forth in this part to disseminate journal articles 
    and reference publications about those claims. For medical devices, 
    manufacturers can use the procedures set forth in this part to 
    disseminate journal articles and reference publications about these 
    types of claims. Otherwise, they must comply with the requirements set 
    forth in Secs. 807.81(a)(3)(ii) or 814.39.
        15. Proposed Sec. 99.3(i) (now redesignated as Sec. 99.3(j)) 
    defined ``scientific or medical journal,'' in part, as a journal that 
    is indexed in Index Medicus. It excluded scientific and medical 
    publications that are in the form of special supplements that have been 
    funded in whole or in part by one or more manufacturers. One comment 
    agreed that special supplements are not appropriate for dissemination 
    under this part. One comment, however, stated that the definition was 
    too narrow by requiring that the publication be listed
    
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    in Index Medicus and by excluding special supplements.
        The definition in FDA's rule, which excludes journals not indexed 
    in Index Medicus and scientific and medical publications that are in 
    the form of special supplements that have been funded in whole or in 
    part by one or more manufacturers, tracks the statutory definition. 
    (See section 556(5) of the act.) Accordingly, no changes to the final 
    rule have been made.
        16. Proposed Sec. 99.3(j) (now redesignated as Sec. 99.3(k)) 
    defined ``supplemental application'' as a supplement to support a new 
    use to an approved new drug application (NDA) for human drugs or a 
    supplement to an approved license application for biologics. Several 
    comments argued that the definition of a supplemental application for a 
    drug should be expanded to include the possibility that a ``new use'' 
    could require a new NDA rather than just a supplemental NDA. One 
    comment claimed that there are certain review divisions in the Center 
    for Drug Evaluation and Research (CDER) that require NDA's for all new 
    uses.
        There may be times when a manufacturer would be required to submit 
    an NDA rather than a supplemental NDA to support a new use. In these 
    instances, the unapproved use would not be covered by this part. 
    However, it would not be appropriate to exclude new uses from this part 
    merely because a review division assigns a new NDA number to the 
    supplement for administrative convenience. In the latter instance, the 
    difference would be in name only. Therefore, although FDA is declining 
    to revise the regulation as suggested by the comments, FDA will treat 
    applications that have been assigned a new NDA number for 
    administrative convenience as a supplemental NDA for purposes of this 
    part.
        17. One comment recommended expanding the definition of 
    supplemental application to cover OTC drugs that are subject to a 
    monograph.
        As set forth previously, OTC drugs that are subject to a monograph 
    are not covered by this provision. Therefore, FDA declines to expand 
    the definition as requested.
        18. For devices, proposed Sec. 99.3(j) (now redesignated as 
    Sec. 99.3(k)) defined ``supplemental application'' as a new 510(k) 
    submission, if the device that is cleared for marketing is the subject 
    of a 510(k) submission, or a supplement to an approved premarket 
    approval application (PMA), if the device that is marketed is the 
    subject of an approved PMA. One comment recommended expanding the 
    definition of supplemental application for devices to include a 510(k) 
    to a 510(k) exempt device.
        FDA agrees that the statutory provision covers 510(k) exempt 
    devices and so has amended the definition of supplemental application 
    accordingly.
        19. Several comments disagreed with FDA's definition of 
    supplemental application for devices because it did not include a PMA 
    for a new use for a device on the market under section 510(k) of the 
    act (21 U.S.C. 360(k)).
        Because there are no supplemental applications for 510(k) devices, 
    FDA could have interpreted the statute to exclude all 510(k) devices 
    from the scope of the rule. FDA drew a distinction between those that 
    require a new 510(k) and those that require a PMA because the agency 
    determined that this was similar to the distinction between a 
    supplemental NDA and an NDA (i.e., a supplemental NDA and a 510(k) are 
    filed on products about which the agency has some accumulated knowledge 
    and experience such that it is not required to start its review from 
    scratch; an NDA and a PMA are filed for products about which the agency 
    has no such accumulated knowledge or experience upon which to base a 
    decision).
        FDA disagrees with the comment that an original PMA submission 
    should be included in the definition of ``supplemental application'' 
    for a device that entered the marketplace through the 510(k) process. 
    The 510(k) process and the PMA process are designed to provide 
    different ways to market regulated products, are supported by a 
    different extent and kind of data, and are predicated on different 
    concepts of how to assure consumer protection.
        A product entering the market via the 510(k) process does so 
    because the agency agrees with the sponsor that the new device is 
    substantially equivalent to a device commercially distributed before 
    May 28, 1976, or to a newer predicate device for the same intended use. 
    For a 510(k) product, the consumer protection objective of the act is 
    met in part by the accumulated experience with the predicate devices 
    and the review and establishment of the device category in the 
    appropriate class and a modicum of device specific information. 
    Information on manufacturing and premarket assurance of conformance to 
    good manufacturing practices (GMP's) are not addressed. The agency does 
    not, in the case of a 510(k), make an individual product determination 
    of safety or effectiveness.
        The act requires a PMA for a device for which there is a new 
    intended use with no predicate, or which raises new issues of safety 
    and effectiveness. Evidence required under a PMA is substantial and the 
    sponsor must show, through the use of well-controlled clinical trials 
    or, at the discretion of the agency, other valid scientific evidence, 
    that there is a reasonable assurance the product is safe and effective 
    for its intended use. As part of its review of a PMA, FDA reviews and 
    audits clinical trial information and the GMP's employed by the 
    manufacturer.
        Allowing an original PMA submission to be regarded in this context 
    as a supplement for a device already marketed under a 510(k) would 
    undermine the statutory and regulatory requirements established to 
    ensure the safety and effectiveness of products subject to PMA's. It 
    would be analogous to applying the dissemination provision to new 
    devices that were never legally marketed. For a PMA product, a new 
    intended use supplement is intended to provide the agency with 
    additional data supporting a new use for an approved device. It relies, 
    in large part, on information previously reviewed regarding product 
    materials, biocompatibility, design, performance, and basic safety 
    data. For a 510(k) product, a PMA would not be providing additional 
    information; it would be providing all of the information.
        To illustrate, a product not currently marketed, but that was 
    marketed as a general use tool without any known labeling or identified 
    product specific intended use in the 1960's preamendment period may be 
    re-introduced through a 510(k) for that same (implied) intended general 
    tool use (e.g., it ablates or thermally destroys tissue). The product 
    will be regarded as an unclassified preamendment product. If a 
    manufacturer wished to market it for a specific intended purpose where 
    that new purpose creates a new use with attendant questions of safety 
    and effectiveness of the new use, it must do so through a PMA. In a 
    recent instance, a company sought to market its unclassified 
    preamendment product, an interuterine probe for a cryosurgery machine 
    (using freezing to thermally destroy tissue), for ablation of the 
    uterine endometrium with ultrasound control of the location and extent 
    of tissue being frozen to control excessive menstrual bleeding. By 
    moving to a tissue and anatomic specific intended use and indication, 
    as well as by incorporation of a new (external) control procedure, the 
    manufacturer has created a new intended use. The product's underlying 
    safety and manufacture have never been evaluated. Even the presumption 
    that ultrasound
    
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    measurement of the extent of tissue being frozen accurately predicts 
    the extent of tissue necrosis and allows proper positioning of the 
    probe remains unevaluated. Nevertheless, the comments would argue that 
    this product could be the subject of an article or text disseminated 
    under section 401 of FDAMA.
        In passing section 401 of FDAMA, Congress intended to provide 
    health care practitioners important scientific information about 
    unapproved uses of approved products. The risks to the public of 
    disseminating information in a case such as that described previously 
    are closer to the risks from instances where there has never been an 
    approved product than those for a new use of a previously approved 
    product. FDA believes that these risks are far greater than those 
    authorized by section 401 of FDAMA.
    2. Subpart B--Information To Be Disseminated
        a. Information that may be disseminated (Sec. 99.101). Proposed 
    Sec. 99.101 discussed the types of information concerning the safety, 
    effectiveness, or benefit of a new use that a manufacturer may 
    disseminate. For example, the proposal required (among other things) 
    that the written information to be disseminated concern a drug or 
    device that has been approved, licensed, or cleared for marketing by 
    FDA and be in the form of an unabridged reprint or copy of a peer-
    reviewed scientific or medical journal article or an unabridged 
    reference publication that pertains to a clinical investigation 
    involving the drug or device and that is considered scientifically 
    sound by experts who are qualified to evaluate the product's safety or 
    effectiveness. Proposed Sec. 99.101 also described criteria for 
    determining whether the information to be disseminated is false or 
    misleading, whether a clinical investigation is ``scientifically 
    sound,'' and whether a reprint or copy of an article or reference 
    publication is ``unabridged.''
        20. One comment urged FDA to include a 60-day window in advance of 
    a drug's Prescription Drug User Fee Act date during which time a 
    manufacturer could submit proposed material for review. In other words, 
    the comment urged FDA to accept dissemination materials for review 
    before a drug has been approved.
        FDA declines to adopt this approach. The statute does not direct 
    FDA to accept submissions on products that have not yet been approved 
    or cleared. If FDA accepts submissions on products that have not yet 
    been approved or cleared, it may be wasting resources reviewing 
    submissions on products that never get approved or cleared.
        21. One comment urged FDA to make clear that this part does not 
    permit the verbal dissemination of unapproved use information. Another 
    comment suggested that companies that disseminate information on a new 
    use should be permitted to discuss the clinical investigation that is 
    the subject of the disseminated materials with the recipient.
        FDA agrees with the first comment that neither this part nor 
    section 401 of FDAMA, would permit the verbal dissemination of 
    information about unapproved uses. Section 551(a) of the act and 
    Sec. 99.101 refer clearly and specifically to ``written'' information. 
    Therefore, a manufacturer (or its representatives or agents) is not 
    permitted to discuss with a recipient the clinical investigation that 
    is the subject of the written materials disseminated under this part.
        22. Several comments asked whether Internet or electronic 
    dissemination would be permitted under this part.
        Although, as set forth previously, FDA agrees that the provision 
    was not meant to cover verbal dissemination, it could cover electronic 
    dissemination. However, a manufacturer seeking to disseminate 
    information electronically would have to ensure that all of the 
    requirements under this part could be met for electronic dissemination. 
    For example, the manufacturer would have to ensure that the recipients 
    of the information are appropriately limited and that all of the 
    required information and disclosures can be attached in accordance with 
    this part. FDA may, in the future, issue guidance on this subject.
        23. One comment noted the importance of requiring manufacturers to 
    disseminate unabridged journal articles so that information from a 
    clinical study is not pulled out of context or released without all 
    relevant data.
        FDA agrees with this comment. Both the statute and the regulation 
    require that a journal article or reference publication disseminated 
    under this part be unabridged.
        24. Several comments objected to the requirement that a reprint or 
    copy of an article be published prior to submission for FDA for review. 
    These comments argued that manufacturers should be allowed to send FDA 
    final manuscripts. Another comment opposed allowing submissions to 
    include manuscripts or preprints of articles that have been accepted 
    for publication. This comment stated that it could take months for 
    these manuscripts to be published and that they might be submitted 
    before the peer-review process is complete.
        FDA understands manufacturers' desire to disseminate new use 
    information as quickly as possible. However, section 552 of the act (21 
    U.S.C. 360aaa-1) requires that the peer-reviewed journal articles 
    disseminated under this part be published. If FDA were to accept 
    manuscripts before publication, it could not be sure that what gets 
    published, and then disseminated, is exactly what it was given to 
    review. The agency might not even be sure that the peer-review process 
    has been completed. FDA does not have the resources to verify this 
    information or to conduct duplicative reviews. Therefore, FDA is not 
    revising the rule to permit submission of unpublished manuscripts.
        25. Several comments took issue with the statement in the proposal 
    that information can be false or misleading if it includes only 
    favorable publications. These comments argued that dissemination should 
    not be prohibited if the only information that has been published is 
    favorable and the research is scientifically rigorous. These comments 
    noted that FDA should make clear that a single favorable publication 
    can be disseminated if it is objective, balanced, and discusses 
    appropriate safety information. One comment noted that a more 
    appropriate manner in which to state the issue would be to cite the 
    exclusion of an unfavorable publication as the example.
        FDA agrees that new use information is not necessarily without 
    balance or misleading just because there is no unfavorable information 
    disseminated with it and FDA did not intend to suggest the contrary. 
    FDA agrees that it would be inappropriate to find a favorable article 
    misleading just because it is disseminated without an unfavorable 
    publication when no unfavorable publication exists. What FDA will be 
    looking for is whether the manufacturer has failed to include 
    unfavorable information that exists and that is necessary to provide 
    balance. FDA has revised the rule to clarify this point.
        26. One comment said that proposed Sec. 99.101(a)(4) was unclear on 
    what ``other information concerning risks and adverse effects that are 
    or may be associated with the new use'' a company would have to include 
    to ensure that the disseminated information is not false or misleading.
        The other information refers to the additional information that FDA 
    can require under Sec. 99.103(a)(4). FDA has revised the rule to 
    clarify this point.
    
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        27. Proposed Sec. 99.101(a)(5) required that the disseminated 
    information not be derived from clinical research conducted by another 
    manufacturer unless the manufacturer disseminating the information has 
    the permission of such other manufacturer to make the dissemination.
        One comment noted that the rule should clarify that contracts or 
    agreements between sponsors may specify how the data are to be used by 
    the sponsoring companies. In other words, cosponsoring companies should 
    be responsible for maintaining their own agreements without FDA input. 
    Several other comments opined that once a peer-reviewed article is 
    published, it is in the public domain and a sponsor should be able to 
    pursue use of the data published by the original sponsor (i.e., without 
    first obtaining permission) as long as proper credit is given. One 
    comment asked FDA to clarify the rule to show that research conducted 
    by an independent academic or similar organization can be disseminated 
    if the information meets the standards for dissemination and is legally 
    available for such use.
        Section 551(b)(3) of the act prohibits the dissemination of 
    information derived from research conducted by another manufacturer 
    without that other manufacturer's permission. The fact that an article 
    has been published does not eliminate the need to get permission from 
    the researching company. If it did, this requirement in the statute 
    would be meaningless because all information disseminated under this 
    part must be published. Therefore, FDA declines to revise the rule to 
    permit the dissemination of all published articles reporting on 
    research conducted by another manufacturer without that manufacturer's 
    permission. However, FDA agrees that cosponsoring companies can make 
    agreements without FDA's input and that research conducted by 
    independent parties does not, by the terms of the statute, require that 
    party's permission.
        28. One comment noted that reference publications will include many 
    unapproved use discussions that reflect research conducted by other 
    manufacturers and that proposed Sec. 99.101(a)(5) would appear to make 
    the disseminating company get permission from every one of those 
    manufacturers.
        As set forth in the proposal, FDA expects that manufacturers that 
    disseminate reference publications under this part will flag the 
    section of the text that describes the clinical investigation of a 
    specific unapproved use (otherwise, they would have to commit to study 
    all of the unapproved uses discussed in the reference publication). 
    Therefore, FDA would expect that a manufacturer would be required only 
    to seek the permission of another manufacturer if that other 
    manufacturer conducted the study for that specific discussion of an 
    unapproved use.
        29. Proposed Sec. 99.101(b)(1) provided that the determination of 
    whether a clinical investigation is considered to be ``scientifically 
    sound'' will rest on whether the design, conduct, data, and analysis of 
    the investigation described or discussed in a reprint or copy of an 
    article or in a reference publication reasonably support the 
    conclusions reached by the authors. It further provided that a clinical 
    investigation described or discussed in an article or reference 
    publication must include a description of the study design and conduct, 
    data presentation and analysis, summary of results, and conclusions 
    pertaining to the new use. The proposal also stated that a clinical 
    investigation presented in a format that does not represent a 
    reasonably comprehensive presentation of the study design, conduct, 
    data, analyses, and conclusions (e.g., letters to the editor, review 
    abstracts, abstracts of a publication) would not qualify for 
    dissemination under this provision.
        The preamble to the proposal provided that in order to provide a 
    basis for determining whether the conclusions are reasonably supported 
    and the findings represent evidence of safety and effectiveness of the 
    new use, the article or reference publication should provide, where 
    applicable, evidence that the investigation: (1) Was prospectively 
    planned; (2) enrolled an appropriately defined and diagnosed patient 
    population for the specific clinical condition of interest; (3) 
    accounted for all patients enrolled, including all patients who 
    discontinued therapy prematurely; (4) utilized clinically meaningful 
    endpoints or utilized surrogate endpoints that are reasonably likely to 
    predict safety and effectiveness; (5) used a well described treatment 
    regimen with a clear description of dose, schedule, duration, and route 
    of administration; (6) used an appropriate control group or made 
    reference to an appropriate historical control; (7) collected and 
    reported adequate information on adverse experiences, and the need for 
    dose reductions and treatment interruptions due to toxicity; and (8) 
    was analyzed in a scientifically appropriate manner. (See 63 FR 31143 
    at 31146 and 31147.)
        Some comments supported FDA's interpretation and applauded the 
    agency's efforts to ensure that journal articles and reference 
    publications are scientifically sound. These comments noted that FDA's 
    interpretation reflected what is required by most peer-reviewed 
    journals.
        In contrast, a number of comments objected to FDA's approach. Some 
    of these comments objected to FDA making any determination that an 
    article or reference publication is scientifically sound. They stated 
    that it was not Congress' intent to have FDA ``do its own peer 
    review.'' Others criticized the criteria set forth in the proposed 
    codified language and/or the eight criteria in the preamble to the 
    proposal. They argued that FDA would be requiring more detail than is 
    ever found in articles or reference publications and/or that FDA's 
    standard is akin to that for a supplemental application. One comment 
    said that FDA should require only enough detail to determine if the 
    article or publication is scientifically sound. One comment urged FDA 
    to adopt a broader definition of scientifically sound by removing the 
    specific requirements, i.e., prospectively planned, and recognizing the 
    value of scientifically sound studies as long as any limitations (e.g., 
    epidemiological data) are fully disclosed. One comment said that FDA 
    should require the journal article to include the ``typical level of 
    detail'' and, if it does not, then the company should be able to attach 
    it to the article. Several comments opposed the specific exclusion of 
    abstracts. Finally, a number of comments specifically criticized the 
    requirement that the clinical investigation be prospectively planned.
        FDA has a role to play with respect to whether an article or 
    reference publication is scientifically sound. The statute includes a 
    requirement that the disseminated article or reference publication 
    pertain to a clinical investigation that would be considered to be 
    scientifically sound by experts qualified by scientific training or 
    experience to evaluate the safety or effectiveness of the drug or 
    device involved. FDA believes that this provision indicates that 
    Congress meant for FDA to look at whether experts would find that the 
    article or publication is about an investigation that experts would 
    consider to be scientifically sound. However, FDA also believes that 
    its role in determining whether an article or publication is 
    scientifically sound is limited. This approach is consistent with the 
    proposed rule and FDA fully expected that most journal articles about a 
    clinical investigation from reputable peer-reviewed journals would meet 
    the definition of scientifically sound set
    
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    forth in its proposal. Nevertheless, to ensure that the provision will 
    be implemented consistent with congressional intent, FDA is revising 
    Sec. 99.101(b)(1) to provide that FDA will find that all journal 
    articles and reference publications (as those terms are defined in 
    Sec. 99.3) are scientifically sound except: (1) Letters to the editor; 
    (2) abstracts of a publication; (3) those regarding Phase 1 trials in 
    healthy people; (4) flagged reference publications that contain little 
    or no substantive discussion of the relevant clinical investigation; 
    and (5) those regarding observations in four or fewer people that do 
    not reflect any systematic attempt to collect data, unless the 
    manufacturer demonstrates to FDA that such reports could help guide a 
    physician in his/her medical practice.
        Section 552(a)(2) of the act prohibits the dissemination of 
    information that is false or misleading. That provision prohibits the 
    dissemination of journal articles and reference publications that 
    contain conclusions that are not supported by the study results. FDA 
    has revised Sec. 99.101(a)(4) accordingly.
        30. One comment asked what FDA would do if an article discussed 
    multiple unapproved uses, but the manufacturer wanted to focus on just 
    one unapproved use.
        FDA expects that there may be articles that discuss multiple 
    unapproved uses and that such articles may be disseminated only if the 
    requirements are met for each of those uses. There also may be 
    instances when an article discusses multiple unapproved use(s), but 
    there is one (or more) predominant unapproved use(s) discussed in the 
    article. Under certain circumstances, it may make sense for the 
    manufacturer to have to meet the requirements set forth in this part 
    only for the predominant use(s). However, FDA will have to make this 
    determination on a case-by-case basis.
        31. One comment argued that dissemination of reference publications 
    is not consistent with the purpose of section 401 of FDAMA because, by 
    their very nature, reference publications are considerably out of date 
    at the time of their publication. The comment further opined that 
    because the authors do not report the methods used to assess the 
    current scientific literature, reference publications should be 
    considered the authors' opinion and thus, not scientifically sound.
        FDA agrees that many reference publications may not be up to date. 
    However, Congress did include reference publications within the scope 
    of section 401 of FDAMA. There is no basis to presume that all 
    reference publications are not scientifically sound.
        32. Several comments opposed the requirement that disseminated 
    information in the form of a reference publication ``pertain to a 
    clinical investigation regarding the drug or device.'' Instead, they 
    argued, the reference publication should ``include information about'' 
    such a study. Some comments interpreted this to mean that the study 
    should meet all of the criteria to establish scientific soundness, but 
    the information about such a study should not be required. One comment 
    said that the language means that the information needs to be based on 
    a scientifically sound clinical investigation, it need not be about or 
    describe such clinical investigation.
        Both the act and this part provide that reference publications must 
    ``include information about a clinical investigation.'' However, this 
    does not mean that the information about that clinical investigation 
    should be any less complete than the information included in a journal 
    article. It means only that the text may have a lot of additional 
    information that is not about the clinical investigation. The idea 
    behind the dissemination provision is that physicians and other 
    recipients be in a position to make treatment decisions based on 
    published reports of clinical trials. If the information that is 
    disseminated gives them little or no information about the actual 
    trial, then it would be difficult to argue that they have a reasonable 
    basis upon which to make such treatment decisions.
        33. A number of comments argued that the proposal has written 
    reference publications out of the statute by requiring the same level 
    of detail as would appear in journal articles. One comment said that 
    FDA should accept the dissemination of peer-reviewed reference 
    publications. Some comments argued that the proposal would make text 
    book dissemination more difficult than it was prior to passage of FDAMA 
    and that FDA should adopt a final rule that is consistent with its 
    existing reference text guidance or it should leave that guidance in 
    place. One comment argued that the statute makes it clear that FDA must 
    allow the dissemination of reference publications that meet the 
    requirements of the statute and that the agency's decision to issue a 
    guidance document on this issue is not an option.
        As set forth previously, FDA does not believe that Congress meant 
    that reference publications disseminated under this part could have 
    less detail about clinical investigations than journal articles. In 
    addition, reference publications are not subject to classic peer-
    review. Therefore, FDA rejects the comment that FDA accept all peer-
    reviewed reference publications. As discussed in the preamble to the 
    proposal, however, FDA recognizes that it will be difficult for many 
    reference publications to meet the statutory criteria. Moreover, as set 
    forth in many of the comments, the new statutory scheme in most 
    respects makes it more difficult to disseminate reference publications 
    than was possible before FDAMA. Thus, FDA plans to permit companies to 
    distribute unabridged reference publications (as defined in the statute 
    and Sec. 99.3(i)) without meeting all of the requirements set forth in 
    this part if the company does not focus on or point to a specific 
    unapproved use in the publication and it includes a disclaimer that the 
    publication includes information about unapproved uses. (Cf. Guidance 
    for Industry Funded Dissemination of Reference Texts (61 FR 52900, 
    October 8, 1996). The agency was enjoined from applying this guidance 
    document in WLF v. Friedman. FDA sought clarification on the scope of 
    the order in that case through a motion to amend the judgment.) FDA 
    plans to issue guidance on this issue at some time in the future 
    following clarification by the court. Of course, manufacturers that 
    want to focus or point to a specific unapproved use will have the 
    option of doing so by meeting the requirements set forth in this part.
        34. One comment argued that Congress intended for manufacturers to 
    be able to disseminate reference publication chapters.
        Section 552(a)(1) of the act clearly requires that the reference 
    publication be unabridged. A chapter from a textbook does not meet this 
    requirement.
        35. Proposed Sec. 99.101(b)(2) provided that journal articles and 
    reference publications disseminated under part 99 cannot be 
    disseminated with any information that is promotional in nature. One 
    comment strongly agreed with the concept of prohibiting promotional 
    material to be distributed with scientific information on a new use. 
    One comment opposed the concept, stating that there is no policy or 
    legal rationale for prohibiting companies from distributing information 
    on approved uses with these reprints. A number of comments requested 
    clarification of this statement. These comments were concerned that it 
    could preclude a sponsor from delivering a promotional piece on a 
    labeled use during the same office visit or detail. These comments 
    suggested that FDA
    
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    clarify that so long as the promotional material concerns an approved 
    use and is kept physically distinct from the unapproved use 
    information, FDA would not consider the two to be distributed together.
        FDA did not intend to prohibit a sponsor from delivering 
    promotional pieces on an approved or cleared use during an office visit 
    or detail in which it has delivered information on an unapproved use. 
    Any unapproved use information, however, must be kept physically 
    distinct from the promotional materials, and the sponsor may not 
    verbally promote the unapproved use or include materials about the 
    unapproved use, beyond those permitted or required under this part.
        b. Mandatory statements and information (Sec. 99.103). Proposed 
    Sec. 99.103 described the information that must accompany the journal 
    article or reference publication. For example, it required a 
    prominently displayed statement disclosing (among other things) that 
    the information being disseminated is about a use that has not been 
    approved or cleared by FDA and is being disseminated under section 551 
    et seq. of the act and, if applicable, a statement that there are 
    products or treatments that have been approved or cleared for the use 
    that is the subject of the dissemination. It also required the official 
    labeling and a bibliography of other articles to accompany the 
    disseminated information. In addition, the proposal described what is 
    meant by a ``prominently displayed'' statement by setting forth 
    criteria that are consistent with the agency's regulations on 
    prescription drug advertising (Sec. 202.1(e)(7)(viii)) and labeling (21 
    CFR 201.10(g)(2)). Proposed Sec. 99.103 required the statement that the 
    use has not been approved and the additional information required by 
    FDA to be attached to the front of the disseminated materials and that 
    all other mandatory information be attached to the disseminated 
    information.
        36. Although some comments supported FDA's position on mandatory 
    statements, there were others that thought the proposal was unduly 
    restrictive. For example, although some comments supported the 
    requirement for a uniform statement disclosing that the new use has not 
    been approved by FDA, there were a number of comments that thought 
    manufacturers should be allowed to use alternative language to convey 
    this message. One comment specifically objected to the phrase ``and is 
    being disseminated under section 551 of the Federal Food, Drug, and 
    Cosmetic Act.'' This comment said that the phrase was unnecessary and 
    could be confusing.
        FDA continues to believe that it is important to have a uniform 
    disclosure stating that the new use has not been approved by FDA. 
    Different statements can be confusing and recipients of the information 
    may believe that they have different meanings. FDA agrees, however, 
    that the phrase: ``and is being disseminated under section 551 et seq. 
    of the Federal Food, Drug, and Cosmetic Act'' is unnecessary and has 
    therefore dropped it from the final rule.
        37. One comment stated that clarification is needed regarding 
    articles that discuss more than one use because, as written, 
    Sec. 99.103(a)(1)(i) uses singular and plural forms in a way that is 
    confusing.
        FDA agrees that clarification was needed and has revised the final 
    rule accordingly.
        38. Proposed Sec. 99.103(a)(1)(iii) required a statement disclosing 
    any authors who have a significant financial interest in the 
    manufacturer. One comment noted that, although the disclosure is 
    appropriate, the final rule should make clear that such disclosure be 
    in line with the level required by the rule on financial disclosure and 
    should apply only to the financial interests at the time the study was 
    conducted and not the author's current interest.
        In the preamble to the proposed rule, FDA stated that an author 
    would have a significant financial interest in a manufacturer when 
    there is a relationship that may give rise to actual or perceived 
    conflicts of interest and that when there is a question as to whether a 
    relationship is significant, it should be disclosed (see 63 FR 31143 at 
    31147). Manufacturers may consult the final rule on financial 
    disclosure by clinical investigators (codified at 21 CFR part 54) to 
    learn the types of financial interests of greatest concern to the 
    agency. However, because the purposes and terminology of this final 
    rule and the final rule on financial disclosure by clinical 
    investigators are different, manufacturers should consult the 
    provisions of this final rule for the requirements that apply to 
    disclosures regarding authors. FDA agrees that the financial disclosure 
    should not necessarily apply to the author's current financial 
    interest. FDA believes, however, that it should apply to the author's 
    financial interests during the time the study was conducted up through 
    1 year after the time the journal article or reference publication was 
    written and published. FDA has revised the final rule to reflect this 
    time limitation. FDA's revision is consistent with part 54.
        39. One comment urged FDA to require that the statement that there 
    are products or treatments that have been approved or cleared for the 
    use that is the subject of the dissemination list the names of other 
    drugs that have been approved by FDA. Another comment asked whether 
    such statement should address adjuvant or supporting therapies.
        FDA's regulation tracks the statute, which does not require a 
    manufacturer to identify the specific products that have been approved 
    or cleared for the new use or the adjuvant or supporting therapy for 
    the new use. (See section 551(b)(6)(A)(v) of the act.) Although FDA can 
    see the benefit of having those specific product names listed, it would 
    be difficult to develop a complete and accurate list. Moreover, the 
    information could be misleading if the manufacturer merely provided a 
    list of names. FDA also does not believe that the statement should 
    address adjuvant or supporting therapies. The idea behind the 
    disclosure is to let health care practitioners and other recipients 
    know that approved/cleared alternatives exist. Therefore, FDA is 
    retaining the requirement that the manufacturer only disclose that such 
    approved/cleared products exist.
        40. Proposed Sec. 99.103(a)(2) provided that the manufacturer must 
    attach the official labeling of the product to the unapproved use 
    information. In the preamble to the proposed rule (63 FR 31143 at 
    31147), FDA noted that devices, unlike drugs, do not always include a 
    package insert in the same form and manner as drugs. Therefore, the 
    agency would expect device manufacturers to provide the same 
    information that is generally found in package inserts, namely: (1) The 
    name of the device, including its trade or proprietary name; (2) the 
    manufacturer's name, address, and telephone number; (3) a statement of 
    intended use, including a general description of the diseases or 
    conditions that the device is intended to diagnose, treat, cure, or 
    mitigate; (4) a description of the patient population for which the 
    device is intended; (5) a description of indications that have been 
    approved or cleared by FDA; (6) a description of any limitations or 
    conditions that have been placed on the sale, distribution, or use of 
    the device; and (7) all warnings, contraindications, side effects, and 
    precautions associated with the use of the device.
        One comment suggested that a device's official labeling be 
    interpreted as: (1) The package insert for the device; (2) the 
    accompanying documents that a manufacturer distributes with its legally
    
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    marketed device to comply with the requirements of 21 CFR 801 or 809.10 
    for in vitro diagnostic products; or (3) the new labeling vehicle 
    created by a manufacturer that contains the listed items from the 
    preamble.
        FDA agrees that this interpretation of official labeling for 
    devices is appropriate provided the third option is used only when the 
    first two options are not available or not feasible and provided the 
    third option includes only the information listed in the preamble 
    (i.e., no promotional statements or representations are included).
        41. Proposed Sec. 99.103(a)(3) required the manufacturer to attach 
    a bibliography of other articles (that concern reports of clinical 
    investigations both supporting and not supporting the new use). One 
    comment noted that a bibliography is not required every time--only when 
    one is not present in the disseminated information. Another comment 
    stated that the bibliography requirement is vague regarding what needs 
    to be included and under what circumstances a bibliography included in 
    the publication is sufficient.
        FDA's proposal provided that the manufacturer need not include a 
    separate bibliography if the disseminated information already includes 
    a bibliography that meets the requirements set forth in 
    Sec. 99.103(a)(3). The bibliography requirement would be met by a list 
    of all other published articles from scientific reference publications 
    or scientific or medical journals that discuss clinical investigations 
    and are specific to the new use discussed in the disseminated 
    information. The bibliography must include articles about clinical 
    investigations that both support and do not support the new use and it 
    must identify which articles relate to the new use. A bibliography 
    already included with the disseminated information would meet this 
    requirement only if it includes all other such published articles. The 
    manufacturer would still have to include its search strategy to show 
    that it took reasonable steps to ensure that the bibliography includes 
    all relevant published articles as described in Sec. 99.103(a)(3).
        42. Proposed Sec. 99.103(a)(4) required a manufacturer to include 
    any additional information required by FDA, including objective and 
    scientifically sound information pertaining to the safety or 
    effectiveness of the new use that FDA determines is necessary to 
    provide objectivity and balance, including information that the 
    manufacturer has submitted to FDA or, where appropriate, a summary of 
    such information, and any other information that can be made publicly 
    available; and an objective statement prepared by FDA, based on data or 
    other scientifically sound information, bearing on the safety or 
    effectiveness of the new use of the product.
        Several comments noted that this provision should specify that FDA 
    must provide the manufacturer notice and an opportunity to meet before 
    requiring such information.
        FDA agrees that a manufacturer must be provided notice and an 
    opportunity to meet before being required to include this additional 
    information. Redesignated Sec. 99.301(a)(2) provides this opportunity 
    and FDA has revised the final rule at Sec. 99.103(a)(4) to include a 
    reference to Sec. 99.301(a)(2).
        43. Several comments opposed the requirement that the statement 
    that the use has not been approved and the additional information 
    required by FDA be attached to the front of the disseminated materials 
    and that all other mandatory information be attached to the 
    disseminated information. One comment suggested that the FDA-required 
    information be attached to the back, and that FDA permit the use of a 
    sticker on the front of the disseminated material stating that the FDA-
    required information is attached to the back.
        FDA believes that it is important to permanently affix the 
    statement indicating that the disseminated information is about an 
    unapproved use to the front of the materials. The recipients of such 
    materials should know, in advance, that they are reading information 
    about an unapproved use. However, FDA agrees that it could be 
    appropriate to attach the additional information required by FDA to the 
    back of the materials, provided there is a sticker or notation on the 
    front referring the recipient to that information. The agency has 
    amended Sec. 99.103(a)(4) accordingly.
        FDA also believes it is important to attach the remaining 
    information to the disseminated materials. Congress included this 
    mandatory information because it determined that it was important for 
    the recipient to receive it. If such information is not attached, it 
    can easily be separated from the disseminated material and never seen 
    by the recipient. This is the information that helps to ensure that the 
    disseminated materials are objective, balanced, and not misleading.
        44. Although some comments stated that the criteria in proposed 
    Sec. 99.103(c) for determining whether the mandatory information is 
    prominently displayed are appropriate, others opposed the factors that 
    FDA will consider in determining whether the mandatory information is 
    prominently displayed. The latter comments argued that manufacturers 
    should retain some flexibility and discretion in this area.
        FDA's approach is flexible. Section 99.103(c) sets forth the 
    factors that FDA will consider and provides that the required 
    statements shall be outlined, boxed, highlighted, or otherwise 
    graphically designed and presented in a matter that achieves emphasis 
    or notice and is distinct from the other information being disseminated 
    (emphasis added). Such an approach is not as proscriptive as the 
    comments imply. FDA has retained this approach in the final rule.
        45. One comment suggested that FDA permit manufacturers to post 
    information, such as balancing articles required by FDA, on the 
    Internet so long as the Internet address is prominently displayed on 
    the information that was disseminated. The comment said that this would 
    reduce paperwork burdens and provide a continuous source of current 
    information.
        FDA does not think that it would be appropriate for manufacturers 
    to use the Internet to balance a published reprint disseminated in hard 
    copy format or to provide recipients of unapproved use information with 
    only part of the information required by the statute and regulations. 
    The idea behind the provision was that physicians would receive, at one 
    time, a balanced package. Such balance would not be achieved if a 
    manufacturer could hand a physician an article and then advise the 
    physician that he/she has to take steps on his/her own to retrieve the 
    balancing information.
        46. Several comments urged FDA to require manufacturers to provide 
    patient labeling for drugs that are the subject of the disseminated 
    information. The comments noted that such labeling should identify the 
    drug by name, notify consumers that the drug has been promoted for an 
    unapproved use, and indicate FDA-approved uses for the drug. They 
    further argued that the patient labeling must include information about 
    the potential risks of the drug and meet the quality and content 
    standards of FDA's 1995 proposed Medication Guide rule. This comment 
    said that FDA-approved patient labeling must be in commercial 
    distribution at the level of the pharmacy before dissemination under 
    this part can begin. One comment stated that the labeling should state 
    that these products are not tested in certain populations and should 
    say ``use at your own risk.''
    
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        FDA recognizes the importance of providing consumers access to 
    information about the products they use. Since 1968, FDA has 
    occasionally required and often encouraged manufacturers to produce 
    patient labeling for certain prescription drugs. However, the comments' 
    request for additional patient labeling on drugs that are the subject 
    of information disseminated under part 99 is outside the scope of 
    section 401 of FDAMA.
        47. Several comments argued that the lack of availability of 
    pediatric studies on a particular use should be clearly and prominently 
    stated in the information being disseminated to health professionals. 
    These comments also urged FDA to require an additional statement for 
    drugs that have not undergone pediatric testing: ``Safety and 
    effectiveness in pediatric populations have not been established for 
    this product for the use that has been approved by FDA or for the use 
    suggested by this information.''
        The suggestion that for drugs and devices that have not undergone 
    pediatric testing, the disseminated information should include a 
    statement to that effect is beyond the scope of this rule. However, for 
    unapproved pediatric uses that are the subject of the information being 
    disseminated, there will be a statement that the use has not been 
    approved or cleared by FDA.
        c. Recipients of information (Sec. 99.105). Proposed Sec. 99.105 
    identified who may receive information disseminated under this part. 
    Specifically, a health care practitioner, pharmacy benefit manager, 
    health insurance issuer, group health plan, or Federal or State 
    Government agency could receive information disseminated under part 99.
        48. Several comments urged FDA to add pharmacists to the list of 
    recipients of information under this part.
        As previously discussed, section 401 of FDAMA specifically lists 
    who can receive the unapproved use information under this provision. To 
    the extent that pharmacists are included in the definitions of ``health 
    care practitioner,'' ``pharmacy benefit manager,'' ``health insurance 
    issuer,'' or ``group health plan'' (see Sec. 99.3), they will be 
    included as recipients of this information.
    3. Subpart C--Manufacturer's Submissions, Requests, and Applications
        a. Manufacturer's submission to the agency (Sec. 99.201). Proposed 
    Sec. 99.201 described the contents of a manufacturer's submission to 
    FDA. This submission would be made 60 days before disseminating 
    information on an unapproved or new use and would include items such as 
    a copy of all of the information to be disseminated, all other clinical 
    trial information that the manufacturer has relating to the safety or 
    effectiveness of the new use, any reports of clinical experience 
    pertinent to the safety of the new use, and, if a supplement for the 
    new use has not been submitted, a certification that the manufacturer 
    will submit a supplement or an application for an exemption from the 
    requirement to submit a supplement. The proposal also discussed what 
    types of information must be submitted when the certification provides 
    that the studies have been completed or that studies will be conducted 
    as well as the contents of the certification. Proposed Sec. 99.201 also 
    provided that the 60-day period begins to run when FDA receives a 
    complete submission.
        49. One comment agreed that manufacturers should have to submit any 
    clinical trial information that they have relating to the safety and 
    effectiveness of the new use. However, another comment argued that the 
    requirement for any clinical trial information is far more exhaustive 
    than that required by the statute.
        Section 551(b)(4)(B) of the act requires manufacturers to submit 
    ``any clinical trial information the manufacturer has relating to the 
    safety or effectiveness of the new use, any reports of clinical 
    experience pertinent to the safety of the new use, and a summary of 
    such information.'' Proposed Sec. 99.201(a)(2) tracked this requirement 
    and described what it included. In the final rule, FDA is making clear 
    that, for effectiveness information, the requirements are limited to 
    information on clinical investigations of the new use; safety 
    information is broader and must include all relevant new data from 
    human experience.
        50. One comment urged FDA to require manufacturers to report only 
    those adverse experiences that they have received directly because 
    companies do not have access to the details of cases submitted to other 
    manufacturers and thus, are unable to evaluate the reports. That same 
    comment stated that FDA should permit adverse experience reports to be 
    submitted in summary or tabular form rather than as individual case 
    reports. Several other comments requested the ability to reference 
    files that FDA already has about adverse experiences. Finally, one 
    comment noted that the search requirements for adverse reports should 
    be more clearly delineated.
        Under the statute and these regulations, manufacturers would have 
    to submit only those adverse experience reports that they have. This 
    would include reports originally made to other manufacturers. If the 
    reports were originally submitted to other manufacturers and the 
    disseminating manufacturer does not know whether to attribute the 
    adverse experience to the new use, it should submit the information to 
    FDA. Manufacturers can submit adverse experience reports in summary or 
    tabular form if FDA already has the individual case reports. With 
    respect to search requirements for postmarket adverse event reports, 
    FDA does not think that it is necessary to be any more specific. 
    Manufacturers gather this information on a regular basis.
        51. One comment said that the literature search requirements in 
    Sec. 99.201(a)(3) should be more clearly delineated. Several comments 
    stated that the requirement for the submission of a search strategy is 
    not required by statute and should be eliminated because it is 
    unnecessary and burdensome and could delay the process.
        FDA believes that it is necessary to include the search strategy. 
    This is how FDA will be able to determine whether the bibliography 
    meets the statutory criteria. FDA has revised Sec. 99.201(a)(3), 
    however, to clarify the bibliography search strategy requirements.
        52. FDA, on its own initiative, revised Sec. 99.201(a)(4)(i)(B) and 
    (a)(4)(ii)(B) to clarify that, for purposes of computing time periods 
    that begin on the date of initial dissemination, FDA will look to the 
    date on which dissemination can begin. This clarification was necessary 
    because FDA will not know when a manufacturer actually begins to 
    disseminate materials. The same revision was made to Secs. 99.203(b) 
    and 99.401(b).
        53. Proposed Sec. 99.201(a)(4)(ii) required a manufacturer that has 
    planned studies that will be needed for a supplement to submit the 
    proposed protocols and schedule for conducting such studies. The 
    protocols must comply with FDA's IND or investigational device 
    exemption (IDE) regulations. One comment asked FDA to clarify whether a 
    manufacturer who has planned studies and wishes to disseminate 
    information must submit a complete IND or IDE in addition to the 
    information required in a submission under this rule. One comment 
    stated that if the protocols are to be treated as IND's, IDE's, or 
    amendments thereto, the manufacturer should be able to commence the 
    studies within 30 days unless the agency places the study on clinical 
    hold. The same comment said that if the agency does not place a
    
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    clinical hold on the protocol within 30 days, the agency should not be 
    able to determine that the protocols are inadequate on day 60 and if 
    the protocol is put on clinical hold within 30 days, it should not be 
    dispositive of the decision. The comment further stated that if the 
    agency decides that the protocols are adequate, it should be bound by 
    this decision and the final rule should reflect this. Finally, several 
    comments urged FDA to permit manufacturers to cross reference IND's and 
    IDE's rather than resubmitting such information.
        FDA intends that the protocols for planned studies under this 
    provision be submitted in compliance with the IND or IDE regulations. 
    However, a manufacturer will not be required to submit these materials 
    twice. If a protocol has already been submitted to an IND or IDE, the 
    IND or IDE can be cross referenced in the dissemination submission.
        Moreover, FDA does not intend to change, in any way, the IND or IDE 
    regulations, including the timeframes. If an IND or IDE is submitted 
    and a clinical hold is not issued within 30 days, the manufacturer can 
    commence the study or studies. However, the fact that FDA does not 
    issue a clinical hold within 30 days, does not prevent FDA from 
    determining, within 60 days, that a protocol is inadequate. FDA can 
    issue a clinical hold at any time after the 30-day period if the 
    requirements for issuing a clinical hold are met. If the protocol is 
    put on clinical hold within 30 days, it may not be dispositive of the 
    issue because the sponsor may remedy the reason for the clinical hold 
    within the 60-day period. However, if the reason for issuing the 
    clinical hold is not resolved, it will be dispositive of the issue. 
    Finally, FDA is declining to revise the rule to provide that if the 
    agency finds that the protocols are adequate, it will be bound by this 
    decision. FDAMA addressed the issue of agreements regarding the 
    parameters of the design and size of clinical trials. (See, e.g., 
    section 505(b)(4)(C) or section 520(g)(7)(A) through (g)(7)(C) of the 
    act (21 U.S.C. 360j(g)(7)(A) through (g)(7)(C)).) FDA will abide by 
    these statutory directives.
        54. Proposed Sec. 99.201(a)(4)(ii) required a manufacturer that has 
    planned studies that will be needed for the submission of a 
    supplemental application for the new use to certify that it will 
    exercise due diligence to complete such studies and submit a supplement 
    within 36 months of dissemination. FDA has revised this section to 
    reflect the possibility that FDA may determine, before the 
    certification is submitted, that the studies needed to submit a 
    supplemental application cannot be completed and submitted within 36 
    months. This change is further reflected in Sec. 99.203.
        55. One comment requested that the 36-month timeframe for 
    submitting a supplement not override the time limits created under 
    separate regulatory or statutory authority. This comment was concerned 
    that if FDA finalizes its proposed 1997 regulation on pediatric 
    research and it includes compliance dates for completing the pediatric 
    studies that are less than 36 months, the 36-month period in this part 
    not override that shorter timeframe.
        As FDA has stated elsewhere in this document, nothing in this 
    regulation is meant to change or supersede other regulatory 
    requirements.
        56. One comment asked FDA to clarify the submission requirements 
    and FDA action requirements with respect to nonsignificant risk 
    devices.
        Protocols submitted for studies for devices considered to be 
    nonsignificant will be reviewed by FDA only to ensure that the protocol 
    for the study is consistent with the new use information to be 
    disseminated. Manufacturers must present the protocol for the 
    nonsignificant risk device study to an institutional review board (IRB) 
    for approval before starting the study. (See 21 CFR 812.1(b)(1).) 
    However, all reporting requirements under this part will apply to 
    nonsignificant risk device studies.
        57. One comment requested that the agency provide the sponsor an 
    opportunity to meet with FDA promptly to review what changes can be 
    made to the protocol to ensure that it meets requisite standards.
        Sections 505(b)(4)(B) and 520(g)(7)(A) and (g)(7)(C) of the act 
    provide sponsors with an opportunity to meet regarding their proposed 
    protocols. Therefore, no changes to this rule are necessary.
        58. One comment recommended that all statements submitted under 
    this part be certified by an officer from the manufacturer's executive 
    committee. Another comment recommended that the language in the 
    certification should include ``to the best of my knowledge'' to reduce 
    the risk that a certifying official could be penalized for an 
    inadvertent mistake not within his/her knowledge.
        The final rule requires that the manufacturer's attorney, agent, or 
    other authorized official sign the submission. Although an officer from 
    the manufacturer's executive committee may be an authorized official, 
    FDA does not think it is necessary for the submission to be signed by 
    such an officer. FDA also does not agree that it would be appropriate 
    to include the words ``to the best of my knowledge'' in the 
    certification. The attorney, agent, or other authorized official who 
    signs the submission and certification on behalf of the manufacturer, 
    and ultimately the manufacturer itself, is responsible for what is 
    submitted to the agency under this part.
        59. Proposed Sec. 99.201(c) described the component in each FDA 
    center that will receive a submission under this part. Several comments 
    noted that it would be appropriate for the review divisions in the 
    centers to also receive copies of the information submitted under this 
    part.
        In the final rule, FDA is retaining the requirement that the 
    submissions go to a single office within each center. Those offices 
    will forward the information to the appropriate review divisions within 
    the agency. The regulation need not spell out all of FDA's internal 
    procedures for processing these submissions.
        60. One comment stated that FDA needs to clarify the required 
    physical organization of the documents submitted under this part.
        FDA does not think it is appropriate to include that kind of detail 
    in this regulation. Nevertheless, FDA expects that materials in a 
    submission will be organized and labeled in accordance with the 
    submission requirements described in this part. If FDA subsequently 
    determines that manufacturers need more guidance in this area, it will 
    issue a guidance document.
        61. A number of comments objected to proposed Sec. 99.201(d), which 
    provided that the 60-day (post submission) period shall begin to run 
    when FDA receives a complete submission and that a submission shall be 
    considered complete if FDA determines that it is sufficiently complete 
    to permit a substantive review. These comments argued that FDA would 
    use this provision to extend the 60-day time period. The concern was 
    that FDA would, on day 59, advise a manufacturer that their submission 
    was not complete and therefore the 60-day time period had not begun. 
    The comments said that Congress meant for FDA to give a final answer 
    within the 60-day time period.
        As further described below, FDA is committing to give manufacturers 
    a final decision within 60 days. FDA has revised Sec. 99.201(d) to 
    provide that the 60-day period shall begin when FDA receives a 
    manufacturer's submission, including, where applicable, a
    
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    certification statement or an application for an exemption.
        62. A number of comments were made regarding the appropriateness of 
    public disclosure of information submitted under this part. Some 
    comments argued that both the fact of the submission and all 
    information in the submission is confidential and should not be 
    released. Other comments argued that all of the previous information 
    should be public because the public, including the patient community, 
    wants to be involved and has a right to know about a submission, the 
    data in such submission, FDA action on the submission, what studies are 
    being conducted, and the status of those studies. Several comments 
    argued that upon receiving a submission, FDA should publish in the 
    Federal Register, the citation for the article and the bibliography, 
    and solicit additional published information that might be appropriate 
    for dissemination. One comment argued that the public should have an 
    opportunity to comment prior to FDA's granting approval for 
    dissemination of information and that FDA should hold an advisory 
    committee meeting and let the public participate in its decision on 
    whether an exemption from the requirement to submit a supplement should 
    be granted.
        FDA declines to amend the rule to require a notice and comment 
    process before permitting dissemination to proceed or before granting 
    an exemption. However, the Freedom of Information Act (FOIA) and FDA's 
    regulations will dictate what information submitted under this 
    provision can be disclosed. Because the agency was required to issue 
    this regulation within such a short period of time, it has been unable 
    to fully examine all issues of disclosability. However, the agency will 
    continue to examine these issues separately.
        b. Request to extend the time for completing planned studies 
    (Sec. 99.203).   Section 554(c)(3) of the act (21 U.S.C. 360aaa-3) 
    describes two types of extensions of time regarding planned studies. 
    Section 554(c)(3)(A) of the act provides that the 36 month period for 
    completing planned studies and submitting a supplemental application 
    may be extended by the Secretary of Health and Human Services (the 
    Secretary) if the Secretary determines that the studies needed to 
    submit such application cannot be completed and submitted within 36 
    months. This type of extension would be granted before such studies are 
    begun. Section 554(c)(3)(B) of the act provides that the period for 
    completing planned studies and submitting a supplemental application 
    may be extended by the Secretary if the manufacturer submits a written 
    request for the extension and the Secretary determines that the 
    manufacturer has acted with due diligence to conduct the studies in a 
    timely manner. The latter extension cannot exceed 24 months. Proposed 
    Sec.  99.203 set forth the procedures that a manufacturer must follow 
    to request an extension of time for submitting a supplemental 
    application and the content of a request for an extension. The 
    provision covered only the extension in section 554(c)(3)(B) of the 
    act.
        63. The comments to this provision indicated that there was some 
    confusion regarding the two different statutory procedures. Several 
    comments asked FDA to more clearly set out the two procedures 
    contemplated by the statute.
        Although the statute specifically refers to a manufacturer request 
    in connection only with the procedure described in section 554(c)(3)(B) 
    of the act and FDA agrees that the agency can, under section 
    554(c)(3)(A), on its own initiative determine before the studies have 
    begun that more than 36 months is needed, FDA believes that 
    manufacturers will come to FDA and ask FDA to make a determination 
    under section 554(c)(3)(A) of the act. Therefore, FDA has revised 
    Sec. 99.203 to establish procedures for the two different types of 
    extensions. The first extension, set forth in Sec. 99.203(a), relates 
    to a request for an extension by the manufacturer at or before the time 
    it submits its dissemination package to FDA because the 36-month period 
    is not enough time to complete a study or studies of the new use and 
    submit a supplemental application. Revised Sec. 99.203(b) sets forth 
    the procedures that a manufacturer must follow to request an extension 
    of time for submitting a supplemental application after a study has 
    begun and the content of a request for an extension.
        c. Application for exemption from the requirement to file a 
    supplemental application (Sec. 99.205). Proposed Sec. 99.205 set forth 
    what a manufacturer must submit when seeking an exemption from the 
    requirement to file a supplemental application for a new use for 
    purposes of disseminating information on that new use. It required the 
    manufacturer to include an explanation as to why an exemption is sought 
    and to include materials demonstrating that it would be economically 
    prohibitive or unethical to conduct the studies needed to submit a 
    supplemental application for the new use.
        64. A number of comments supported the standards that FDA proposed 
    to determine whether it would be economically prohibitive or unethical 
    to conduct the studies needed to submit a supplemental application. 
    Some noted that FDA's standards are consistent with congressional 
    intent that exemptions be limited in scope and infrequent or rare. One 
    comment argued that pediatric exemptions should be extremely rare. One 
    comment stated that exemptions should never be granted.
        FDA agrees that Congress intended that exemptions from the 
    requirement to file a supplemental application for a new use be granted 
    in limited circumstances (see H. Conf. Rept. No. 399, 105th Cong., 1st 
    sess. at 100 (1997); 143 Congressional Record S9,837 (daily ed. Sept. 
    24, 1997) (Statement of the Managers)). There is nothing in the statute 
    or legislative history that gives FDA authority to apply a different 
    standard in the case of pediatric exemptions. Moreover, the act 
    provides for exemptions, so FDA does not agree that such exemptions 
    should never be granted. In light of the comments received to the 
    standards set forth in its proposal (discussed in more detail below), 
    FDA is adopting a different standard for the economically prohibitive 
    exemption. Although, FDA is not changing the standard for the unethical 
    exemption, it has, as discussed in the following paragraphs, clarified 
    how it will apply that exemption.
    Economically Prohibitive Exemption
        Under proposed Sec. 99.205(b)(1), a manufacturer seeking an 
    exemption from the requirement to file a supplemental application on 
    the basis that it would be economically prohibitive to conduct the 
    needed studies would have to: (1) Explain why existing data, including 
    data from the scientifically sound study described in the information 
    to be disseminated, are not adequate to support approval of the new 
    use; and (2) show, at a minimum, that the estimated cost of the 
    necessary studies would exceed the estimated total revenue from the 
    product minus the cost of goods sold and marketing and administrative 
    expenses attributable to the product and that there are not less 
    expensive ways to obtain the needed information.
        Proposed Sec. 99.205(b)(1) set forth the type of evidence that the 
    manufacturer would have to include to meet the requirements for an 
    economically prohibitive exemption. These included:
        (1) A description of the current and projected U.S. patient 
    population for the product and an estimate of the current and projected 
    economic benefit to the
    
    [[Page 64569]]
    
    manufacturer from the use of the drug or device in this population. The 
    estimate would assume that the total potential market for the drug or 
    device is equal to the prevalence of all of the diseases or conditions 
    that the drug or device will be used to treat and involve the following 
    considerations: (a) The estimated market share for the drug or device 
    during any exclusive market period, a summary of the exclusive market 
    period for the product, and an explanation of the basis for the 
    estimate; (b) a projection of and justification for the price at which 
    the drug or device will be sold; and (c) comparisons with sales of 
    similarly situated drugs or devices, where available.
        (2) A description of the additional studies that the manufacturer 
    believes are necessary to support the submission of a supplemental 
    application for the new use and an estimate of the projected costs for 
    such studies; and
        (3) An attestation by a responsible individual of the manufacturer 
    verifying that the estimates included with the submission are accurate 
    and were prepared in accordance with generally accepted accounting 
    procedures. The data underlying and supporting the estimates shall be 
    made available to FDA upon request.
        65. As set forth previously, some of the comments agreed with FDA's 
    construction of ``economically prohibitive'' These comments argued that 
    such exemptions should be granted rarely and that the criteria for such 
    an exemption should be rigorous. One comment argued that the cost for 
    the studies should substantially exceed revenues to qualify for the 
    exemption. Several comments opposed such an equation.
        FDA agrees that exemptions should be granted only in limited 
    circumstances. As set forth below, however, FDA was convinced by the 
    comments that the standard set forth in its proposal was inappropriate 
    and has revised the standard.
        66. A number of comments objected to how the agency proposed to 
    determine what is economically prohibitive. First, they objected to the 
    agency's use of the term ``rare'' in describing when such exemptions 
    would be granted. One comment opined that Congress meant for the 
    exemption to arise in a ``fair number of circumstances.'' Second, they 
    objected to the absence of the criteria listed in the statute and 
    report language from the standard set forth in the codified regulation. 
    Third, they claimed that the proposed rule's standard for determining 
    what is economically prohibitive is too high.
        One comment argued that the exemption should be granted if it does 
    not make economic sense to pursue a supplement. Others argued that it 
    should be based on the revenue from the new use, not all uses of the 
    product. Some argued that the standard should be whether the cost of 
    the studies would exceed the revenues from the new use; others argued 
    that it should be whether the cost of the studies exceeds the new use 
    revenues that resulted from approval of the supplement (i.e., the 
    increase in revenues from the new use that result from submission of 
    the supplement). Several comments argued that FDA should automatically 
    grant an exemption if the new use is for a rare disease or condition 
    because for such use there is no reasonable expectation that the cost 
    of developing and making available a drug for such disease will be 
    recovered from sales in the United States of such drug. Several 
    comments argued that the economically prohibitive exemption should 
    automatically be granted if: (1) There is no market exclusivity for the 
    product (from patent, orphan drug status, or Waxman-Hatch); or (2) the 
    patient population likely to be served by the new indication will not 
    exceed an established number (e.g., 1,000). One comment opined that 
    interpreting ``prohibitive'' to mean anything other than the point at 
    which an economically rational company will not pursue research ignores 
    the needs of patients with rare disorders.
        FDA agrees that Congress did not use the term ``rare'' in the 
    legislative history. Nevertheless, Congress did state that exemptions 
    to the requirement to submit a supplement would be appropriate only in 
    ``limited circumstances,'' which in FDA's view implies fewer than in a 
    ``fair number of circumstances.'' Moreover, Congress strongly 
    emphasized the critical importance of getting information about new 
    uses onto the label. Although FDA did not include the criteria listed 
    in the statute and the legislative history in the standard for 
    economically prohibitive, they were included as types of evidence that 
    would be required to support the exemption.
        FDA's proposed criterion did not focus solely on sales from the new 
    use because the agency believed that there might be many circumstances 
    where the cost of the study requirements would exceed the sales from 
    just the new use. The agency explained that in some of these 
    situations, even if it were not economically ``wise'' to conduct the 
    studies, the cost would not rise to the level of being ``prohibitive.'' 
    This view was judged consistent with the legislative history, which 
    foresaw the granting of economic exemptions only in limited 
    circumstances. The agency noted, however, that defining a practical 
    ``economically prohibitive'' exemption was particularly troublesome, 
    because it would be so difficult for the agency to assess cost and 
    income projections. In view of these difficulties, FDA acknowledged 
    that it was not certain that the proposed approach was optimal and 
    sought comment on other possible ways to define economically 
    prohibitive.
        Unfortunately, the agency has received widely conflicting public 
    comment on this issue and remains uncertain about the elements of a 
    standard that would be most appropriate and effective in achieving the 
    statutory goals. An approach that would grant automatic exemptions if: 
    (1) The new use were for a rare disease or condition; (2) there was no 
    market exclusivity for the product (from patent, orphan drug status, or 
    Waxman-Hatch); or (3) the patient population likely to be served by the 
    new indication would not exceed an established number (e.g., 1,000) 
    would be inappropriate. Neither the statute nor the legislative history 
    provide for automatic exemptions in these circumstances. Rather, they 
    direct FDA to take both market exclusivity and population size into 
    account. The legislative history made clear that the size of the 
    patient population would not necessarily justify an exemption. In fact, 
    the legislative history stated that an exemption based on the size of 
    the patient population was intended to be the exception rather than the 
    rule in cases of populations suffering from orphan or rare diseases or 
    conditions. The legislative history made clear that FDA should consider 
    the importance of getting products for these diseases or conditions 
    approved. It noted that for many years, Congress has sought to 
    encourage research into orphan diseases and support the approval of 
    innovative drugs for their treatment. Congress, therefore, has directed 
    FDA to recognize the vital importance of encouraging applications for 
    new products intended to treat rare diseases and to examine very 
    carefully whether an exemption from filing a supplemental application 
    might hinder such research (see H. Conf. Rept. No. 399, 105th Cong., 
    1st sess. at 100 (1997); H. Rept. No. 310, 105th Cong. 1st. sess. at 62 
    (1997)).
        Because the agency remains uncertain about the elements of a 
    standard that would be most appropriate and effective, FDA plans to 
    continue its search for a policy that would satisfy the congressional 
    expectation of approving exemptions in only limited
    
    [[Page 64570]]
    
    circumstances, without foreclosing the dissemination of useful 
    information by firms that could not otherwise conduct the needed 
    studies. In the meantime, FDA will implement the statute by basing its 
    evaluation of each exemption on a case-by-case determination of whether 
    the cost of the study for the new use reasonably exceeds the total 
    expected revenue from the new use minus the cost of goods sold and 
    marketing and administrative expenses attributable to the new use of 
    the product. This standard may not always meet a strict profitability 
    criterion because it considers all new use revenues, rather than just 
    the new use revenues that would result from approval of the supplement. 
    Nevertheless, it is consistent with most of the comments submitted by 
    the affected industry on this issue, it is consistent with the 
    statutory directive, and it attempts to strike a fair balance between 
    assuring the widest possible information dissemination while granting 
    economic exemptions only in ``limited circumstances.''
        The final rule sets forth the statutory standard and the 
    information that FDA would need to make this case-by-case 
    determination. This will include information about: (1) The cost of the 
    study for the new use; (2) the expected patient population for the new 
    use; (3) the expected total revenue for the new use minus the cost of 
    goods sold and marketing and administrative expenses attributable to 
    the new use of the product; (4) the amount of exclusivity for the drug 
    or new use; and (5) other information that the manufacturer believes 
    demonstrates that conducting the studies on the new use would be 
    economically prohibitive.
        As this revised criterion may significantly expand the number of 
    exemption applications beyond that anticipated by the Congress, the 
    agency is determined to review its experience with these requests as 
    they are submitted and, if necessary, to contract with outside economic 
    experts to help develop an approach that most appropriate and effective 
    and workable for the agency.
        67. A number of comments objected to the requirement to submit 
    detailed financial data. These comments argued that manufacturers 
    should be not required to submit highly sensitive and proprietary 
    information. Others felt that FDA is not qualified to review and 
    evaluate this data.
        Congress directed FDA to grant an economic exemption only upon 
    making a determination that conducting the studies and submitting a 
    supplement would be economically prohibitive. FDA cannot make this 
    determination without examining the relevant company data. Therefore, 
    the final rule retains these requirements.
        68. Several comments regarding FDA's approach to economic 
    exemptions recommended that FDA require a manufacturer to submit a 
    certified public accountant's (CPA's) opinion on the economic 
    feasibility of filing a supplemental NDA. FDA could contest the claim 
    by providing a CPA's statement to the contrary.
        FDA declines to adopt this approach because it removes the agency 
    from the statutorily-specified role of determining whether it would be 
    economically prohibitive to conduct the studies.
        69. One comment recommended that manufacturers be given the 
    flexibility to present whatever information they determine is relevant 
    to the ``economically prohibitive'' factor, that the manufacturer be 
    able to use its own assumptions, and that each situation be evaluated 
    on a case-by-case basis.
        As set forth previously, FDA is adopting a case-by-case 
    determination and has specified the information that is essential for 
    this determination. Nevertheless, manufacturers are free to provide 
    whatever additional information they think is relevant to the 
    determination. This could include information that would explain why a 
    study is so expensive to conduct. For example, one factor might be the 
    difficulty of enrolling patients in a clinical investigation if the new 
    use has become the standard of care.
        70. Proposed Sec. 99.205(b)(1)(ii)(A) stated that the estimated 
    economic benefit for a drug or device shall assume that the total 
    potential market is equal to the prevalence of the disease(s) or 
    condition(s) that such product will be used to treat. Several comments 
    argued that this assumption should be deleted because the potential 
    market for the drug or device may be less than the prevalence of the 
    disease in question if other therapies are likely to be used in some 
    portion of the total patient population.
        FDA agrees that this assumption should be deleted and has done so 
    in the final rule.
        71. One comment argued that the manufacturer should not be required 
    to provide a ``justification'' of the price at which the drug will be 
    sold. According to this manufacturer, only a projection is relevant.
        FDA has to be able to determine whether the manufacturer's proposed 
    price is reasonable. It may be that ``justification'' for the price is 
    not appropriate. Therefore, in Sec. 99.205(b)(ii)(C) of the final rule, 
    FDA will seek an explanation of the price at which the drug or device 
    will be sold.
        72. One comment opined that permitting an exemption because of cost 
    is an ethical decision because it is placing a monetary value on 
    people's lives and safety.
        FDA does not agree that an economically prohibitive exemption is 
    placing a monetary value on people's lives and safety. The standard in 
    FDA's regulation is intended to best effectuate the goals of the 
    statute.
        73. Proposed Sec. 99.205(b)(1)(ii)(C) required a manufacturer to 
    provide an attestation by a responsible individual of the manufacturer 
    verifying that the estimates included with a submission are accurate 
    and were prepared in accordance with generally accepted accounting 
    procedures. In addition, the data underlying and supporting the 
    estimates would have to be made available to FDA upon request. In the 
    preamble to the proposed rule, FDA noted that it had considered 
    requiring a report of an independent CPA with respect to the estimates 
    and FDA solicited comment on whether such a report should be required 
    in lieu of, or as an alternative to, the attestation that would be 
    required by the proposal.
        Some comments supported the submission of the CPA report discussed 
    previously, others felt that such a report should not be required. 
    Still other comments stated that the CPA report should be submitted in 
    lieu of the underlying data or that the CPA should make the 
    determination of economic feasibility instead of FDA.
        As stated previously, FDA refuses to adopt a procedure by which it 
    surrenders decision making to a CPA. However, FDA is not convinced that 
    it is necessary to require a report of an independent CPA with respect 
    to the estimates. Under Sec. 99.205(b)(1)(iii), therefore, FDA will 
    accept either an attestation by a responsible individual of the 
    manufacturer or by a CPA verifying that the estimates included with a 
    submission are accurate and were prepared in accordance with generally 
    accepted accounting procedures.
    Unethical Exemption
        Proposed Sec. 99.205(b)(2) required a manufacturer seeking an 
    exemption on the basis that it would be unethical to conduct the 
    studies needed to submit a supplement, to: (1) Explain why existing 
    data, including data from the scientifically sound study described in 
    the information to be disseminated, are not adequate to support 
    approval of the new use; and (2) show that, notwithstanding the 
    insufficiency of existing data to support the submission of a 
    supplemental application for the
    
    [[Page 64571]]
    
    new use, the data are persuasive to the extent that withholding the 
    drug or device in the course of conducting a controlled study would 
    pose an unreasonable risk of harm to human subjects.
        The proposed codified language provided that an unreasonable risk 
    of harm would ordinarily arise only in situations in which the new use 
    of the drug or device appears to affect mortality or irreversible 
    morbidity. Evidence suggesting that the drug or device is the standard 
    of care for the new use can add weight to an argument that conduct of a 
    needed study or studies would be unethical.
        To support its argument that the conduct of a needed study or 
    studies would be unethical, the proposal provided that a manufacturer 
    would need to address the possibility of conducting studies in 
    different populations or of modified design (e.g., adding the new 
    therapy to existing treatments or using an alternative dose if 
    monotherapy studies could not be conducted).
        The proposal further provided that in assessing the appropriateness 
    of conducting studies to support the new use, the manufacturer may 
    provide evidence that the new use represents standard medical treatment 
    or therapy. Evidence that the new use represents standard medical 
    therapy can be one element of an argument that studies cannot ethically 
    be conducted, but the persuasiveness of available data is equally 
    important. Evidence that the new use represents standard medical 
    therapy might be obtained from a number of different sources. The 
    preamble to the proposal set forth the following possible 
    considerations: (1) Whether the new use meets the requirements of 
    section 1861(t)(2)(B) of the Social Security Act, which defines 
    ``medically accepted indications'' with respect to the use of a drug; 
    (2)  Whether a medical specialty society that is represented in or 
    recognized by the Council of Medical Specialty Societies (or is a 
    subspecialty of such society) or is recognized by the American 
    Osteopathic Association has found that the new use is consistent with 
    sound medical practice; (3)  Whether the new use is described in a 
    recommendation or medical practice guideline of a Federal health 
    agency, including the National Institutes of Health, the Agency for 
    Health Care Policy and Research, and the Centers for Disease Control 
    and Prevention of the Department of Health and Human Services; and (4)  
    Whether the new use is described in a current compendia such as the 
    United States Pharmacopoeia Drug Information for the Health Care 
    Professional, the American Medical Association Drug Evaluations, or the 
    American Hospital Formulary Service (see 63 FR 31143 at 31150).
        74. A number of comments objected to FDA's proposed criteria for 
    the unethical exemption--particularly the emphasis on the requirement 
    that it ordinarily would arise only in situations in which the new use 
    appears to affect mortality or irreversible morbidity. Some comments 
    believed that the criteria set forth in the legislative history (that 
    are discussed in the preamble) should be in the codified language. 
    Finally, a number of comments argued that if the new use is the 
    standard of medical care, FDA must automatically grant an exemption.
        The act clearly does not require FDA to automatically grant an 
    exemption if a new use is the standard of medical care. The act says 
    that FDA must consider (among other considerations that the Secretary 
    finds appropriate) whether the new use is the standard of medical care, 
    and that is what FDA proposed to do. Moreover, an automatic exemption 
    would not be reasonable from a scientific standpoint because there are 
    many instances in which the results of a controlled clinical trial have 
    demonstrated that a drug or device is unsafe or ineffective for a new 
    use for which it is considered to be the standard of care.
        The standard set forth in Sec. 99.205 is consistent with how FDA 
    determines what studies are unethical in other contexts (i.e., when a 
    manufacturer argues that it would be unethical to conduct a study). 
    Moreover, the standard is consistent with the legislative history, 
    which provides that such exemptions should be granted in limited 
    circumstances. Therefore, FDA is retaining the proposed basic standard 
    for the unethical exemption in the final rule (i.e., the data are 
    persuasive to the extent that withholding the drug or device in the 
    course of conducting a controlled study would pose an unreasonable risk 
    of harm to human subjects). FDA continues to believe an effect on 
    irreversible morbidity or mortality is what ordinarily would be 
    required to show an unreasonable risk of harm. Nevertheless, there 
    could be other circumstances in which the agency would find that it 
    would be unethical to do the study, i.e., because there would be an 
    unreasonable risk of harm even though the new use does not affect 
    irreversible morbidity or mortality. In making a determination that it 
    would be unethical to conduct a study, the agency must consider whether 
    informed consent and proper IRB review would address the concerns 
    raised by questions about whether it is appropriate to conduct a study.
        FDA rejects the suggestion that the factors set forth in the 
    legislative history that FDA may consider in deciding whether to grant 
    an exemption be included as requirements in the codified language. FDA 
    has included the statutory factors in the codified language. The 
    legislative history provides that FDA may consider those factors among 
    other factors, and thus, consideration of these factors is neither 
    mandatory nor is it exclusive.
        75. One comment argued that the standard needs to take into account 
    the difficulty of enrolling patients in a study in which some subjects 
    will receive a placebo when a patient can go to a doctor and receive a 
    prescription for the drug. The comment further noted that physicians 
    refuse to participate in placebo controlled studies of therapies they 
    already believe to be effective.
        FDA agrees that it can be difficult to enroll patients in placebo 
    controlled trials and that this could be a relevant consideration. 
    Moreover, not all controlled studies are placebo controlled. Companies 
    may be able to conduct studies of a different design, depending on the 
    situation. For example, a company may be able to compare the new use to 
    another therapy that is known to work or may be able to rely on 
    historical controls. In some cases, the new use could be added to 
    existing therapy and compared with placebo added to existing therapy. 
    If these alternate study designs mean that the study or studies will 
    take longer, FDA can consider whether to extend the time to conduct the 
    studies and submit a supplemental application.
        76. One comment suggested that FDA should grant an exemption if the 
    new use is listed in the USP DI or Hospital Formulary. Another comment 
    suggested that an unethical exemption should be granted if the 
    unapproved use: (1) Is accepted in a monograph of the USP; (2) is 
    approved by another ``first world'' country; or (3) is approved by a 
    state FDA. Finally, one comment suggested that FDA should automatically 
    grant an unethical exemption if the new use: (1) Represents the 
    standard of care, as represented by inclusion in specified compendia or 
    practice guidelines, or (2) involves a combination of products or more 
    than one sponsor and should grant other exemptions on a case-by-case 
    basis.
         FDA does not agree that any of these individual factors is enough 
    to show that studying a new use would be unethical. Moreover, there is 
    nothing in the statute or legislative history to
    
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    suggest that any of the single factors should be sufficient to meet the 
    unethical exemption. FDA will, however, consider these factors in 
    making its determination of when it would be unethical to conduct a 
    study.
        77. One comment noted that, although it supported the list of 
    sources to be used to provide evidence that a new use represents 
    standard medical therapy, after 1998, the American Medical 
    Association's (AMA's) Drug Evaluation and the USP DI may no longer be 
    available.
        If the AMA's Drug Evaluation and/or the USP DI become unavailable, 
    FDA will stop using them as evidence that a new use is the standard of 
    care.
        78. One comment noted that there are diverse opinions in the 
    medical community about what standard of care means. Another noted that 
    ``consistent with sound medical practice'' is not the same as 
    ``standard of care'' and that an unapproved treatment may be considered 
    to be sound medical practice but should still be studied. Several 
    comments noted that FDA should take care in how it interprets 
    ``standard medical treatment or therapy.'' These comments noted that 
    manufacturers should not be allowed to take advantage of a situation of 
    their own creation. In other words, standard medical treatment should 
    not be interpreted as meaning treatment that is regularly used because 
    physicians have no other choice because to do so would eliminate the 
    requirements for completing any pediatric research.
        FDA agrees that just because a certain treatment is consistent with 
    sound medical practice does not mean that it is the standard of care. 
    FDA has stated that whether a medical specialty society that is 
    represented in or recognized by the Council of Medical Specialty 
    Societies (or is a subspecialty of such society) or is recognized by 
    the American Osteopathic Association has found that a new use is 
    consistent with sound medical practice will be considered as evidence 
    that it is the standard of care. Moreover, just because an unapproved 
    use of a drug or device is the standard of care, does not mean that it 
    is automatically exempt from the requirement to conduct the study 
    needed to submit a supplemental application.
        79. Several comments noted that it is almost inconceivable that the 
    study of a new use for children could be viewed as unethical.
        FDA will make this determination on a case-by-case basis.
        80. Several comments argued for making the exemption process 
    public. One comment said that all information should be made public as 
    soon as a manufacturer requests an exemption and that if an exemption 
    is granted all information should remain in the public domain so that 
    interested parties will be able to play a role in keeping FDA informed 
    as to when it should be revoked. Another suggested that prior to 
    granting any exemption, FDA should hold a meeting of the appropriate 
    advisory committee so that the public has the opportunity to review and 
    comment upon the request.
        As set forth previously, FDA declines to adopt a notice and comment 
    process for considering exemption requests. The information will be 
    made available to the public consistent with FOIA and FDA's 
    regulations. FDA has the option of consulting advisory committees about 
    exemption requests, when appropriate.
    4. Subpart D--FDA Action on Submissions, Requests, and Applications
        a. Agency action on a submission (Sec. 99.301). Proposed 
    Sec. 99.301 described the range of FDA's actions when it receives a 
    submission. For example, under the proposal, FDA could determine that a 
    manufacturer's submission does not comply with the regulatory 
    requirements, request additional information or documents to assist the 
    agency in determining whether the information to be disseminated 
    complies with applicable requirements, or determine that the 
    information fails to provide data, analyses, or other written matter 
    that is objective and balanced. The proposal also described FDA actions 
    in response to a manufacturer's submission when the manufacturer is 
    committing to submit a supplement on completed studies or is agreeing 
    to conduct the necessary studies and then submit a supplement.
        81. Proposed Sec. 99.301(a) provided that, within 60 days, FDA may 
    determine that a submission does not comply with the requirements of 
    the proposal or that it needs more information. A number of comments 
    objected to the proposal because they believed that FDA would use it to 
    extend the 60-day time period. The concern was that FDA would, on day 
    59, advise a manufacturer that their submission was not complete and 
    therefore the 60-day time period had not begun. The comments said that 
    Congress meant for FDA to give a final answer within the 60-day time 
    period. Some comments argued that FDA should let manufacturers know if 
    their submission is complete within a short period of time, e.g., 
    within 15 days of receiving the submission.
        In response to these comments, FDA has eliminated proposed 
    Sec. 99.301(a)(2) so that manufacturers will have a final decision 
    within 60 days. Within the 60-day period, FDA will either notify a 
    manufacturer that it has not met the requirements set forth in the law 
    or allow the dissemination to go forward. FDA is not adopting the 
    comment's suggestion that it advise sponsors as to whether their 
    submissions are complete within a certain number of days (e.g., 15). 
    The 60-day statutory timeframe is too short for the agency to make a 
    commitment to provide such advice.
        82. One comment stated that FDA should be required to notify the 
    manufacturer promptly if it approves a submission in less than 60 days.
        There is no requirement in the statute that FDA notify a 
    manufacturer unless it intends to stop the dissemination of information 
    under this part. Therefore, FDA is not revising the regulation as 
    suggested. The agency will, however, make an effort to notify 
    manufacturers promptly if it approves a submission in less than 60 
    days.
        83. One comment requested that FDA change the ``may'' in proposed 
    Sec. 99.301(a) to ``shall'' and to clarify that a sponsor may begin to 
    disseminate material if it has not heard from FDA within 60 days. 
    Another comment suggested that FDA clarify Sec. 99.301 to indicate that 
    FDA will review an IND or IDE and will notify the manufacturer of the 
    IND or IDE approval and that, until such notification, the manufacturer 
    cannot disseminate the information.
        FDA declines to change the ``may'' to ``shall'' in Sec. 99.301(a). 
    FDA is not required to do any of the things listed in Sec. 99.301(a), 
    and so use of the word ``shall'' would be inappropriate. Moreover, it 
    is not true that a manufacturer may, in every circumstance, begin 
    dissemination if it has not heard from FDA within 60 days. Under 
    section 554(c) of the act, a manufacturer that has certified that it 
    will conduct the studies needed to submit a supplement and that has 
    submitted a proposed protocol and schedule for conducting such studies 
    cannot disseminate unless the Secretary has determined that the 
    proposed protocol is adequate and that the schedule for completing the 
    studies is reasonable. Nevertheless, FDA has revised Sec. 99.301(b) to 
    state clearly that the agency will make a positive or negative 
    determination on the manufacturer's protocols (and, where appropriate, 
    its schedules) within 60 days after receiving a submission under part 
    99.
        84. Proposed Sec. 99.301(a)(3) (now redesignated as 
    Sec. 99.301(a)(2)) provided
    
    [[Page 64573]]
    
    that FDA shall provide a manufacturer notice and an opportunity for a 
    meeting regarding the agency's determination that the information 
    submitted is not objective and balanced, and requires additional 
    information. One comment suggested that there should be a specific 
    timeline for when such a meeting would occur.
        The statute does not require that FDA set a timeline for such a 
    meeting. Nevertheless, FDA will provide for such an opportunity as soon 
    as is mutually convenient for FDA and the manufacturer. In any event, 
    the meeting will take place within the 60-day period. Furthermore, 
    should FDA determine that additional articles are necessary to provide 
    objectivity and balance, the agency will apply the same standards for 
    scientific soundness to those additional articles.
        85. Proposed Sec. 99.301(a)(4) (now redesignated as 
    Sec. 99.301(a)(3)) provided that within 60 days of receiving a 
    manufacturer's submission, FDA may require the manufacturer to maintain 
    records that will identify individual recipients of the information 
    that is to be disseminated.
        Some comments supported FDA's not requiring individualized 
    recordkeeping in all situations. Others, however, thought it should be 
    invoked in all situations and still others thought that ever requiring 
    it was too burdensome. One comment argued that the proposed standard 
    for individual recordkeeping was too vague and suggested that FDA make 
    such a request ``only in rare circumstances, when warranted because of 
    special safety considerations associated with a new use.'' One comment 
    argued that FDA should provide notice and an opportunity to meet in the 
    event that it requires a company to maintain records identifying 
    individual recipients.
        Section 553(b) of the act (21 U.S.C. 360aaa-2(b)) expressly 
    requires a manufacturer to keep records that the manufacturer may use 
    if it is required to take corrective action. Section 553(b) of the act 
    also states that, ``Such records, at the Secretary's discretion, may 
    identify the recipient of information provided * * * or the categories 
    of such recipients.'' FDA does not believe that it would be appropriate 
    to require individual recordkeeping in all circumstances. Similarly, 
    FDA does not believe that it would be appropriate to require 
    recordkeeping of categories of recipients in all circumstances. FDA 
    agrees, however, that it should better define the standard for 
    individual recordkeeping and will adopt, with slight modifications, the 
    standard suggested by the comments. Section 99.301(a)(3) provides for 
    individual recordkeeping when warranted because of special safety 
    considerations associated with the new use. FDA did not adopt the 
    ``only in rare circumstances'' language because although it expects to 
    require this in limited circumstances, it does not yet have experience 
    implementing this provision and nothing in the statute or legislative 
    history indicates that Congress intended it to be rare.
        86. One comment was concerned that because the agency has to review 
    all submissions within 60 days, sometimes the timeframe will expire and 
    allow information dissemination or exemptions to happen without agency 
    review and thus patients could be harmed before FDA has time to 
    terminate a deemed approval. This comment encouraged the agency to 
    provide information to health care providers on the process by which 
    the review will occur.
        FDA recognizes that the act would allow information to be 
    disseminated without agency review. The agency is committed to 
    reviewing all of this information so that inappropriate information 
    does not get disseminated.
        87. Proposed Sec. 99.301(b) required FDA to notify the manufacturer 
    if the agency determines that its protocol and schedule for conducting 
    studies are adequate and reasonable. Until FDA provides such 
    notification, dissemination cannot begin. One comment noted that it was 
    not the intent of Congress that the 60-day timeframe be delayed as a 
    result of ongoing IND/IDE negotiations.
        The statute provides that a manufacturer who submits a protocol and 
    proposed schedule for conducting the studies needed to submit a 
    supplement, cannot begin to disseminate until FDA determines that they 
    are adequate. (See section 554(c)(1) of the act.) However, as stated 
    earlier, FDA has revised Sec. 99.301(b) to state that the agency will 
    make a positive or negative determination on the manufacturer's 
    protocols (and, where appropriate, its schedules) within 60 days after 
    receiving a submission under 21 CFR part 99.
        88. Proposed Sec. 99.301(b) described FDA action on a 
    manufacturer's proposed protocols and schedules for completing studies. 
    One comment said that the rule should clarify which functional groups 
    within FDA will be responsible for the review of protocols and studies 
    and provide for a timeline for such review.
        FDA has stated previously that clinical information, including 
    protocols, that is submitted under this part will be reviewed by the 
    appropriate review divisions. It is not necessary for the rule to 
    detail FDA's internal procedure. FDA will review such protocols and 
    schedules within 60 days. Section 99.301(b) includes that timeframe.
        89. Under proposed Sec. 99.301(b)(2), if a manufacturer has 
    completed studies that it believes would be an adequate basis for the 
    submission of a supplemental application for the new use and has 
    certified that it will submit such supplement within 6 months, FDA 
    would conduct a preliminary review of the study reports to determine 
    whether the studies are potentially adequate to support the filing of a 
    supplemental application for the new use. If FDA determines that the 
    study reports are inadequate to support the filing of a supplemental 
    application for the new use or are not complete, FDA will notify the 
    manufacturer and the manufacturer shall not disseminate the new use 
    information under this subpart. One comment argued that FDA should not 
    be allowed to take a ``sneak peek'' at preliminary clinical trial data 
    prior to its submission in a supplemental application.
        Section 99.201(a)(4)(i) requires manufacturers that have completed 
    studies that they believe would be an adequate basis for the submission 
    of a supplemental application for the new use and have certified that 
    it will submit such supplement within 6 months to submit the protocols 
    for those studies. FDA, will, as in the case of the 36-month 
    certification, review those protocols to determine whether they are 
    adequate. The final rule has been revised to indicate that FDA will 
    review the protocols submitted and not the study reports. However, this 
    does not in any way affect the agency's ability to determine, based on 
    information it has, including information about clinical trials, that 
    the information a manufacturer seeks to disseminate is false or 
    misleading or would pose a significant risk to public health.
        b. Extension of time for completing planned studies (Sec. 99.303). 
    Proposed Sec. 99.303 described FDA's ability to: (1) On its own 
    initiative, allow a manufacturer more than 36 months to submit a 
    supplemental application, based on the review of the protocols(s) and 
    planned schedule; or (2) grant a manufacturer's request to extend the 
    36-month period (for up to 24 months). Proposed Sec. 99.303(a) 
    described FDA's ability to determine, on its own initiative and before 
    any studies have begun, that a manufacturer needs more than 36 months 
    to complete the studies needed for submission of a
    
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    supplemental application and to submit such application. Proposed 
    Sec. 99.303(b) and (c) described FDA's ability, after such studies have 
    begun and the sponsor has submitted a request, to grant an extension of 
    the time to submit a supplement by up to 24 months. FDA would grant 
    such an extension if the manufacturer makes a request for an extension 
    in writing and FDA determines that the manufacturer has acted with due 
    diligence to conduct the studies needed for the submission of a 
    supplemental application for a new use and to submit such a 
    supplemental application, but still needs more time.
        90. The comments to this provision indicated that there was some 
    confusion regarding these two different procedures. Several comments 
    asked FDA to more clearly set out the two procedures contemplated by 
    the statute. Several comments asked FDA to make clear that the 24-month 
    limitation applies only to an extension request made after a study has 
    begun. One comment suggested that there could be more than one 24-month 
    extension.
        FDA has revised this section to make clear that there are two 
    different types of extensions. The first extension (in Sec. 99.303 (a)) 
    relates to FDA's ability to determine, with or without a request from 
    the manufacturer, that 36 months is not enough time to complete a study 
    of the new use and submit a supplemental application. This would occur 
    before any studies are begun, either before the submission is made or 
    at the time of the submission. There is no limit on how much time FDA 
    may give a manufacturer under this subsection.
        The second type of extension (described in revised Sec. 99.303(b)) 
    relates to FDA's ability to grant a manufacturer's request for an 
    extension after a study has begun because, even though it appeared that 
    36 months would be sufficient and the manufacturer has acted with due 
    diligence, the manufacturer has run into problems and needs more time. 
    This type of extension is limited to 24 months and the statute does not 
    provide that FDA can give more than one 24-month extension.
        c. Exemption from the requirement to file a supplemental 
    application (Sec. 99.305). Proposed Sec. 99.305 described FDA action on 
    a request for an exemption from the requirement to submit a 
    supplemental application and the criteria to be considered in deciding 
    whether to grant a request for an exemption, either because it would be 
    economically prohibitive to conduct the studies needed for a 
    supplemental application or it would be unethical to conduct the 
    clinical studies needed to approve the new use.
        91. Proposed Sec. 99.305(a)(1) states that FDA must act on an 
    application for an exemption within 60 days of receipt or it will be 
    deemed approved. However, under proposed Sec. 99.305(a)(2), FDA could, 
    at any time, terminate such deemed approval if it determines that the 
    requirements for granting an exemption have not been met. One comment 
    noted that FDA can terminate such deemed approval only if a 
    manufacturer is disseminating information under section 551 of the act.
        Section 554(d)(3)(B) of the act provides that if a manufacturer 
    disseminates information under section 551 of the act under a deemed 
    approval of a request for an exemption, FDA may, at any time, terminate 
    a deemed approval and order the manufacturer to cease disseminating the 
    information under section 553(b)(3) of the act. FDA does not believe 
    that it has to wait for a manufacturer to actually disseminate 
    information in order to terminate the deemed approval.
        92. A number of comments suggested that FDA provide a manufacturer 
    an opportunity to meet concerning: (1) FDA's determination that the 
    manufacturer cannot disseminate information under this part; (2) FDA's 
    determination that the manufacturer should maintain records of 
    individual recipients; (3) FDA's determination of a company's request 
    for an extension of time to complete the necessary studies and submit a 
    supplement; (4) FDA's denial of an exemption.
        Section 401 of FDAMA directed FDA to provide manufacturers an 
    opportunity to meet regarding a determination that the information to 
    be disseminated is not balanced and objective and regarding the 
    cessation of information dissemination in certain circumstances. The 
    statute does not direct FDA to meet in the circumstances described 
    previously. Nevertheless, as always, FDA will honor requests for 
    meetings to the fullest extent feasible. Given the short timeframes set 
    forth in section 401 of FDAMA, FDA's resource constraints, and the fact 
    that FDA does not know how many submissions it will receive under this 
    part, FDA is not imposing on itself any additional requirements for 
    meetings by making those meetings a part of the regulation.
    5. Subpart E--Corrective Actions and Cessation of Dissemination
        Subpart E, as proposed, contained provisions describing the 
    corrective actions that FDA could take or order the manufacturer to 
    take, termination of approvals of applications for exemption, and the 
    applicability of labeling, adulteration, and misbranding authority in 
    the event that dissemination failed to comply with section 551 of the 
    act.
        93. One comment claimed that proposed subpart E was ``hollow and 
    meaningless'' because Congress did not give FDA the authority to seek 
    civil money penalties against noncomplying manufacturers.
        FDA disagrees with the comment's characterization of subpart E and 
    notes that the agency does, indeed, have the authority to seek civil 
    money penalties from any person who violates most requirements of the 
    act pertaining to devices (see section 303(f) of the act (21 U.S.C. 
    333(f)). Additionally, arguments regarding other civil money penalty 
    authority for violations of these regulations are beyond the scope of 
    this rulemaking.
        a. Corrective actions and cessation of dissemination of information 
    (Sec. 99.401). Proposed Sec. 99.401 authorized FDA to take corrective 
    actions and to order a manufacturer to cease dissemination of 
    information and take corrective action. In general, the proposal would 
    provide for corrective action or an order to cease dissemination of 
    information based on post dissemination data, information disseminated 
    by the manufacturer, or the manufacturer's supplemental application for 
    the new use (or its failure to submit or to complete the studies 
    necessary for the supplemental application). Proposed Sec. 99.401 also 
    described the procedures to be observed, such as consultation with the 
    manufacturer, notice regarding FDA's intent to issue an order to cease 
    dissemination, and opportunities for a meeting, and described when a 
    manufacturer shall cease disseminating information in the event of its 
    noncompliance with the regulations.
        94. Several comments would revise proposed Sec. 99.401 to give 
    manufacturers a mechanism for appealing the agency's decision to 
    require corrective action. The comments would either amend the rule to 
    refer to the dispute resolution provision at section 562 of the act (21 
    U.S.C. 360bbb-1), the regulations for internal agency review of 
    decisions (Sec. 10.75 (21 CFR 10.75)), or other appeals processes.
        FDA declines to revise the rule to refer to statutory or regulatory 
    appeals mechanisms. Such appeals mechanisms are available regardless of 
    whether Sec. 99.401 refers to them or not, and it would be both 
    impractical and unnecessary to list all possible statutory and 
    regulatory appeals mechanisms in Sec. 99.401. Moreover, such a list 
    would either become obsolete or useless if any
    
    [[Page 64575]]
    
    statutory or regulatory citations for the appeals mechanisms changed or 
    would require FDA to monitor constantly all cross-references without 
    any appreciable benefit.
        95. Several comments would amend Sec. 99.401 to permit 
    manufacturers to continue disseminating information pending the outcome 
    of any appeal except where a significant safety issue or public health 
    concern exists. In contrast, one comment said that a manufacturer 
    should cease disseminating information while it and FDA are resolving 
    any outstanding issues. FDA declines to revise the rule to allow 
    manufacturers to continue disseminating information pending the outcome 
    of any appeal. In general, section 555 of the act (21 U.S.C. 360aaa-4) 
    authorizes the agency to order a manufacturer to cease dissemination of 
    information on the unapproved/new use; it does not require the agency 
    to stay or defer the effectiveness of such an order pending any appeal 
    by the manufacturer. This outcome is consistent with the appeals or 
    dispute resolution provisions cited by the comments (section 562 of the 
    act and Sec. 10.75), as well as other regulatory mechanisms for 
    requesting reconsideration (see, e.g., 21 CFR 10.33 (administrative 
    reconsideration of action) and 21 CFR 10.35 (administrative stay of 
    action)); none of these mechanisms results in an automatic stay of 
    agency action while the agency reconsiders its decision or considers an 
    appeal.
        96. One comment suggested that FDA define ``appropriate corrective 
    action.'' The comment would amend the rule to give examples of 
    corrective action and to describe the circumstances under which 
    specific corrective actions might apply.
        By using the term ``appropriate corrective action,'' FDA meant to 
    give itself the flexibility to fashion the corrective action to remedy 
    the underlying problem or deficiency. As stated in the preamble to the 
    proposed rule, these actions include, but are not limited to, ordering 
    the manufacturer to send ``Dear Doctor'' letters, to publish corrective 
    advertising, to include warning labels on the product, or to include 
    warnings or otherwise revise the product labeling (63 FR 31143 at 
    31151). FDA declines to define ``appropriate corrective action'' or to 
    give examples and to specify when it might order a manufacturer to take 
    a particular corrective action. The agency's regulatory experience 
    indicates that regulations containing lists or examples often are 
    misconstrued as providing an exclusive list (thereby resulting in 
    unnecessary disputes as to whether a particular corrective action is 
    within the regulation or whether the manufacturer's action is even 
    capable of being addressed by the agency) and that regulations that 
    describe specific responses to specific situations can deprive the 
    agency of the flexibility to tailor a corrective action to fit a 
    particular situation. Nevertheless, FDA would note that it expects that 
    ``Dear Doctor'' letters and/or corrective advertising would be used 
    much more often than the addition of warning statements or product 
    labeling, which are likely to be used in the more extreme cases.
        97. Proposed Sec. 99.401(a) permitted FDA to take appropriate 
    action to protect the public health, including ordering a manufacturer 
    to cease dissemination and take corrective action, if FDA determines, 
    based on data received after the dissemination has begun, that the new 
    use that is the subject of the disseminated information may not be 
    effective or may pose a significant risk to public health. The 
    provision required FDA to consult with the manufacturer before taking 
    any such action.
        One comment disagreed that FDA should have any obligation to 
    consult a manufacturer before ordering the manufacturer to cease 
    disseminating information on an unapproved/new use.
        Section 555(a)(1) of the act, regarding corrective actions 
    following the receipt of data after a manufacturer has begun 
    disseminating information, expressly states that the agency, ``after 
    consultation with the manufacturer,'' shall take ``such action 
    regarding the dissemination of the information as [the agency] 
    determines to be appropriate for the protection of the public health, 
    which may include ordering that the manufacturer to cease dissemination 
    of the information.'' Thus, with respect to corrective actions based on 
    post-dissemination data, the act requires FDA to consult the 
    manufacturer before taking any action, and Sec. 99.401(a) correctly 
    reflects this statutory requirement.
        98. FDA revised Sec. 99.401(c)(3) and (c)(4), by changing the 
    references to Sec. 99.303 from paragraphs (a) or (c) to paragraphs (a) 
    or (b). This change was needed to correct an error and to reflect the 
    changes made to Sec. 99.303, which were previously discussed.
        99. Proposed Sec. 99.401(b) discussed FDA's ability to order 
    cessation of dissemination or corrective action because the information 
    being disseminated by a manufacturer does not comply with part 99. 
    Proposed Sec. 99.401(b)(1) directed FDA to give a manufacturer the 
    opportunity to bring itself into compliance if the manufacturer's 
    noncompliance constituted a minor violation. Proposed Sec. 99.401(b)(2) 
    permitted FDA to order the manufacturer to cease dissemination of 
    information after providing notice to the manufacturer and an 
    opportunity for a meeting.
        One comment would revise Sec. 99.401(b)(2) to specify a timeframe 
    for a meeting, but did not explain why such specificity would be 
    beneficial.
        FDA declines to revise the rule as suggested by the comment. 
    Because FDA cannot require a manufacturer to cease dissemination until 
    it has provided an opportunity for a meeting, it has an incentive to 
    schedule such meetings at the earliest possible time, particularly when 
    the new use at issue raises significant safety concerns. By not 
    specifying a timeframe for a meeting, the regulation provides the 
    appropriate flexibility to schedule meetings.
        100. One comment said that FDA should afford manufacturers an 
    opportunity to resolve outstanding issues before taking any corrective 
    action to avoid burdensome and erroneous corrective action.
        Section 555(b)(1) of the act requires FDA to delay issuing an order 
    to provide a manufacturer an opportunity to correct a minor violation 
    before ordering such manufacturer to cease dissemination. Section 
    99.401(b) provides that opportunity. Moreover, FDA will always consider 
    whether and when corrective action is appropriate.
        101. Proposed Sec. 99.401(c) described FDA actions based on a 
    manufacturer's supplemental application. For example, under proposed 
    Sec. 99.401(c)(1), FDA could order a manufacturer to cease 
    dissemination and to take corrective action if the agency determined 
    that the supplemental application does not contain adequate information 
    for approval of the new use.
        One comment said that FDA should not automatically require a 
    manufacturer to cease dissemination if FDA does not approve a 
    supplemental application for the unapproved/new use because it fails to 
    establish effectiveness. The comment said corrective action should be 
    reserved for situations in which ``some significant public health 
    concern is identified that would be materially addressed by such 
    corrective action.''
        FDA declines to revise Sec. 99.401(c) to limit corrective actions 
    as suggested by the comment. If FDA, based on the supplemental 
    application submitted by the manufacturer, determines that the drug or 
    device is not effective for that use, it could be contrary to the 
    interests
    
    [[Page 64576]]
    
    of public health to allow the manufacturer to continue disseminating 
    information on that use. Section 555(b)(2) of the act contemplates such 
    a result by stating that the agency may order a manufacturer to cease 
    dissemination if the agency determines that the supplemental 
    application does not contain adequate information for approval of the 
    new use.
        Furthermore, one should note that both section 555(b)(2) of the act 
    and Sec. 99.401(c) give FDA discretion in issuing an order to cease 
    dissemination of information on the unapproved/new use if FDA does not 
    approve the supplemental application. Thus, contrary to the comment's 
    assertion, an order to cease dissemination under such circumstances is 
    not ``automatic.''
        102. One comment said that if FDA does not approve a supplemental 
    application because the studies failed to demonstrate efficacy, the 
    manufacturer should advise health care practitioners who previously 
    received information on the unapproved/new use.
        Requiring a manufacturer to notify recipients or categories of 
    recipients that a drug or device is not effective for the unapproved/
    new use would be within the range of corrective actions that FDA may 
    take. Section 553(b) of the act contemplates such a result by requiring 
    manufacturers to keep records of categories of recipients or individual 
    recipients of the disseminated information and to use such records if 
    the manufacturer is required to take corrective action. Thus, 
    corrective actions, in Sec. 99.401, are not confined to orders to cease 
    dissemination of information on an unapproved/new use.
        103. One comment sought clarification as to when FDA may determine 
    that a supplemental application does not contain adequate information 
    for approval of the new use. The comment suggested that proposed 
    Sec. 99.401(c)(1) could be interpreted as applying even if FDA 
    requested additional information or clarification of a supplemental 
    application. The comment stated that dissemination of information on an 
    unapproved/new use should cease only when FDA determines that the 
    supplemental application is not approvable.
        Section 555(b)(2) of the act permits FDA to order a manufacturer to 
    cease dissemination if FDA determines that a supplemental application 
    submitted by such manufacturer (for the new use) does not contain 
    adequate information for approval of the new use. Section 99.401(c)(1) 
    tracks this language. FDA agrees that a decision to seek additional 
    data or clarification regarding a supplemental application would 
    generally not constitute a determination that the supplement does not 
    contain adequate information for approval of the new use. However, 
    there may be circumstances in which it is appropriate for the agency to 
    order a manufacturer to cease dissemination of information when 
    additional data is required. Accordingly, FDA will make these 
    determinations on a case-by-case basis.
        104. Proposed Sec. 99.401(c)(2) permitted FDA to order a 
    manufacturer to cease dissemination if the manufacturer had certified 
    that it would submit a supplemental application within 6 months, and 
    the manufacturer failed to submit a supplemental application within 6 
    months.
        One comment said FDA should not seek corrective action for a 
    manufacturer's failure to submit a supplemental application within 6 
    months if there is ``good cause'' for the delay. The comment said that 
    FDA should meet with a manufacturer to determine if there is good cause 
    for the delay before automatically requiring corrective action and that 
    manufacturers should notify FDA as soon as possible if they will not 
    meet any deadline.
        FDA declines to revise the rule as requested by the comment. 
    Section 99.401(c)(2) does not require any specific corrective action in 
    the event that the manufacturer fails to submit a supplemental 
    application on time. Instead, it gives FDA the discretion to order the 
    manufacturer to cease dissemination of information and to take 
    corrective action. FDA will consider, among other things, the reasons 
    for a manufacturer's inability to submit a supplemental application on 
    time when deciding what type of corrective action to take or whether 
    any corrective action is needed.
        Thus, while FDA would appreciate any advance notice from 
    manufacturers who believe that they will be unable to submit a 
    supplemental application on time and will meet with manufacturers as 
    time and resources permit, given the agency's discretion regarding 
    corrective actions in Sec. 99.401(c)(2), revising the rule to require 
    such meetings is unnecessary.
        105. Proposed Sec. 99.401(d) considered an order to cease 
    dissemination of information to be effective upon the date of issuance 
    unless otherwise stated by FDA.
        One comment said it would be more efficient if an order to cease 
    dissemination of information were effective upon date of receipt by the 
    manufacturer. The comment explained that a manufacturer may be unaware 
    when FDA issues an order to cease dissemination of information, so the 
    order should be effective when the manufacturer receives it. The 
    comment also stated that it would be unlikely that a manufacturer could 
    stop dissemination of information throughout the United States on the 
    same day it receives an order to cease dissemination. Consequently, the 
    comment would revise the rule to give manufacturers some time (the 
    comment suggested 60 days) in which to comply with the order.
        FDA agrees, in part, with the comment and has revised 
    Sec. 99.401(d) to make an order to cease dissemination of information 
    effective upon receipt by the manufacturer, unless otherwise indicated 
    in the order. The agency does not agree that manufacturers should have 
    a specified amount of time after receipt to comply with an order. A 
    manufacturer is expected to comply immediately. If the manufacturer is 
    unable to comply immediately, it should notify FDA, and FDA will 
    evaluate the situation on a case-by-case basis.
        106. Proposed Sec. 99.401(e) required a manufacturer to cease 
    dissemination if it fails to comply with the regulations pertaining to 
    dissemination of information on unapproved/new uses. This would include 
    discontinuation, termination, and a failure to conduct with due 
    diligence clinical studies. The proposal also required the manufacturer 
    to notify FDA if it ceases dissemination under Sec. 99.401(e).
        One comment would revise the rule to require a manufacturer to 
    notify FDA of any failure to comply as soon as the manufacturer 
    realizes the failure and ceases dissemination. The comment also would 
    require the manufacturer to notify FDA immediately if the manufacturer 
    ceases dissemination. Section 99.401(e) already requires a manufacturer 
    to notify FDA if it ceases dissemination.
        FDA agrees that the agency should be notified immediately and has 
    revised Sec. 99.401(e) accordingly.
        b. Termination of approvals of applications for exemption 
    (Sec. 99.403).  Under the act, if FDA fails to act within 60 days on an 
    application for an exemption from the requirement to file a 
    supplemental application, the application is deemed approved. Proposed 
    Sec. 99.403 allowed FDA to terminate the deemed approval of an 
    application for an exemption if FDA determines that the manufacturer 
    has failed to meet the requirements for granting an exemption. In 
    addition, the agency may order the manufacturer to cease disseminating 
    information about the new use and, if appropriate, to take corrective 
    action.
    
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        107. One comment would revise Sec. 99.403(a)(3) to apply if FDA 
    determines that it would be economically and ethically possible to 
    conduct the studies needed for a supplement rather than economically or 
    ethically possible to conduct such studies.
        FDA agrees and has revised the rule accordingly.
        108. One comment requested that FDA provide notice and an 
    opportunity to meet when FDA terminates approval of an application for 
    an exemption.
        Section 99.403(c), (d), and (e) provide for notice to the 
    manufacturer, and Sec. 99.403(d) also mentions consultation between FDA 
    and the manufacturer if FDA determines that the manufacturer no longer 
    meets the requirements for an exemption on the basis that it is 
    economically prohibitive or unethical to conduct the studies needed to 
    support a supplemental application for the new use. Thus, no further 
    change to the rule is necessary.
        c. Applicability of labeling, adulteration, and misbranding 
    authority (Sec. 99.405). Proposed Sec. 99.405 provided that the 
    dissemination of information about a new use could constitute labeling, 
    evidence of a new intended use, adulteration or misbranding of the 
    product if it fails to comply with the requirements in section 551 of 
    the act and the requirements of this part.
        109. One comment claimed that proposed Sec. 99.405 was too broad 
    and exceeded the statute by considering a failure to comply with part 
    99 to constitute labeling, evidence of a new intended use, 
    adulteration, or misbranding of a drug or device. The comment 
    acknowledged that labeling that is false or misleading renders a drug 
    misbranded and that each introduction of the drug into interstate 
    commerce constitutes a separate prohibited act under section 301 of the 
    act (21 U.S.C. 331). The comment further acknowledged that FDA can 
    pursue various enforcement actions, such as seizures, injunctions, and 
    criminal penalties, for each prohibited act. However, the comment 
    argued that a failure to comply with part 99 should be a single 
    violation rather than a violation for each product sold and that if a 
    manufacturer tries to follow part 99, the act prescribes specific 
    enforcement consequences, such as corrective action, before FDA resorts 
    to other sanctions.
        FDA disagrees with this comment. Although section 401 of FDAMA 
    provided FDA additional enforcement tools for violative dissemination 
    of off-label information, it did not in any way eliminate or limit 
    FDA's ability to use its already existing enforcement mechanisms.
    6. Subpart F--Recordkeeping and Reports
        Recordkeeping and reports (Sec. 99.501). Proposed Sec. 99.501 
    required a manufacturer that disseminates information under part 99 to 
    maintain records sufficient to allow it to take corrective action that 
    is required by FDA and described some of the records to be kept. The 
    proposal gave manufacturers the option of maintaining records that 
    identify recipients of the disseminated information by name or by 
    category, but would require manufacturers who choose to identify 
    recipients by category to ensure that any corrective action FDA 
    requires will be sufficiently conspicuous so as to reach the 
    individuals who have received the information about the new use. The 
    proposal also permitted FDA to require manufacturers to keep records 
    identifying recipients by name and required a manufacturer to keep 
    records for 3 years after it has ceased disseminating the information 
    on an unapproved or new use and to make the records available to FDA 
    for inspection and copying.
        110. One comment suggested that FDA permit manufacturers to submit 
    reports via the Internet. The comment said that this would reduce 
    paperwork burdens and provide a continuous source of current 
    information.
        FDA currently receives certain submissions from industry in 
    electronic form and encourages increased utilization of this means. 
    Initiatives are underway to formalize a process for electronic 
    submission.
        111. Several comments focused on proposed Sec. 99.501(a)(1)(i), 
    which required records to identify, by name, the persons receiving the 
    disseminated information. This provision would apply if the 
    manufacturer did not keep records identifying recipients by category or 
    if FDA required the manufacturer to keep records identifying recipients 
    by name. One comment supported the provision as written. Several 
    comments would amend the rule to require manufacturers to keep records 
    identifying recipients by name in all cases. These comments explained 
    that requiring manufacturers to maintain records of specific recipients 
    would help ensure timely action or notification if the new use is 
    ineffective or presents a significant risk to the public health. The 
    comments said such records also would help ensure that the manufacturer 
    disseminated the information to the appropriate recipients. Two 
    comments suggested requiring manufacturers to keep records of health 
    professionals by name, health plans, and pharmacies that receive 
    information in cases of a recall.
        In contrast, several comments objected to ever requiring 
    manufacturers to identify recipients by name. Some comments 
    acknowledged that section 553(b) of the act ``technically'' gives FDA 
    the discretion to require such records, but nevertheless said the 
    provision was ``unnecessary'' or ``unduly burdensome.'' These comments 
    would delete the requirement and only require manufacturers to maintain 
    records identifying recipients by category.
        FDA declines to revise the rule as suggested by the comments. 
    Section 553(b) of the act expressly requires a manufacturer to keep 
    records that the manufacturer may use if it is required to take 
    corrective action. Section 553(b) of the act also states that, ``Such 
    records, at the Secretary's discretion, may identify the recipient of 
    the information provided * * * or the categories of such recipients.'' 
    To require manufacturers to keep records identifying the recipients in 
    all cases, or in no cases, as suggested by the comments, would be 
    contrary to the express terms in section 553(b) of the act. As 
    previously discussed, however, FDA has better defined the standard for 
    individual recordkeeping. Section 99.301(a)(3) of the final rule 
    provides for individual recordkeeping when warranted because of special 
    safety considerations associated with the new use.
        112. One comment claimed that proposed Sec. 99.501(a)(1)(i) 
    exceeded the statutory requirement. The comment said that if FDA 
    requires a manufacturer to maintain records identifying recipients by 
    category, then if corrective action is later required, FDA should not 
    expect manufacturers to generate lists of individual recipients that 
    are to receive such corrective action.
        The comment misinterprets the rule. Under Sec. 99.301(a)(3), when 
    FDA reviews a manufacturer's submission, the agency would determine 
    whether records identifying individual recipients must be kept. FDA 
    would impose such a requirement in limited circumstances before the 
    manufacturer disseminates any information on the unapproved/new use. 
    Section 99.501(a)(1)(i) does not provide a new mechanism for requiring 
    manufacturers to keep records identifying individual recipients nor 
    does it contemplate requiring manufacturers not previously required to 
    identify individual recipients to generate such records if corrective 
    action becomes necessary.
    
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        113. Several comments discussed the semiannual submissions to FDA 
    under proposed Sec. 99.501(b). Several comments objected to proposed 
    Sec. 99.501(b)(3) and (b)(4), which required a notice and summary of 
    any additional clinical research or other data relating to the safety 
    or effectiveness of the new use and periodic progress reports on the 
    manufacturer's studies. The comments stated that such reporting 
    requirements would duplicate information that FDA already receives 
    under existing reporting requirements for IND's and NDA's. One comment 
    objected to the semiannual frequency of the reports. Another argued 
    that FDA failed to set forth ``limits on the responsibilities'' of 
    manufacturers ``as the Secretary deems appropriate'' regarding 
    additional information that must be submitted. Finally, one comment 
    asked FDA to acknowledge that these reports are exempt from disclosure 
    under FOIA.
        Section 99.501(b)(3) and (b)(4) reflect the statutory requirement 
    at sections 555(a)(2) and 554(c)(2) of the act respectively. Section 
    555(a)(2) of the act states that, after a manufacturer disseminates 
    information, the manufacturer shall submit ``a notification of any 
    additional knowledge of the manufacturer on clinical research or other 
    data that relate to the safety or effectiveness of the new use 
    involved.'' Section 554(c)(2) of the act requires a manufacturer to 
    submit periodic progress reports on its clinical studies. FDA drafted 
    the proposed rule to have these periodic progress reports submitted on 
    a semiannual basis in order to coincide with the reporting frequency 
    for the lists of articles and categories of providers required by 
    section 553(a) of the act. This would be more convenient for both 
    manufacturers and the agency to have the reports and lists submitted at 
    the same time. Thus, FDA did not intend to require duplicate reporting 
    of information that is already submitted to the agency under other FDA 
    regulations nor did FDA intend to make the submission of such reports 
    burdensome.
        To the extent that the information described in Sec. 99.501(b)(3) 
    and (b)(4) is already submitted to FDA as part of the routine reporting 
    for an application for investigational use or for a marketing 
    application, manufacturers may comply with Sec. 99.501(b)(3) and (b)(4) 
    by making a cross-reference to the relevant application for 
    investigational use or for a marketing application. Thus, a 
    manufacturer does not have to duplicate information that it has already 
    submitted to FDA. Moreover, FDA did set limits on the manufacturers' 
    responsibilities by requiring that the information be reported on a 
    semiannual basis. Finally, as stated earlier, public disclosure of 
    information submitted under this rule is dictated by the FOIA and FDA's 
    regulations.
        114. One comment sought clarification that a manufacturer must 
    submit any additional article or publication to FDA before it can be 
    disseminated. The concern was that manufacturers would interpret the 
    semiannual filing requirement as sufficient once a manufacturer has 
    received approval to disseminate information about a particular use.
        The statute and regulation make clear that the manufacturer has to 
    come to FDA before beginning to disseminate a journal article or 
    reference publication that has not previously been submitted to FDA. In 
    other words, once FDA has approved or passed on a specific journal 
    article or reference text, the manufacturer can disseminate it to as 
    many qualified recipients as it chooses, as long as the manufacturer 
    continues to meet the requirements of this part. However, even if FDA 
    has approved or passed on one journal article or reference publication 
    for a new use, the manufacturer may not disseminate additional/
    different journal articles or reference publications for that same use 
    without making a separate submission.
        115. If a manufacturer received an exemption from the requirement 
    to submit a supplemental application, proposed Sec. 99.501(b)(5) would 
    require the manufacturer to submit any new or additional information 
    that relates to whether the manufacturer continues to meet the 
    requirements for the exemption. One comment objected to this 
    requirement, saying that it would need extensive market data to 
    continue justifying the need for an exemption on economic grounds and 
    that the cost of generating such information would itself be 
    economically prohibitive.
        FDA disagrees that it would be economically prohibitive to comply 
    with this requirement. The regulation requires manufacturers only to 
    provide new or additional information.
        116. Proposed Sec. 99.501(c) required a manufacturer to maintain a 
    copy of all information, lists, records, and reports required or 
    disseminated under part 99 for 3 years after it has ceased 
    dissemination of such information and to make such documents available 
    to FDA for inspection and copying. One comment requested clarification 
    of this provision. The comment explained that if FDA approves the 
    manufacturer's supplemental application, then the manufacturer would no 
    longer be disseminating information on an unapproved/new use and would 
    not be subject to part 99. Instead, any postapproval dissemination of 
    information would be on an approved use and, therefore, would not be 
    subject to the recordkeeping requirement in Sec. 99.501(c).
        The comment's interpretation of Sec. 99.501(c) is correct. If FDA 
    approves the manufacturer's supplemental application, the use is then 
    ``approved'' and dissemination of information on the approved use would 
    be outside the scope of part 99. However, documents relating to the 
    dissemination of information before approval would remain subject to 
    Sec. 99.501.
    7. Conforming Amendment to 21 CFR Part 16
        The proposed rule would amend 21 CFR 16.1(b)(2) to add the due 
    diligence determination under proposed Sec. 99.401(c) to the list of 
    regulatory actions that may be the subject of a part 16 hearing.
        FDA received no comments on this provision and has finalized it 
    without change.
    
    IV. Analysis of Impacts
    
        FDA has examined the impacts of the final rule under Executive 
    Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612). 
    Executive Order 12866 directs agencies to assess all costs and benefits 
    of available regulatory alternatives and, when regulation is necessary, 
    to select regulatory approaches that maximize net benefits (including 
    potential economic, environmental, public health and safety, and other 
    advantages). Under the Regulatory Flexibility Act, unless an agency 
    certifies that a rule will not have a significant economic impact on a 
    substantial number of small entities, the agency must analyze 
    regulatory options that would minimize the impact of the rule on small 
    entities. Title II of the Unfunded Mandates Reform Act (Pub. L. 104-4) 
    (in section 202) requires that agencies prepare an assessment of 
    anticipated costs and benefits before proposing any rule that may 
    result in an expenditure in any 1 year by State, local, and tribal 
    governments, in the aggregate, or by the private sector, of $100 
    million or more (adjusted annually for inflation).
        The agency has reviewed this rule and has determined that it is 
    consistent with the regulatory philosophy and principles identified in 
    Executive Order 12866, and in these two statutes. Although this rule is 
    not an economically significant regulatory action, it is still a 
    significant regulatory action as defined by the Executive Order due to 
    the novel policy issues it raises.
    
    [[Page 64579]]
    
     With respect to the Regulatory Flexibility Act, the agency certifies 
    that the rule will not have a significant economic impact on a 
    substantial number of small entities. Because the final rule does not 
    impose any mandates on State, local, or tribal governments, or the 
    private sector that will result in a 1-year expenditure of $100 million 
    or more, FDA is not required to perform a cost-benefit analysis under 
    the Unfunded Mandates Reform Act.
        The rule implements section 401 of FDAMA by describing the new use 
    information that a manufacturer may disseminate and by setting forth 
    procedures that manufacturers must follow before disseminating 
    information on the new use. The benefits of the rule will derive from 
    the public health gains associated with the earlier dissemination of 
    objective, balanced, and accurate information on important unapproved 
    uses of approved products. In addition, the rule may encourage new 
    studies or the collection of evidence about these new uses.
        The costs of the rule are modest. A firm would typically conduct 
    clinical studies in support of a supplemental application for a new use 
    only if the firm believed that the added revenues associated with the 
    new indication would exceed the costs of the supporting studies. 
    Because this rule will accelerate the receipt of these revenues, it is 
    possible that some new use supplemental applications that would not 
    have been economically justified in the absence of this rule, will now 
    be submitted. No comments on the proposed rule attempted to project the 
    magnitude of this incentive and FDA similarly could not estimate the 
    number or cost of the additional clinical studies that might accompany 
    these applications. The agency notes, however, that they would be 
    undertaken voluntarily by the affected firms in the expectation that 
    they would increase company profitability.
         Manufacturers choosing not to disseminate new use information will 
    incur no costs. Firms voluntarily choosing to disseminate new use 
    information will experience added paperwork costs for each submission 
    to the agency, but gain sales revenues from the information 
    dissemination. FDA cannot make a precise estimate of the number of 
    submissions that will be filed, but as explained in section V of this 
    document, the agency tentatively forecasts that it will receive 
    approximately 300 submissions each year from manufacturers for the 
    purpose of disseminating new use information. FDA also estimates that 
    the statutory and regulatory paperwork burdens associated with these 
    submissions might total almost 52,000 hours, at an average labor cost 
    of $35 per hour.\1\ Thus, the total cost of the added paperwork is 
    estimated to cost industry approximately $1.8 million per year. FDA 
    received no public comments that specifically addressed its paperwork 
    estimates.
    ---------------------------------------------------------------------------
    
        \1\ Updated from Eastern Research Group, Inc., ``Final Report--
    Economic Threshold and Regulatory Flexibility Assessment of Proposed 
    Changes to the Current Good Manufacturing Practice Regulations for 
    Manufacturing, Processing, Packaging, or Holding Drugs (21 CFR 210 
    and 211),'' March 13, 1995. Calculation allocates 50 percent of 
    hours to middle management, 25 percent to upper management, and 25 
    percent to support staff.
    ---------------------------------------------------------------------------
    
        The final rule should not have an adverse impact on any 
    manufacturer. One comment asserted that the agency's definition of 
    economically prohibitive implies that some manufacturers will 
    disseminate information despite a resulting reduction in net income. 
    The comment further indicated that this reduction in net income 
    requires FDA to undertake additional analysis under the Regulatory 
    Flexibility Act. The agency disagrees with this comment, because the 
    final rule simply makes the dissemination of unapproved use information 
    an option for those firms that find it beneficial to do so. Firms will 
    compare the expected sales revenue from the new dissemination activity 
    to the associated paperwork cost and disseminate the new information 
    only if it increases their profitability. As noted previously, firms 
    choosing not to disseminate new use information will face no increased 
    costs. Because no firm is likely to experience a reduced net income, 
    the rule will not have a significant adverse economic effect on a 
    substantial number of small entities and no further analysis is 
    required under the Regulatory Flexibility Act.
    
    V. Paperwork Reduction Act of 1995
    
        This 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). A description of these provisions is given below in this section 
    of the document with an estimate of the annual reporting and 
    recordkeeping burden. Included in the estimate is the time for 
    reviewing instructions, searching existing data sources, gathering and 
    maintaining the data needed, and completing and reviewing each 
    collection of information.
        FDA had submitted the information collection requirements for the 
    proposed rule to OMB for its review. In its Notice of Office of 
    Management and Budget Action, dated July 30, 1998, OMB stated that it 
    had concerns regarding the burden and utility of the information 
    collection that were to be ``assessed in light of public comments 
    received.'' The terms of OMB clearance further stated that OMB:
        is particularly interested in determining whether the public has 
    comments on the burden and utility of the information required to be 
    included in a submission to FDA, including information submitted to 
    meet the economically prohibitive' exception, and the three year 
    recordkeeping requirement proposed in the rule. FDA shall 
    specifically address any comments received on these and other issues 
    related to the information collection requirements * * *.
    The proposed rule provided an opportunity for public comment on the 
    information collection requirements, but FDA received no comments that 
    provided any contrary or different estimates. The agency did receive 
    one comment declaring that the estimated information collection burden 
    for the proposed rule ``may not be an accurate reflection of the actual 
    burden,'' but the comment provided no data or further information that 
    would enable FDA to revise the estimated information collection burden 
    for the final rule.
        The agency received several comments that questioned the utility of 
    the information collection requirements. For example, several comments 
    requested changes to the information that would be required to obtain 
    an exemption when a manufacturer felt it would be ``economically 
    prohibitive'' or ``unethical'' to conduct studies necessary to support 
    a supplemental application. These comments generally stated that the 
    proposed rule's criteria were too restrictive. The agency revised the 
    ``economically prohibitive'' criteria in response to the comments and 
    modified the language in the ``unethical'' exemption. These issues are 
    discussed in more detail in the preamble to the final rule.
        The agency received several comments that questioned the utility of 
    the information collection requirements. For example, several comments 
    requested changes to the information that would be required to obtain 
    an exemption when a manufacturer felt it would be ``economically 
    prohibitive'' or ``unethical'' to conduct studies necessary to support 
    a supplemental application. These comments generally stated that the 
    proposed rule's criteria were too restrictive. The agency revised the 
    ``economically prohibitive'' criteria in response to the comments and 
    modified the language in the ``unethical'' exemption. These issues are
    
    [[Page 64580]]
    
    discussed in more detail in the preamble to the final rule.
        The agency did not receive any comments that questioned the utility 
    of the 3-year recordkeeping requirement. One comment sought 
    clarification as to whether the recordkeeping requirement would still 
    apply if FDA approved the supplemental application for the new use, and 
    FDA has addressed that comment in its discussion of the recordkeeping 
    provision.
        FDA did, however, simplify the provision concerning the 
    ``economically prohibitive'' exception in response to comments it 
    received. FDA discusses the impact of this revision on the estimated 
    annual reporting burden later in this section.
        FDA requested emergency processing of the information collection 
    requirements for this final rule. OMB granted approval to the 
    collection of information and assigned a control number (OMB 0910-
    0390). The final rule's information collection requirements, therefore, 
    are effective upon November 20, 1998. However, the agency is also 
    submitting the information collection requirements for the final rule 
    to OMB for routine processing. Consequently, FDA is providing an 
    opportunity for public comment on the final rule's information 
    collection requirements.
        FDA invites 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 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: Dissemination of Treatment Information on Unapproved/New 
    Uses for Marketed Drugs, Biologics, and Devices.
        Description: The rule implements sections 551 through 557 of the 
    act (21 U.S.C. 360aaa-360aaa-6) as amended by FDAMA, which requires a 
    manufacturer that intends to disseminate certain treatment information 
    on unapproved uses for a marketed drug, biologic, or device to submit 
    that information to FDA. The rule sets forth the criteria and 
    procedures for making such submissions. Under the rule, a submission 
    would include a certification that the manufacturer has completed 
    clinical studies necessary to submit a supplemental application to FDA 
    for the new use and will submit the supplemental application within 6 
    months after dissemination of information can begin. If the 
    manufacturer has planned, but not completed, such studies, the 
    submission would include proposed protocols and a schedule for 
    conducting the studies, as well as a certification that the 
    manufacturer will complete the clinical studies and submit a 
    supplemental application no later than 36 months after dissemination of 
    information can begin. The rule also permits manufacturers to request 
    extensions of the time period for completing a study and submitting a 
    supplemental application and to request an exemption from the 
    requirement to submit a supplemental application. The rule prescribes 
    the timeframe within which the manufacturer shall maintain records that 
    would enable it to take corrective action. The rule requires the 
    manufacturer to submit lists pertaining to the disseminated articles 
    and reference publications and the categories of persons (or 
    individuals) receiving the information and to submit a notice and 
    summary of any additional research or data (and a copy of the data) 
    relating to the product's safety or effectiveness for the new use. The 
    rule requires the manufacturer to maintain a copy of the information, 
    lists, records, and reports for 3 years after it has ceased 
    dissemination of the information and to make the documents available to 
    FDA for inspection and copying.
        Description of Respondents: All manufacturers (persons and 
    businesses, including small businesses) of drugs, biologics, and device 
    products.
        The estimated burden associated with the information collection 
    requirements for this rule is 52,208 hours.
        FDA estimates the burden of this collection of information as 
    follows:
    
                                      Table 1.--Estimated Annual Reporting Burden1
    ----------------------------------------------------------------------------------------------------------------
                                                          Annual
             21 CFR Section               No. of       Frequency per   Total Annual      Hours per      Total Hours
                                        Respondents      Response        Responses       Response
    ----------------------------------------------------------------------------------------------------------------
    99.201(a)(1)                          172               1.7           297              40          11,880
    99.201(a)(2)                          172               1.7           297              24           7,128
    99.201(a)(3)                          172               1.7           297               1             297
    99.201(a)(4)(i)(A)                     52               1.7            89              30           2,670
    99.201(a)(4)(ii)(A)                    52               1.7            89              60           5,340
    99.201(a)(5)                           52               1.7            89               1              89
    99.201(b)                             172               1.7           297               0.5           148.5
    99.201(c)                             172               1.7           297               0.5           148.5
    99.203(a)                               1               1.7             1              10              10
    99.203(b)                               1               1.7             1              10              10
    99.203(c)                               2               1               2               0.5             1
    99.205(b)                              17               1.8            30              82           2,460
    99.501(b)(1)                          172               3.4           594               8           4,752
    99.501(b)(2)                          172               3.4           594               1             594
    99.501(b)(3)                          172               3.4           594              20          11,880
    99.501(b)(4)                            2               1.7             3               2               6
    99.501(b)(5)                           17               1.8            30              41           1,230
    Total Hours                                                                                        48,644
    ----------------------------------------------------------------------------------------------------------------
    \1\ There are no capital costs or operating and maintenance costs associated with this collection of
      information.
    
    
    [[Page 64581]]
    
    
                                    Table 2.--Estimated Annual Recordkeeping Burden1
    ----------------------------------------------------------------------------------------------------------------
                                                          Annual
             21 CFR Section               No. of       Frequency per   Total Annual      Hours per      Total Hours
                                       Recordkeepers   Recordkeeping      Records      Recordkeeper
    ----------------------------------------------------------------------------------------------------------------
    99.501(a)(1)                          172               1.7           297              10           2,970
    99.501(a)(2)                          172               1.7           297               1             297
    99.501(c)                             172               1.7           297               1             297
    Total Hours                                                                                         3,564
    ----------------------------------------------------------------------------------------------------------------
    \1\ There are no capital costs or operating and maintenance costs associated with this collection of
      information.
    
        FDA derived these estimates primarily from existing data on 
    submissions made under supplemental applications and other submissions 
    to the agency, as well as information from industry sources regarding 
    similar or related reporting and recordkeeping burdens.
        However, because the final rule revises the ``economically 
    prohibitive'' exception requirement, FDA has decreased the estimated 
    burden associated with an exemption request under Sec. 99.205(b) and 
    has increased the number of annual responses seeking an exemption. In 
    the preamble to the proposed rule, FDA estimated that 1 percent or 
    approximately 2 of the 172 manufacturers would submit an exemption 
    request. The estimated reporting burden for Sec. 99.205(b), as 
    originally proposed, was 125 hours per response. This was based on a 
    similar reporting burden for certain submissions under (Sec. 316.20 (21 
    CFR 316.20)) even though FDA stated that the actual reporting burden 
    would probably be less because proposed Sec. 99.205(b) was not as 
    extensive as Sec. 316.20. For the final rule, FDA has reduced the 
    estimated reporting burden per response to 82 hours because the revised 
    requirements are not as extensive as those in the proposal and has 
    increased the total number of respondents and annual responses to 17 
    and 30 respectively (or approximately 10 percent of all respondents and 
    submissions). This results in a total hour burden of 2,460 hours for 
    Sec. 99.205(b). Additionally, FDA has revised Sec. 99.203 to permit 
    manufacturers to request an extension of the 36-month time period for 
    conducting studies and submitting a supplemental application before it 
    makes a submission to FDA. FDA, therefore, has adjusted the information 
    collection tables to reflect this revision.
        The estimated increase in the number of exemption requests results 
    in a corresponding decrease in the remaining number of submissions 
    under Sec. 99.201(a)(4)(i)(A), (a)(4)(ii)(A), and (a)(5). FDA assumes 
    that the remaining 267 submissions will be divided equally among 
    Sec. 99.201(a)(4)(i)(A), (a)(4)(ii)(A), and (a)(5) resulting in 89 
    responses in each provision and approximately 52 respondents per 
    provision. Although FDA has not altered the estimated burden hours per 
    response for Sec. 99.201(a)(4)(i)(A), (a)(4)(ii)(A), and (a)(5), the 
    total burden hours for each of these provisions is reduced due to the 
    smaller number of annual responses.
        Additionally, the final rule accounts for the estimated annual 
    reporting and recordkeeping burdens for several provisions 
    (Secs. 99.201(a)(1), 99.201(a)(2), 99.203(a), 99.501(a)(1), 
    99.501(b)(1), 99.501(b)(3), 99.501(b)(5), and 99.501(c)). These 
    provisions were omitted from the Paperwork Reduction Act discussion in 
    the preamble to the proposed rule. The final rule also accounts for the 
    statutory reporting burden associated with Sec. 99.201(a)(4).
        The agency has submitted the information collection requirements of 
    this rule to OMB for review. Interested persons are requested to send 
    comments regarding information collection by January 19, 1999, to the 
    Dockets Management Branch (address above).
    
    VI. Environmental Impact
    
        The agency has determined under 21 CFR 25.30(h) 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.
    
    List of Subjects
    
    21 CFR Part 16
    
         Administrative practice and procedure.
    
    21 CFR Part 99
    
        Administrative practice and procedure, Biologics, Devices, Drugs, 
    Reporting and recordkeeping requirements.
        Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
    authority delegated to the Acting Commissioner of Food and Drugs, 21 
    CFR chapter I is amended to read as follows:
    
    PART 16--REGULATORY HEARING BEFORE THE FOOD AND DRUG ADMINISTRATION
    
        1. The authority citation for 21 CFR part 16 is revised to read as 
    follows:
    
         Authority: 15 U.S.C. 1451-1461; 21 U.S.C. 141-149, 321-394, 
    467f, 679, 821, 1034; 28 U.S.C. 2112; 42 U.S.C. 201-262, 263b, 364.
        2. Section 16.1 is amended in paragraph (b)(2) by numerically 
    adding an entry for Sec. 99.401(c) to read as follows:
    
    
    Sec. 16.1  Scope.
    
     * * * * *
        (b) *   *   *
        (2) Regulatory provisions:
     * * * * *
        Sec. 99.401(c), relating to a due diligence determination 
    concerning the conduct of studies necessary for a supplemental 
    application for a new use of a drug or device.
     * * * * *
        3. Part 99 is added to read as follows:
    
    PART 99--DISSEMINATION OF INFORMATION ON UNAPPROVED/NEW USES FOR 
    MARKETED DRUGS, BIOLOGICS, AND DEVICES
    
    Subpart A--General Information
    
    Sec.
    99.1   Scope.
    99.3    Definitions.
    
    Subpart B--Information to be Disseminated
    
    99.101   Information that may be disseminated.
    99.103    Mandatory statements and information.
    99.105   Recipients of information.
    
    Subpart C--Manufacturer's Submissions, Requests, and Applications
    
    99.201    Manufacturer's submission to the agency.
    99.203   Request to extend the time for completing planned studies.
    99.205   Application for exemption from the requirement to file a 
    supplemental application.
    
    [[Page 64582]]
    
    Subpart D--FDA Action on Submissions, Requests, and Applications
    
    99.301   Agency action on a submission.
    99.303   Extension of time for completing planned studies.
    99.305    Exemption from the requirement to file a supplemental 
    application.
    
    Subpart E--Corrective Actions and Cessation of Dissemination
    
    99.401   Corrective actions and cessation of dissemination of 
    information.
    99.403   Termination of approvals of applications for exemption.
    99.405   Applicability of labeling, adulteration, and misbranding 
    authority.
    
    Subpart F--Recordkeeping and Reports
    
    99.501   Recordkeeping and reports.
        Authority: 21 U.S.C. 321, 331, 351, 352, 355, 360, 360c, 360e, 
    360aa-360aaa-6, 371, and 374; 42 U.S.C. 262.
    
    Subpart A--General Information
    
    
    Sec. 99.1  Scope.
    
        (a) This part applies to the dissemination of information on human 
    drugs, including biologics, and devices where the information to be 
    disseminated:
        (1) Concerns the safety, effectiveness, or benefit of a use that is 
    not included in the approved labeling for a drug or device approved by 
    the Food and Drug Administration for marketing or in the statement of 
    intended use for a device cleared by the Food and Drug Administration 
    for marketing; and
        (2) Will be disseminated to a health care practitioner, pharmacy 
    benefit manager, health insurance issuer, group health plan, or Federal 
    or State Government agency.
        (b) This part does not apply to a manufacturer's dissemination of 
    information that responds to a health care practitioner's unsolicited 
    request.
    
    
    Sec. 99.3   Definitions.
    
        (a) Agency or FDA means the Food and Drug Administration.
        (b) For purposes of this part, a clinical investigation is an 
    investigation in humans that tests a specific clinical hypothesis.
        (c) Group health plan means an employee welfare benefit plan (as 
    defined in section 3(1) of the Employee Retirement Income Security Act 
    of 1974 (29 U.S.C. 1002(1))) to the extent that the plan provides 
    medical care (as defined in paragraphs (c)(1) through (c)(3) of this 
    section and including items and services paid for as medical care) to 
    employees or their dependents (as defined under the terms of the plan) 
    directly or through insurance, reimbursement, or otherwise. For 
    purposes of this part, the term medical care means:
        (1) Amounts paid for the diagnosis, cure, mitigation, treatment, or 
    prevention of disease, or amounts paid for the purpose of affecting any 
    structure or function of the body;
        (2) Amounts paid for transportation primarily for and essential to 
    medical care referred to in paragraph (c)(1) of this section; and
        (3) Amounts paid for insurance covering medical care referred to in 
    paragraphs (c)(1) and (c)(2) of this section.
        (d) Health care practitioner means a physician or other individual 
    who is a health care provider and licensed under State law to prescribe 
    drugs or devices.
        (e) Health insurance issuer means an insurance company, insurance 
    service, or insurance organization (including a health maintenance 
    organization, as defined in paragraph (e)(2) of this section) which is 
    licensed to engage in the business of insurance in a State and which is 
    subject to State law which regulates insurance (within the meaning of 
    section 514(b)(2) of the Employee Retirement Income Security Act of 
    1974 (29 U.S.C. 1144(b)(2))).
        (1) Such term does not include a group health plan.
        (2) For purposes of this part, the term health maintenance 
    organization means:
        (i) A Federally qualified health maintenance organization (as 
    defined in section 1301(a) of the Public Health Service Act (42 U.S.C. 
    300e(a)));
        (ii) An organization recognized under State law as a health 
    maintenance organization; or
        (iii) A similar organization regulated under State law for solvency 
    in the same manner and to the same extent as such a health maintenance 
    organization.
        (f) Manufacturer means a person who manufactures a drug or device 
    or who is licensed by such person to distribute or market the drug or 
    device. For purposes of this part, the term may also include the 
    sponsor of the approved, licensed, or cleared drug or device.
        (g) New use means a use that is not included in the approved 
    labeling of an approved drug or device, or a use that is not included 
    in the statement of intended use for a cleared device.
        (h) Pharmacy benefit manager means a person or entity that has, as 
    its principal focus, the implementation of one or more device and/or 
    prescription drug benefit programs.
        (i) A reference publication is a publication that:
        (1) Has not been written, edited, excerpted, or published 
    specifically for, or at the request of, a drug or device manufacturer;
        (2) Has not been edited or significantly influenced by such a 
    manufacturer;
        (3) Is not solely distributed through such a manufacturer, but is 
    generally available in bookstores or other distribution channels where 
    medical textbooks are sold;
        (4) Does not focus on any particular drug or device of a 
    manufacturer that disseminates information under this part and does not 
    have a primary focus on new uses of drugs or devices that are marketed 
    or are under investigation by a manufacturer supporting the 
    dissemination of information; and
        (5) Does not present materials that are false or misleading.
        (j) Scientific or medical journal means a scientific or medical 
    publication:
        (1) That is published by an organization that has an editorial 
    board, that uses experts who have demonstrated expertise in the subject 
    of an article under review by the organization and who are independent 
    of the organization, to review and objectively select, reject, or 
    provide comments about proposed articles, and that has a publicly 
    stated policy, to which the organization adheres, of full disclosure of 
    any conflict of interest or biases for all authors or contributors 
    involved with the journal or organization;
        (2) Whose articles are peer-reviewed and published in accordance 
    with the regular peer-review procedures of the organization;
        (3) That is generally recognized to be of national scope and 
    reputation;
        (4) That is indexed in the Index Medicus of the National Library of 
    Medicine of the National Institutes of Health; and
        (5) That is not in the form of a special supplement that has been 
    funded in whole or in part by one or more manufacturers.
        (k) Supplemental application means:
        (1) For drugs, a supplement to support a new use to an approved new 
    drug application;
        (2) For biologics, a supplement to an approved license application;
        (3) For devices that are the subject of a cleared 510(k) submission 
    and devices that are exempt from the 510(k) process, a new 510(k) 
    submission to support a new use or, for devices that are the subject of 
    an approved premarket approval application, a supplement to support a 
    new use to an approved premarket approval application.
    
    [[Page 64583]]
    
    Subpart B--Information to be Disseminated
    
    
    Sec. 99.101  Information that may be disseminated.
    
        (a) A manufacturer may disseminate written information concerning 
    the safety, effectiveness, or benefit of a use not described in the 
    approved labeling for an approved drug or device or in the statement of 
    intended use for a cleared device, provided that the manufacturer 
    complies with all other relevant requirements under this part. Such 
    information shall:
        (1) Be about a drug or device that has been approved, licensed, or 
    cleared for marketing by FDA;
        (2) Be in the form of:
        (i) An unabridged reprint or copy of an article, peer-reviewed by 
    experts qualified by scientific training or experience to evaluate the 
    safety or effectiveness of the drug or device involved, which was 
    published in a scientific or medical journal. In addition, the article 
    must be about a clinical investigation with respect to the drug or 
    device and must be considered to be scientifically sound by the experts 
    described in this paragraph; or
        (ii) An unabridged reference publication that includes information 
    about a clinical investigation with respect to the drug or device, 
    which experts qualified by scientific training or experience to 
    evaluate the safety or effectiveness of the drug or device that is the 
    subject of the clinical investigation would consider to be 
    scientifically sound;
        (3) Not pose a significant risk to the public health;
        (4) Not be false or misleading. FDA may consider information 
    disseminated under this part to be false or misleading if, among other 
    things, the information includes only favorable publications when 
    unfavorable publications exist or excludes articles, reference 
    publications, or other information required under Sec. 99.103(a)(4) or 
    the information presents conclusions that clearly cannot be supported 
    by the results of the study; and
        (5) Not be derived from clinical research conducted by another 
    manufacturer unless the manufacturer disseminating the information has 
    the permission of such other manufacturer to make the dissemination.
        (b) For purposes of this part:
        (1) FDA will find that all journal articles and reference 
    publications (as those terms are defined in Sec. 99.3) are 
    scientifically sound except:
        (i) Letters to the editor;
        (ii) Abstracts of a publication;
        (iii) Those regarding Phase 1 trials in healthy people;
        (iv) Flagged reference publications that contain little or no 
    substantive discussion of the relevant clinical investigation; and
        (v) Those regarding observations in four or fewer people that do 
    not reflect any systematic attempt to collect data, unless the 
    manufacturer demonstrates to FDA that such reports could help guide a 
    physician in his/her medical practice.
        (2) A reprint or copy of an article or reference publication is 
    ``unabridged'' only if it retains the same appearance, form, format, 
    content, or configuration as the original article or publication. Such 
    reprint, copy of an article, or reference publication shall not be 
    disseminated with any information that is promotional in nature. A 
    manufacturer may cite a particular discussion about a new use in a 
    reference publication in the explanatory or other information attached 
    to or otherwise accompanying the reference publication under 
    Sec. 99.103.
    
    
    Sec. 99.103  Mandatory statements and information.
    
        (a) Any information disseminated under this part shall include:
        (1) A prominently displayed statement disclosing:
        (i) For a drug, ``This information concerns a use that has not been 
    approved by the Food and Drug Administration.'' For devices, the 
    statement shall read, ``This information concerns a use that has not 
    been approved or cleared by the Food and Drug Administration.'' If the 
    information to be disseminated includes both an approved and unapproved 
    use or uses or a cleared and uncleared use or uses, the manufacturer 
    shall modify the statement to identify the unapproved or uncleared new 
    use or uses. The manufacturer shall permanently affix the statement to 
    the front of each reprint or copy of an article from a scientific or 
    medical journal and to the front of each reference publication 
    disseminated under this part;
        (ii) If applicable, the information is being disseminated at the 
    expense of the manufacturer;
        (iii) If applicable, the names of any authors of the information 
    who were employees of, or consultants to, or received compensation from 
    the manufacturer, or who had a significant financial interest in the 
    manufacturer during the time that the study that is the subject of the 
    dissemination was conducted up through 1 year after the time the 
    article/reference publication was written and published;
        (iv) If applicable, a statement that there are products or 
    treatments that have been approved or cleared for the use that is the 
    subject of the information being disseminated; and
        (v) The identification of any person that has provided funding for 
    the conduct of a study relating to the new use of a drug or device for 
    which such information is being disseminated; and
        (2) The official labeling for the drug or device;
        (3) A bibliography of other articles (that concern reports of 
    clinical investigations both supporting and not supporting the new use) 
    from a scientific reference publication or scientific or medical 
    journal that have been previously published about the new use of the 
    drug or device covered by the information that is being disseminated, 
    unless the disseminated information already includes such a 
    bibliography; and
        (4) Any additional information required by FDA under 
    Sec. 99.301(a)(2). Such information shall be attached to the front of 
    the disseminated information or, if attached to the back of the 
    disseminated information, its presence shall be made known to the 
    reader by a sticker or notation on the front of the disseminated 
    information and may consist of:
        (i) Objective and scientifically sound information pertaining to 
    the safety or effectiveness of the new use of the drug or device and 
    which FDA determines is necessary to provide objectivity and balance. 
    This may include information that the manufacturer has submitted to FDA 
    or, where appropriate, a summary of such information and any other 
    information that can be made publicly available; and
        (ii) An objective statement prepared by FDA, based on data or other 
    scientifically sound information, bearing on the safety or 
    effectiveness of the new use of the drug or device.
        (b) Except as provided in paragraphs (a)(1)(i) and (a)(4) of this 
    section, the statements, bibliography, and other information required 
    by this section shall be attached to such disseminated information.
        (c) For purposes of this section, factors to be considered in 
    determining whether a statement is ``prominently displayed'' may 
    include, but are not limited to, type size, font, layout, contrast, 
    graphic design, headlines, spacing, and any other technique to achieve 
    emphasis or notice. The required statements shall be outlined, boxed, 
    highlighted, or otherwise graphically designed and presented in a 
    manner that achieves emphasis or notice and is distinct from the other 
    information being disseminated.
    
    [[Page 64584]]
    
    Sec. 99.105  Recipients of information.
    
        A manufacturer disseminating information on a new use under this 
    part may only disseminate that information to a health care 
    practitioner, a pharmacy benefit manager, a health insurance issuer, a 
    group health plan, or a Federal or State Government agency.
    
    Subpart C--Manufacturer's Submissions, Requests, and Applications
    
    
    Sec. 99.201  Manufacturer's submission to the agency.
    
        (a) Sixty days before disseminating any written information 
    concerning the safety, effectiveness, or benefit of a new use for a 
    drug or device, a manufacturer shall submit to the agency:
        (1) An identical copy of the information to be disseminated, 
    including any information (e.g., the bibliography) and statements 
    required under Sec. 99.103;
        (2) Any other clinical trial information which the manufacturer has 
    relating to the effectiveness of the new use, any other clinical trial 
    information that the manufacturer has relating to the safety of the new 
    use, any reports of clinical experience pertinent to the safety of the 
    new use, and a summary of such information. For purposes of this part, 
    clinical trial information includes, but is not limited to, published 
    papers and abstracts, even if not intended for dissemination, and 
    unpublished manuscripts, abstracts, and data analyses from completed or 
    ongoing investigations. The reports of clinical experience required 
    under this paragraph shall include case studies, retrospective reviews, 
    epidemiological studies, adverse event reports, and any other material 
    concerning adverse effects or risks reported for or associated with the 
    new use. If the manufacturer has no knowledge of clinical trial 
    information relating to the safety or effectiveness of the new use or 
    reports of clinical experience pertaining to the safety of the new use, 
    the manufacturer shall provide a statement to that effect;
        (3) An explanation of the manufacturer's method of selecting the 
    articles for the bibliography (e.g., the databases or sources and 
    criteria (i.e., subject headings/keywords) used to generate the 
    bibliography and the time period covered by the bibliography); and
        (4) If the manufacturer has not submitted a supplemental 
    application for the new use, one of the following:
        (i) If the manufacturer has completed studies needed for the 
    submission of a supplemental application for the new use:
        (A) A copy of the protocol for each completed study or, if such 
    protocol was submitted to an investigational new drug application or an 
    investigational device exemption, the number(s) for the investigational 
    new drug application or investigational device exemption covering the 
    new use, the date of submission of the protocol(s), the protocol 
    number(s), and the date of any amendments to the protocol(s); and
        (B) A certification stating that, ``On behalf of [insert 
    manufacturer's name], I certify that [insert manufacturer's name] has 
    completed the studies needed for the submission of a supplemental 
    application for [insert new use] and will submit a supplemental 
    application for such new use to the Food and Drug Administration no 
    later than [insert date no later than 6 months from date that 
    dissemination of information under this part can begin]''; or
        (ii) If the manufacturer has planned studies that will be needed 
    for the submission of a supplemental application for the new use:
        (A) The proposed protocols and schedule for conducting the studies 
    needed for the submission of a supplemental application for the new 
    use. The protocols shall comply with all applicable requirements in 
    parts 312 of this chapter (investigational new drug applications) and 
    812 of this chapter (investigational device exemptions). The schedule 
    shall include the projected dates on which the manufacturer expects the 
    principal study events to occur (e.g., initiation and completion of 
    patient enrollment, completion of data collection, completion of data 
    analysis, and submission of the supplemental application); and
        (B) A certification stating that, ``On behalf of [insert 
    manufacturer's name], I certify that [insert manufacturer's name] will 
    exercise due diligence to complete the clinical studies necessary to 
    submit a supplemental application for [insert new use] and will submit 
    a supplemental application for such new use to the Food and Drug 
    Administration no later than [insert date no later than 36 months from 
    date that dissemination of information under this part can begin or no 
    later than such time period as FDA may specify pursuant to an extension 
    granted under Sec. 99.303(a)];'' or
        (iii) An application for exemption from the requirement of a 
    supplemental application; or
        (5) If the manufacturer has submitted a supplemental application 
    for the new use, a cross-reference to that supplemental application.
        (b) The manufacturer's attorney, agent, or other authorized 
    official shall sign the submission and certification statement or 
    application for exemption. If the manufacturer does not have a place of 
    business in the United States, the submission and certification 
    statement or application for exemption shall contain the signature, 
    name, and address of the manufacturer's attorney, agent, or other 
    authorized official who resides or maintains a place of business in the 
    United States.
        (c) The manufacturer shall send three copies of the submission and 
    certification statement or application for exemption to FDA. The 
    outside of the shipping container shall be marked as ``Submission for 
    the Dissemination of Information on an Unapproved/New Use.'' The 
    manufacturer shall send the submission and certification statement or 
    application for exemption to the appropriate FDA component listed in 
    paragraphs (c)(1) through (c)(3) of this section.
        (1) For biological products and devices regulated by the Center for 
    Biologics Evaluation and Research, the Advertising and Promotional 
    Labeling Staff (HFM-602), Center for Biologics Evaluation and Research, 
    Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 20852;
        (2) For human drug products, the Division of Drug Marketing, 
    Advertising, and Communications (HFD-40), Center for Drug Evaluation 
    and Research, Food and Drug Administration, 5600 Fishers Lane, 
    Rockville, MD 20857; or
        (3) For medical devices, the Promotion and Advertising Policy Staff 
    (HFZ-302), Office of Compliance, Center for Devices and Radiological 
    Health, Food and Drug Administration, 2098 Gaither Rd., Rockville, MD 
    20850.
        (d) The 60-day period shall begin when FDA receives a 
    manufacturer's submission, including, where applicable, a certification 
    statement or an application for an exemption.
    
    
    Sec. 99.203  Request to extend the time for completing planned studies.
    
        (a) A manufacturer may request, prior to or at the time of making a 
    submission to FDA under Sec. 99.201, that FDA extend the 36-month time 
    period for completing the studies and submitting a supplemental 
    application for the new use that is the subject of the information to 
    be disseminated. Such request must set forth the reasons that such 
    studies cannot be completed and submitted in a supplemental application 
    within 36 months.
        (b) A manufacturer who has certified that it will complete the 
    studies necessary to submit a supplemental application for a new use 
    within a
    
    [[Page 64585]]
    
    specified period of time from the date that dissemination of 
    information under this part can begin under Sec. 99.201(a)(4)(ii), but 
    later finds that it will be unable to complete such studies and submit 
    a supplemental application within that time period may request an 
    extension of time from FDA. The manufacturer, in its request for 
    extension, shall identify the product, the new use, and shall:
        (1) Describe the study or studies that cannot be completed on time 
    and explain why the study or studies cannot be completed on time;
        (2) Describe the current status of the incomplete study or studies 
    and summarize the work conducted, including the dates on which 
    principal events concerning the study or studies occurred; and
        (3) Estimate the additional time needed to complete the studies and 
    submit a supplemental application. The requested extension shall not 
    exceed an additional 24 months.
        (c) The manufacturer shall send three copies of the request for 
    extension to the same FDA office that received the manufacturer's 
    initial submission and certification statement. The outside of the 
    envelope shall be marked as ``Request for Time Extension--Dissemination 
    of Information on an Unapproved Use.''
    
    
    Sec. 99.205  Application for exemption from the requirement to file a 
    supplemental application.
    
        (a) In certain circumstances, described in paragraph (b) of this 
    section, a manufacturer may submit an application for an exemption from 
    the requirement to submit a supplemental application for a new use for 
    purposes of disseminating information on that use.
        (b) The manufacturer's application for an exemption shall identify 
    the basis for the proposed exemption and shall include materials 
    demonstrating that it would be economically prohibitive or that it 
    would be unethical to conduct the studies necessary to submit a 
    supplemental application for the new use.
        (1) If the basis for the manufacturer's application for exemption 
    is that it would be economically prohibitive to incur the costs 
    necessary to submit a supplemental application for a new use, the 
    manufacturer shall, at a minimum, provide:
        (i) Evidence explaining why existing data characterizing the safety 
    and effectiveness of the drug or device, including data from the study 
    described in the information to be disseminated, are not adequate to 
    support the submission of a supplemental application for the new use. 
    Such evidence shall include an analysis of all data relevant to the 
    safety and effectiveness of the use, a summary of those data, and any 
    documentation resulting from prior discussions with the agency 
    concerning the adequacy of the existing data; and
        (ii) Evidence demonstrating that the cost of the study or studies 
    for the new use reasonably exceeds the expected revenue from the new 
    use minus the costs of goods sold and marketing and administrative 
    expenses attributable to the new use of the product. Such evidence 
    shall include:
        (A) A description of the additional studies that the manufacturer 
    believes are necessary to support the submission of a supplemental 
    application for the new use, including documentation from prior 
    discussions, if any, with the agency concerning the studies that would 
    be needed, and an estimate of the projected costs for such studies;
        (B) The expected patient population for the new use;
        (C) The expected revenue for the new use, including an explanation 
    of the price at which the drug or device will be sold;
        (D) Any exclusivity for the drug or device for the new use; and
        (E) Any other information that the manufacturer has showing that 
    conducting the studies on the new use would be economically 
    prohibitive; and
        (iii) An attestation by a responsible individual of the 
    manufacturer or an individual acting on the manufacturer's behalf 
    verifying that the estimates included with the submission are accurate 
    and were prepared in accordance with generally accepted accounting 
    procedures. The data underlying and supporting the estimates shall be 
    made available to FDA upon request. Alternatively, a manufacturer may 
    submit a report of an independent certified public accountant in 
    accordance with the Statement of Standards for Attestation established 
    by the American Institute of Certified Public Accountants and agreed 
    upon procedures performed with respect to the estimates submitted under 
    this section.
        (2) If the basis for the manufacturer's application for exemption 
    is that it would be unethical to conduct the studies necessary for the 
    supplemental application for a new use, the manufacturer shall provide 
    evidence:
        (i) Explaining why existing data characterizing the safety and 
    effectiveness of the drug or device, including data from the study 
    described in the information to be disseminated, are not adequate to 
    support the submission of a supplemental application for the new use. 
    Such evidence shall include an analysis of all data relevant to the 
    safety and effectiveness of the new use, a summary of those data, and 
    any documentation resulting from prior discussions with the agency 
    concerning the adequacy of the existing data; and
        (ii) Explaining why it would be unethical to conduct the further 
    studies that would be necessary for the approval of the new use. Such 
    evidence shall establish that, notwithstanding the insufficiency of 
    available data to support the submission of a supplemental application 
    for the new use, the data are persuasive to the extent that withholding 
    the drug or device in a controlled study (e.g., by providing no 
    therapy, a placebo, an alternative therapy, or an alternative dose) 
    would pose an unreasonable risk of harm to human subjects. In assessing 
    the appropriateness of conducting studies to support the new use, the 
    manufacturer may provide evidence showing that the new use is broadly 
    accepted as current standard medical treatment or therapy. The 
    manufacturer shall also address the possibility of conducting studies 
    in different populations or of modified design (e.g., adding the new 
    therapy to existing treatments or using an alternative dose if 
    monotherapy studies could not be conducted).
    
    Subpart D--FDA Action on Submissions, Requests, and Applications
    
    
    Sec. 99.301  Agency action on a submission.
    
        (a) Submissions. Within 60 days after receiving a submission under 
    this part, FDA may:
        (1) Determine that the manufacturer does not comply with the 
    requirements under this part and that, as a result, the manufacturer 
    shall not disseminate any information under this part;
        (2) After providing the manufacturer notice and an opportunity for 
    a meeting, determine that the information submitted regarding a new use 
    fails to provide data, analyses, or other written matter that is 
    objective and balanced and:
        (i) Require the manufacturer to disseminate additional information, 
    including information that the manufacturer has submitted to FDA or, 
    where appropriate, a summary of such information or any other 
    information that can be made publicly available, which, in the agency's 
    opinion:
        (A) Is objective and scientifically sound;
    
    [[Page 64586]]
    
        (B) Pertains to the safety or effectiveness of the new use; and
        (C) Is necessary to provide objectivity and balance; and
        (ii) Require the manufacturer to disseminate an objective statement 
    prepared by FDA that is based on data or other scientifically sound 
    information available to the agency and bears on the safety or 
    effectiveness of the drug or device for the new use; and
        (3) Require the manufacturer to maintain records that will identify 
    individual recipients of the information that is to be disseminated 
    when such individual records are warranted due to special safety 
    considerations associated with the new use.
        (b) Protocols/Studies. Within 60 days after receiving a submission 
    under this part, FDA shall:
        (1) If the manufacturer has planned studies that will be needed for 
    the submission of a supplemental application for the new use, review 
    the manufacturer's proposed protocols and schedule for completing such 
    studies and determine whether the proposed protocols are adequate and 
    whether the proposed schedule for completing the studies is reasonable. 
    FDA shall notify the manufacturer of its determination; or
        (2) If the manufacturer has completed studies that the manufacturer 
    believes would be an adequate basis for the submission of a 
    supplemental application for the new use, conduct a review of the 
    protocols submitted for such studies to determine whether they are 
    adequate. FDA shall notify the manufacturer of its determination.
    
    
    Sec. 99.303  Extension of time for completing planned studies.
    
        (a) Upon review of a drug or device manufacturer's proposed 
    protocols and schedules for conducting studies needed for the 
    submission of a supplemental application for a new use, FDA may, with 
    or without a request for an extension from the manufacturer, determine 
    that such studies cannot be completed and submitted within 36 months. 
    The agency may exercise its discretion in extending the time period for 
    completing the studies and submitting a supplemental application. 
    Extensions under this paragraph are not subject to any time limit, but 
    shall be made before the manufacturer begins the studies needed for the 
    submission of a supplemental application for the new use.
        (b) The manufacturer may, after beginning the studies needed for 
    the submission of a supplemental application for a new use, request in 
    writing that FDA extend the time period for conducting studies needed 
    for the submission of a supplemental application for a new use and 
    submitting a supplemental application to FDA. FDA may grant or deny the 
    request or, after consulting the manufacturer, grant an extension 
    different from that requested by the manufacturer. FDA may grant a 
    manufacturer's request for an extension if FDA determines that the 
    manufacturer has acted with due diligence to conduct the studies needed 
    for the submission of a supplemental application for a new use and to 
    submit such a supplemental application to FDA in a timely manner and 
    that, despite such actions, the manufacturer needs additional time to 
    complete the studies and submit the supplemental application. 
    Extensions under this paragraph shall not exceed 24 months.
        (c) If FDA extends the time period for completing the studies and 
    submitting a supplemental application under paragraph (a) of this 
    section after the manufacturer has submitted a certification under 
    Sec. 99.201(a)(4)(ii)(B), or if FDA grants a manufacturer's request for 
    an extension under paragraph (b) of this section, the manufacturer 
    shall submit a new certification under Sec. 99.201(a)(4)(ii)(B) that 
    sets forth the timeframe within which clinical studies will be 
    completed and a supplemental application will be submitted to FDA.
    
    
    Sec. 99.305  Exemption from the requirement to file a supplemental 
    application.
    
        (a) Within 60 days after receipt of an application for an exemption 
    from the requirement of a supplemental application, FDA shall approve 
    or deny the application.
        (1) If FDA does not act on the application for an exemption within 
    the 60-day period, the application for an exemption shall be deemed to 
    be approved.
        (2) If an application for an exemption is deemed to be approved, 
    FDA may, at any time, terminate such approval if it determines that the 
    requirements for granting an exemption have not been met. FDA shall 
    notify the manufacturer if the approval is terminated.
        (b) In reviewing an application for an exemption, FDA shall 
    consider the materials submitted by the manufacturer and may consider 
    any other appropriate information, including, but not limited to, any 
    pending or previously approved applications for exemption submitted by 
    the manufacturer.
        (c) FDA may grant an application for an exemption if FDA determines 
    that:
        (1) It would be economically prohibitive for the manufacturer to 
    incur the costs necessary to submit a supplemental application for a 
    new use, which at a minimum requires:
        (i) That existing data characterizing the safety and effectiveness 
    of the drug or device, including data from the study described in the 
    information to be disseminated are not adequate to support the 
    submission of a supplemental application for the new use; and
        (ii) That the cost of the study or studies for the new use 
    reasonably exceeds the expected revenue from the new use minus the cost 
    of goods sold and marketing and administrative expenses attributable to 
    the new use of the product, and there are not less expensive ways to 
    obtain the needed information; or
        (2) It would be unethical to conduct clinical studies needed to 
    support the submission of a supplemental application for the new use 
    because:
        (i) Existing data characterizing the safety and effectiveness of 
    the drug or device, including data from the study described in the 
    information to be disseminated are not adequate to support the 
    submission of a supplemental application for the new use; and
        (ii) Although available evidence would not support the submission 
    of a supplemental application for the new use, the data are persuasive 
    to the extent that withholding the drug or device in a controlled study 
    would pose an unreasonable risk of harm to human subjects and no 
    studies in different populations or of modified design can be utilized. 
    In determining whether it would be unethical to conduct clinical 
    studies, the agency shall consider, in addition to the persuasiveness 
    of available evidence of effectiveness, whether the new use of the drug 
    or device is broadly accepted as current standard medical treatment or 
    therapy.
    
    Subpart E--Corrective Actions and Cessation of Dissemination
    
    
    Sec. 99.401  Corrective actions and cessation of dissemination of 
    information.
    
        (a) FDA actions based on post dissemination data. If FDA receives 
    data after a manufacturer has begun disseminating information on a new 
    use and, based on that data, determines that the new use that is the 
    subject of information disseminated under this part may not be 
    effective or may present a significant risk to public health, FDA shall 
    consult the manufacturer and, after such consultation, take appropriate 
    action to protect the public health. Such action may include ordering 
    the manufacturer to cease disseminating
    
    [[Page 64587]]
    
    information on the new use and to take appropriate corrective action.
        (b) FDA actions based on information disseminated by a 
    manufacturer. If FDA determines that a manufacturer is disseminating 
    information that does not comply with the requirements under this part, 
    FDA may:
        (1) Provide to the manufacturer an opportunity to bring itself into 
    compliance with the requirements under this part if the manufacturer's 
    noncompliance constitutes a minor violation of these requirements; or
        (2) Order the manufacturer to cease dissemination of information 
    and to take corrective action. FDA shall issue such an order only after 
    it has:
        (i) Provided notice to the manufacturer regarding FDA's intent to 
    issue an order to cease dissemination; and
        (ii) Provided to the manufacturer an opportunity for a meeting. FDA 
    need not provide an opportunity for a meeting if the manufacturer 
    certified that it will submit a supplemental application for the new 
    use within 6 months of the date that dissemination can begin and the 
    noncompliance involves a failure to submit such supplemental 
    application.
        (c) FDA actions based on a manufacturer's supplemental application. 
    FDA may order a manufacturer to cease disseminating information under 
    this part and to take corrective action if:
        (1) In the case of a manufacturer that has submitted a supplemental 
    application for the new use, FDA determines that the supplemental 
    application does not contain adequate information for approval of the 
    new use;
        (2) In the case of a manufacturer that has certified that it will 
    submit a supplemental application for the new use within 6 months, the 
    manufacturer has not, within the 6-month period, submitted a 
    supplemental application for the new use;
        (3) In the case of a manufacturer that has certified that it will 
    submit a supplemental application for the new use within 36 months or 
    within such time as FDA has determined to be appropriate under 
    Sec. 99.303(a) or (b), such manufacturer has not submitted the 
    supplemental application within the certified time, or FDA, after an 
    informal hearing, has determined that the manufacturer is not acting 
    with due diligence to initiate or complete the studies necessary to 
    support a supplemental application for the new use; or
        (4) In the case of a manufacturer that has certified that it will 
    submit a supplemental application for the new use within 36 months or 
    within such time as FDA has determined to be appropriate under 
    Sec. 99.303(a) or (b), the manufacturer has discontinued or terminated 
    the clinical studies that would be necessary to support a supplemental 
    application for a new use.
        (d) Effective date of orders to cease dissemination. An order to 
    cease dissemination of information shall be effective upon date of 
    receipt by the manufacturer, unless otherwise stated in such order.
        (e) Cessation of dissemination by a noncomplying manufacturer. A 
    manufacturer that begins to disseminate information in compliance with 
    this part, but subsequently fails to comply with this part, shall 
    immediately cease disseminating information under this part. A 
    manufacturer that discontinues, terminates, or fails to conduct with 
    due diligence clinical studies that it certified it would complete 
    under Sec. 99.201(a)(4)(ii) shall be deemed not in compliance with this 
    part. A manufacturer shall notify FDA immediately if it ceases 
    dissemination under this paragraph.
    
    
    Sec. 99.403  Termination of approvals of applications for exemption.
    
        (a) FDA may, at any time, terminate the approval of an application 
    for an exemption from the requirement to file a supplemental 
    application if:
        (1) The application for an exemption had been deemed to be approved 
    because the agency had not acted on the application within 60 days 
    after its receipt by FDA;
        (2) The manufacturer is disseminating written information on the 
    new use; and
        (3) FDA determines that it would be economically and ethically 
    possible for the manufacturer to conduct the clinical studies needed to 
    submit a supplemental application for the new use.
        (b) If FDA terminates a deemed approval of an application for an 
    exemption under paragraph (a) of this section, FDA also may:
        (1) Order the manufacturer to cease disseminating information; and
        (2) Order the manufacturer to take action to correct the 
    information that has been disseminated if FDA determines that the new 
    use described in the disseminated information would pose a significant 
    risk to public health.
        (c) FDA shall notify the manufacturer if it terminates the deemed 
    approval of an application for an exemption under paragraph (a) of this 
    section. If FDA also issues an order to cease dissemination of 
    information, the manufacturer shall comply with the order no later than 
    60 days after its receipt.
        (d) FDA may, at any time, terminate the approval of an application 
    for an exemption from the requirement to file a supplemental 
    application for a new use if, after consulting with the manufacturer 
    that was granted such exemption, FDA determines that the manufacturer 
    no longer meets the requirements for an exemption on the basis that it 
    is economically prohibitive or unethical to conduct the studies needed 
    to submit a supplemental application for the new use.
        (e) If FDA terminates an approval of an application for an 
    exemption under paragraph (d) of this section, the manufacturer must, 
    within 60 days of being notified by FDA that its exemption approval has 
    been terminated, file a supplemental application for the new use that 
    is the subject of the information being disseminated under the 
    exemption, certify, under Sec. 99.201(a)(4)(i) or (a)(4)(ii) that it 
    will file a supplemental application for the new use, or cease 
    disseminating the information on the new use. FDA may require a 
    manufacturer that ceases dissemination of information on the new use to 
    undertake corrective action.
    
    
    Sec. 99.405  Applicability of labeling, adulteration, and misbranding 
    authority.
    
        The dissemination of information relating to a new use for a drug 
    or device may constitute labeling, evidence of a new intended use, 
    adulteration, or misbranding of the drug or device if such 
    dissemination fails to comply with section 551 of the Federal Food, 
    Drug, and Cosmetic Act (the act) (21 U.S.C. 360aaa) and the 
    requirements of this part. A manufacturer's failure to exercise due 
    diligence in submitting the clinical studies that are necessary for the 
    approval of a new use that is the subject of information disseminated 
    under this part or in beginning or completing such clinical studies 
    shall be deemed a failure to comply with section 551 of the act and the 
    requirements of this part.
    
    Subpart F--Recordkeeping and Reports
    
    
    Sec. 99.501  Recordkeeping and reports.
    
        (a) A manufacturer disseminating information under this part shall:
         (1) Maintain records sufficient to allow the manufacturer to take 
    corrective action as required by FDA. The manufacturer shall make such 
    records available to FDA, upon request, for inspection and copying. 
    Such records shall either:
    
    [[Page 64588]]
    
         (i) Identify, by name, those persons receiving the disseminated 
    information; or
        (ii) Identify, by category, the recipients of the disseminated 
    information, unless FDA requires the manufacturer to retain records 
    identifying individual recipients of the disseminated information. 
    Manufacturers whose records identify recipients by category only shall:
        (A) Identify subcategories of recipients where appropriate (e.g., 
    oncologists, pediatricians, obstetricians, etc.); and
        (B) Ensure that any corrective action to be taken will be 
    sufficiently conspicuous to individuals within that category of 
    recipients;
        (2) Maintain an identical copy of the information disseminated 
    under this part; and
        (3) Upon the submission of a supplemental application to FDA, 
    notify the appropriate office identified in Sec. 99.201(c) of this 
    part.
        (b) A manufacturer disseminating information on a new use for a 
    drug or device shall, on a semiannual basis, submit to the FDA office 
    identified in Sec. 99.201(c) of this part:
        (1) A list containing the titles of articles and reference 
    publications relating to the new use of drugs or devices that the 
    manufacturer disseminated to a health care practitioner, pharmacy 
    benefit manager, health insurance issuer, group health plan, or Federal 
    or State Government agency. The list shall cover articles and reference 
    publications disseminated in the 6-month period preceding the date on 
    which the manufacturer provides the list to FDA;
        (2) A list identifying the categories of health care practitioners, 
    pharmacy benefit managers, health insurance issuers, group health 
    plans, or Federal or State Government agencies that received the 
    articles and reference publications in the 6-month period described in 
    paragraph (b)(1) of this section. The list shall also identify which 
    category of recipients received a particular article or reference 
    publication;
         (3) A notice and summary of any additional clinical research or 
    other data relating to the safety or effectiveness of the new use, and, 
    if the manufacturer possesses such clinical research or other data, a 
    copy of the research or data. Such other data may include, but is not 
    limited to, new articles published in scientific or medical journals, 
    reference publications, and summaries of adverse effects that are or 
    may be associated with the new use;
        (4) If the manufacturer is conducting studies necessary for the 
    submission of a supplemental application, the manufacturer shall submit 
    periodic progress reports on these studies to FDA. Such reports shall 
    describe the studies' current status (i.e., progress on patient 
    enrollment, any significant problems that could affect the 
    manufacturer's ability to complete the studies, and expected completion 
    dates). If the manufacturer discontinues or terminates a study before 
    completing it, the manufacturer shall, as part of the next periodic 
    progress report, state the reasons for such discontinuation or 
    termination; and
        (5) If the manufacturer was granted an exemption from the 
    requirements to submit a supplemental application for the new use, any 
    new or additional information that relates to whether the manufacturer 
    continues to meet the requirements for such exemption. This information 
    may include, but is not limited to, new or additional information 
    regarding revenues from the product that is the subject of the 
    dissemination and new or additional information regarding the 
    persuasiveness of the data on the new use, including information 
    regarding whether the new use is broadly accepted as current standard 
    medical treatment or therapy.
        (c) A manufacturer shall maintain a copy of all information, lists, 
    records, and reports required or disseminated under this part for 3 
    years after it has ceased dissemination of such information and make 
    such documents available to FDA for inspection and copying.
    
        Dated: November 17, 1998.
    Michael A. Friedman,
    Acting Commissioner for Food and Drugs.
    Donna E. Shalala,
    Secretary of Health and Human Services.
    [FR Doc. 98-31242 Filed 11-19-98; 8:45 am]
    BILLING CODE 4160-01-F
    
    
    

Document Information

Effective Date:
11/20/1998
Published:
11/20/1998
Department:
Food and Drug Administration
Entry Type:
Rule
Action:
Final rule.
Document Number:
98-31242
Dates:
The final rule is effective November 20, 1998. Written comments on the information collection requirements should be submitted by January 19, 1999.
Pages:
64556-64588 (33 pages)
Docket Numbers:
Docket No. 98N-0222
RINs:
0910-AB23: Dissemination of Treatment Information on Unapproved Uses for Marketed Drugs and Devices
RIN Links:
https://www.federalregister.gov/regulations/0910-AB23/dissemination-of-treatment-information-on-unapproved-uses-for-marketed-drugs-and-devices
PDF File:
98-31242.pdf
CFR: (38)
21 CFR 99.3)
21 CFR 99.103(a)(3)
21 CFR 99.301(a)(2)
21 CFR 99.301(a)
21 CFR 99.301(a)(2))
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