[Federal Register Volume 73, Number 11 (Wednesday, January 16, 2008)]
[Proposed Rules]
[Pages 2848-2854]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E8-702]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 314, 601, and 814

[Docket No. 2008N-0021]


Supplemental Applications Proposing Labeling Changes for Approved 
Drugs, Biologics, and Medical Devices

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend 
its regulations regarding changes to an approved new drug application 
(NDA), biologics license application (BLA), or medical device premarket 
approval application (PMA) to codify the agency's longstanding view on 
when a change to the labeling of an approved drug, biologic, or medical 
device may be made in advance of the agency's review of such change. 
FDA is proposing to reaffirm its longstanding position that a 
supplemental application submitted under those provisions is 
appropriate to amend the labeling for an approved product only to 
reflect newly acquired information, as well as to clarify that such a 
supplemental application may be used to add or strengthen a 
contraindication, warning, precaution, or adverse reaction only if 
there is sufficient evidence of a causal association with the drug, 
biologic, or device. The amendments proposed by this document are 
intended to reflect the agency's existing practices with respect to 
supplemental applications submitted to FDA.

DATES: Submit written or electronic comments on the amendments proposed 
by this document by March 17, 2008. See section VIII of this document 
for the proposed effective date of any final rule that may publish 
based on this proposal.

ADDRESSES: You may submit comments, identified by Docket No. 2007M-0468 
and/or RIN number ---- (if a RIN number has been assigned), by any of 
the following methods:
Electronic Submissions
    Submit electronic comments in the following ways:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.
     Agency Web site: http://www.fda.gov/dockets/ecomments. 
Follow the instructions for submitting comments on the agency Web site.
Written Submissions
    Submit written submissions in the following ways:
     FAX: 301-827-6870.
     Mail/Hand delivery/Courier [For paper, disk, or CD-ROM 
submissions]: Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    To ensure more timely processing of comments, FDA is no longer 
accepting comments submitted to the agency by e-mail. FDA encourages 
you to continue to submit electronic comments by using the Federal 
eRulemaking Portal or the agency Web site, as described previously, in 
the ADDRESSES portion of this document under Electronic Submissions.
    Instructions: All submissions received must include the agency name 
and Docket No(s). and Regulatory Information Number (RIN) (if a RIN 
number has been assigned) for this rulemaking. All comments received 
may be posted without change to http://www.fda.gov/ohrms/dockets/default.htm, including any personal

[[Page 2849]]

information provided. For additional information on submitting 
comments, see the ``Comments'' heading of the SUPPLEMENTARY INFORMATION 
section of this document.
    Docket: For access to the docket to read background documents or 
comments received, go to http://www.fda.gov/ohrms/dockets/default.htm 
and insert the docket number(s), found in brackets in the heading of 
this document, into the ``Search'' box and follow the prompts and/or go 
to the Division of Dockets Management, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Erik Mettler, Office of Policy (HF-
11), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 
20857, 301-827-3360, FAX: 301-594-6777, e-mail: 
[email protected].

SUPPLEMENTARY INFORMATION:

I. Background and Proposed Amendments

    FDA is proposing to amend its regulations regarding changes to an 
approved NDA, BLA, or PMA to codify the agency's longstanding view on 
when a change to the labeling of an approved drug, biologic, or medical 
device may be made in advance of the agency's review and approval of 
such change. With respect to drugs, FDA's current regulation, 21 CFR 
314.70(c)(6)(iii), provides that certain labeling changes related to an 
approved drug may be implemented upon receipt by the agency of a 
supplemental new drug application (sNDA) that includes the change.\1\ 
The corresponding regulation for biologics, 21 CFR 601.12(f)(2), 
provides that products with certain labeling changes may be distributed 
before FDA approval. Similarly, with respect to devices, 21 CFR 
814.39(d) provides that certain labeling changes may be placed into 
effect upon submission of a PMA supplement, but prior to the sponsor's 
receipt of a written FDA order approving the supplement. The 
supplements described by Sec. Sec.  314.70(c), 601.12(f)(2), and 
814.39(d) are commonly referred to as ``changes being effected 
supplements'' or ``CBE supplements.''\2\ FDA is proposing to amend 
these provisions to reaffirm that a CBE supplement is appropriate to 
amend the labeling for an approved product only to reflect newly 
acquired information and to clarify that a CBE supplement may be used 
to add or strengthen a contraindication, warning, precaution, or 
adverse reaction only if there is sufficient evidence of a causal 
association with the drug, biologic, or medical device.
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    \1\ CBE changes are not available for generic drugs approved 
under an abbreviated new drug application under 21 U.S.C. 355(j). To 
the contrary, a generic drug manufacturer is required to conform to 
the approved labeling for the listed drug. See 21 CFR 
314.150(b)(10); see also 57 FR 17950, 17953, and 17961.
    \2\ For devices, such supplements are also referred to as 
Special PMA Supplements. For convenience, this document will use the 
term CBE supplement.
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    FDA is the expert public health agency charged by Congress with 
ensuring that drugs, biologics, and medical devices are safe and 
effective, and ensuring that the labeling for approved products 
appropriately informs users of the risks and benefits of the product. 
Accordingly, the Federal Food, Drug, and Cosmetic Act (the act) 
requires new drugs, biologics, and certain Class III medical devices to 
be approved by FDA prior to their distribution in interstate commerce. 
See 21 U.S.C. 505(a); 42 U.S.C. 262(a)(1); 21 U.S.C. 360e(a). Under 
these provisions, FDA's review and prior approval of both the product 
and its proposed labeling is a necessary condition of lawful 
distribution of the product in interstate commerce.
    The CBE supplement procedures set forth in Sec. Sec.  
314.70(c)(6)(iii), 601.12(f)(2), and 814.39(d) must be understood in 
light of these statutory requirements. Allowing sponsors to 
unilaterally amend the labeling for approved products without 
limitation--even if done to add new warnings--would undermine the FDA 
approval process required by Congress. Indeed, permitting a sponsor to 
unilaterally rewrite the labeling for a product following FDA's 
approval of a product and its labeling would disrupt FDA's careful 
balancing of how the risks and benefits of the product should be 
communicated. Accordingly, FDA has issued regulations providing that, 
prior to a sponsor making most labeling changes, it must submit a 
supplemental application fully explaining the basis for the change and 
obtain the prior approval by FDA of the supplemental application. See 
Sec. Sec.  314.70(b), 601.12(f)(1), 814.39(a)(2).
    The CBE supplement procedures are narrow exceptions to this general 
rule. Although CBE supplements permit sponsors to implement labeling 
changes before FDA approval of the change, FDA views a CBE supplement 
as a mechanism primarily designed to provide information to FDA so that 
the agency can decide when safety information should be included in the 
labeling for a product. As with prior approval supplements, FDA will 
carefully review any labeling change proposed in a CBE supplement, as 
well as the underlying information or data supporting the change. FDA 
has the authority to accept, reject, or request modifications to the 
proposed changes as the agency deems appropriate, and has the authority 
to bring an enforcement action if the added information makes the 
labeling false or misleading. See 21 U.S.C. 352(a). For these reasons, 
as a practical matter, FDA encourages sponsors to consult with FDA 
prior to adding safety-related information to the labeling for an 
approved product even when such a change is submitted in a CBE 
supplement, and sponsors typically do so. The ultimate authority over 
drug, biologic, and medical device labeling, therefore, continues to 
rest with FDA.
    The history of the CBE procedure supports this narrow understanding 
of these provisions. The CBE procedure can be traced to a 1965 policy 
that was based on FDA's enforcement discretion. In 1965, the agency 
stated that ``certain kinds of changes in the labeling and 
manufacturing of new drugs, proposed in supplemental new drug 
applications, should be placed into effect at the earliest possible 
time.'' (30 FR 993, January 30, 1965). FDA announced, therefore, that 
agency would ``take no action'' if a sponsor implemented certain 
labeling changes ``prior to his receipt of a written notice of approval 
of the supplemental new-drug application,'' assuming certain conditions 
were satisfied. (30 FR 993 at 994.)
    FDA proposed what is essentially the current CBE procedure in 1982. 
When proposed, the agency made clear that CBE supplements were intended 
to apply only if the sponsor became aware of newly discovered safety 
information that was appropriate for inclusion in the labeling for the 
product. Indeed, in the preamble to the proposed rule for the CBE 
provision for drugs, the agency stated: ``[S]ome information, although 
still the subject of a supplement, would no longer require agency 
preclearance. These supplements would describe changes placed into 
effect to correct concerns about newly discovered risks from the use of 
the drug.'' (47 FR 46622, 46623, October 19, 1982) (emphasis added). In 
that preamble, the agency also emphasized that the CBE procedure was a 
limited exception to the general requirement of prior FDA approval for 
a labeling change:

    Although most changes in labeling would require the applicant to 
submit a supplement and obtain FDA approval before making a change, 
the following changes in labeling, which would make available 
important new information about the safe use of a drug product, 
could be made if the applicant submits a supplement when the change 
is

[[Page 2850]]

made: Changes that add or strengthen a contraindication, warning, 
precaution, or statement about an adverse reaction, drug abuse, 
dependence, or overdosage, or any other instruction about dosage and 
administration that is intended to improve the safe use of the 
product.

(47 FR 46622 at 46635) (emphasis added). Similarly, in the preamble to 
the final rule, FDA again emphasized that CBE supplements were intended 
as a narrow exception to the general rule that labeling changes require 
FDA's prior approval:
    Drug labeling serves as the standard under which FDA determines 
whether a product is safe and effective. Substantive changes in 
labeling * * * are more likely than other changes to affect the 
agency's previous conclusions about the safety and effectiveness of 
the drug. Thus, they are appropriately approved by FDA in advance, 
unless they relate to important safety information, like a new 
contraindication or warning, that should be immediately conveyed to 
the user.

(50 FR 7452-01, 7470, February 22, 1985).
    Recent changes to the act made by the Food and Drug Administration 
Amendments Act (FDAAA), Public Law 110-85, 121 Stat. 823 (September 27, 
2007) confirm that Congress intends FDA to carefully regulate the 
content of labeling for approved products. Among other provisions, 
FDAAA provided new authority to FDA to initiate labeling changes for 
approved drugs and biologics. Under the act as amended, ``[i]f the 
Secretary becomes aware of new safety information that the Secretary 
believes should be included in the labeling of the drug,'' the agency 
may trigger a process to rapidly amend the labeling for the product (21 
U.S.C. 355(o)(4)(A)). The FDAAA provisions were intended to ensure that 
FDA-initiated labeling changes would be made quickly in order to 
respond to new or emerging information about an approved drug or 
biologic. These provisions provide streamlined authority for FDA to 
respond to new and emerging safety information.\3\ FDA believes that 
its understanding of Sec. Sec.  314.70(c)(6)(iii) and 601.12(f)(2) as 
reflected in this document is consistent with this enhanced authority 
for FDA to control the labeling for drugs and biologics.
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    \3\ As FDA has stated, Federal law governs not only what 
information must appear in labeling, but also what information may 
not appear. (71 FR 3922 at 3935, January 24, 2006) (``FDA interprets 
the act to establish both a `floor' and a `ceiling,' such that 
additional disclosures of risk information can expose a manufacturer 
to liability under the act if the additional statement is 
unsubstantiated or otherwise false or misleading.'')
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    In the device context, FDA has previously stated that a CBE 
supplement constitutes ``a narrow exception to the general rule that 
prior FDA approval of changes to a PMA, including the labeling for a 
device, is a condition of lawful distribution.'' See Draft Guidance: 
Modifications to Devices Subject to Premarket Approval (PMA)--The PMA 
Supplement Decision-Making Process (March 9, 2007) (http://www.fda.gov/cdrh/ode/guidance/1584.pdf). ``Allowing a manufacturer to add a safety-
related warning using a [CBE supplement] based on information that was 
known to the FDA during the rigorous PMA review process would undermine 
that important process.'' Id. For this reason, a CBE supplement may 
only be utilized where ``the manufacturer has newly acquired safety-
related information.'' Id. Moreover, ``any such change should be 
considered temporary while FDA reviews the supplement, including the 
basis for * * * how the change enhances the safety of the device or the 
safety in the use of the device.'' Id.
    For these reasons, FDA believes it necessary to amend its 
regulations to make explicit the agency's understanding that a sponsor 
may utilize the limited CBE provisions only to reflect newly acquired 
safety information. FDA intends to consider information ``newly 
acquired'' if it consists of data, analyses, or other information not 
previously submitted to the agency, or submitted within a reasonable 
time period prior to the CBE supplement, that provides novel 
information about the product, such as a risk that is different in type 
or severity than previously known risks about the product. For example, 
if a postmarket study demonstrates that an approved product has a more 
severe risk of a significant adverse reaction than previously known, a 
CBE supplement may be appropriate. However, if a postmarket study 
provides data about a product that is cumulative of information 
previously submitted to FDA, a CBE supplement would not be appropriate. 
Similarly, if a sponsor receives reports of adverse events of a 
different type or greater severity or frequency than previously 
included in submissions to FDA, such information may be considered 
newly acquired information that could form the basis for an appropriate 
CBE supplement. However, if the reports of adverse events are 
consistent in type, severity, and frequency with information previously 
provided to FDA, such reports may not constitute newly acquired 
information appropriate for a CBE supplement. FDA also intends to 
consider significant new analyses of previously submitted data (e.g., 
meta-analyses) that provide novel information about the product to 
constitute newly acquired information. FDA invites comments regarding 
the circumstances when information regarding a safety issue associated 
with a drug, biologic, or medical device should be considered newly 
acquired and thus appropriate to be included in a CBE supplement.
    Moreover, FDA proposes to clarify that a CBE supplement may be used 
only to implement labeling changes regarding contraindications,\4\ 
warnings, precautions, or adverse reactions in circumstances when there 
is sufficient evidence of a causal association with the drug, biologic, 
or medical device.
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    \4\ For drugs and biologics subject to the labeling requirements 
codified at Sec.  201.57 (21 CFR 201.57), see also Sec.  201.56 (21 
CFR 201.56), generally contraindications cannot be substantively 
amended by a CBE supplement. Because all contraindications must be 
described in Highlights, 21 CFR 201.57(a)(9), and because Highlights 
cannot be amended by a CBE supplement, Sec. Sec.  314.70(c)(6)(iii), 
601.12(f)(2), adding or substantively amending a contraindication 
requires a prior approval supplement, unless FDA requests that the 
change be made under Sec.  314.70(c)(6)(iii)(E) or Sec.  
601.12(f)(2)(E) or the sponsor submits, and FDA approves, a waiver 
request under Sec.  314.90.
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    FDA's regulations regarding the content and format of labeling for 
prescription drugs and biologics are codified in Sec. Sec.  201.57 and 
201.80 (21 CFR part 201).\5\ Section 201.57(c) provides criteria for 
when safety information is appropriate for inclusion in the labeling 
for an approved drug or biologic. With respect to warnings and 
precautions, a sponsor is obligated to update labeling for an approved 
product to include ``a warning about a clinically significant hazard as 
soon as there is reasonable evidence of a causal association with a 
drug'', even though a causal relationship ``need not have been 
definitely established.'' (Sec.  201.57(c)(6) (emphasis added)). With 
respect to adverse reactions, the rule requires the listing of adverse 
reactions that are ``reasonably associated with use of a drug'' (Sec.  
201.57(c)(7) (emphasis added)). The rule provides that not all adverse 
events observed during use of a drug are eligible for inclusion in 
labeling, but rather ``only those adverse events for which there is 
some basis to believe there is a causal relationship between the drug 
and the occurrence of the adverse event.'' Id. (emphasis added), c.f. 
Sec.  314.80(e) (sponsor need not submit a 15-day alert report for an 
adverse drug experience obtained from a

[[Page 2851]]

postmarketing study ``unless the applicant concludes that there is a 
reasonable possibility that the drug caused the adverse experience''). 
Similarly, with respect to contraindications, Sec.  201.57 provides 
that labeling should include situations in which the drug should not be 
used because the risk of use clearly outweighs any possible therapeutic 
benefit. The rule directs that sponsors list only ``[k]nown hazards and 
not theoretical possibilities'' as contraindications (Sec.  
201.57(c)(5); see also 71 FR 3922 at 3927) (``FDA believes that 
including relative or hypothetical hazards [as contraindications] 
diminishes the usefulness of this section.'').
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    \5\ Section 201.57 is applicable to recently approved drugs and 
biologics and certain other products (see also Sec.  201.56) 
(describing implementation schedule). Older products generally are 
subject to the labeling requirements set forth in Sec.  201.80.
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    Section 201.80 sets forth similar, although not identical, criteria 
for the inclusion of safety-related information in the labeling for 
products subject to that provision. Because Sec.  201.57 represents the 
agency's most recent consideration of this topic, (see 71 FR 3922), FDA 
proposes that, if a sponsor intends to utilize the limited CBE 
procedure set forth in Sec.  314.70(c)(6)(iii) or Sec.  601.12(f), it 
must possess information regarding causation sufficient to satisfy the 
criteria set forth in Sec.  201.57(c), regardless of whether the drug 
or biologic is subject to the labeling requirements of Sec.  201.57 or 
Sec.  201.80. FDA invites comments on this topic.
    Medical devices subject to PMA approval follow similar labeling 
standards. For example, in 1991 FDA published a memorandum describing 
the agency's approach to device labeling. See Device Labeling Guidance, 
General Program Memorandum G91-1 (March 8, 1991) (http://www.fda.gov/cdrh/g91-1.htm). In that guidance, the agency stated that the labeling 
for a medical device should include a warning ``if there is reasonable 
evidence of an association of a serious hazard with the use of the 
device,'' even though a causal relationship ``need not have been 
proved.'' Id. at section V (emphasis added). With respect to adverse 
reactions, the agency advised that labeling should include a listing of 
adverse reactions that are ``reasonably associated with use of a 
device.'' Id. at section VI (emphasis added). With respect to 
contraindications, the guidance recommended that labeling include 
situations in which the device should not be used because the risk of 
use clearly outweighs any possible benefit. Labeling should include 
only ``[k]nown hazards and not theoretical possibilities.'' Id. at 
section V. For example, if a hypersensitivity to an ingredient in a 
device has not been demonstrated, it should not be listed as a 
contraindication in the labeling. Id. Accordingly, FDA proposes that in 
order to utilize the limited CBE exception, there should be, at 
minimum, reasonable evidence of a causal association between the device 
and the warning, precaution, adverse event, or contraindication sought 
to be added.
    Explicitly requiring that CBE supplements are utilized in a manner 
proposed by this amendment ensures that only scientifically justified 
information is provided in the labeling for an approved product. 
Exaggeration of risk, or inclusion of speculative or hypothetical 
risks, could discourage appropriate use of a beneficial drug, biologic, 
or medical device or decrease the usefulness and accessibility of 
important information by diluting or obscuring it. As FDA has stated, 
labeling that includes theoretical hazards not well-grounded in 
scientific evidence can cause meaningful risk information to lose its 
significance. See, e.g., ``Write it Right: Recommendations for 
Developing User Instruction Manuals for Medical Devices Used in Home 
Health Care'' (August 1993) (http://www.fda.gov/cdrh/dsma/897.pdf) 
(``Overwarning has the effect of not warning at all. The reader stops 
paying attention to excess warnings.'') For this reason, sponsors 
should seek to utilize Sec. Sec.  314.70(c)(6)(iii)(A), 601(f)(2)(A), 
and 814.39(d)(2)(i) only in situations when there is sufficient 
evidence of a causal association between the drug, biologic, or medical 
device and the information sought to be added. For example, Draft 
Guidance, Public Availability of Labeling Changes in ``Changes Being 
Effected Supplements'' (September 2006) (http://www.fda.gov/cder/guidance/7113dft.htm) (``FDA would not allow a change to labeling to 
add a warning in the absence of reasonable evidence of an association 
between the product and an adverse event.''); Colacicco v. Apotex Inc., 
No. 06-3107, Br. of United States (3d Cir. filed December 4, 2006) 
(stating that Sec.  314.70(c)(6)(iii) ``does not alter the requirement 
that any warning must be based on 'reasonable evidence of an 
association of a serious hazard with a drug.''' (citations omitted)). 
Accordingly, FDA is proposing to amend Sec. Sec.  314.70(c)(6)(iii)(A), 
601.12(f)(2)(A), and 814.39(d)(2)(i) to make explicit the agency's view 
that CBE supplements may be used to strengthen a contraindication, 
warning, precaution, or adverse reaction only when there is sufficient 
evidence of a causal association.
    These proposed amendments to FDA's CBE regulations are consistent 
with the agency's role in protecting the public health. Before 
approving an NDA, BLA, or PMA, the FDA undertakes a detailed review of 
the proposed labeling, allowing only information for which there is 
scientific basis to be included in the FDA-approved labeling. Under the 
act, the Public Health Service Act (PHS Act), and FDA regulations, the 
agency makes approval decisions, including the approval of supplemental 
applications, based on a comprehensive scientific evaluation of the 
product's risks and benefits under the conditions of use prescribed, 
recommended, or suggested in the labeling. See, e.g., 21 U.S.C. 355(d); 
42 U.S.C. 262; 21 U.S.C. 360e(d)(2). FDA's comprehensive review is 
embodied in the labeling for the product which reflects thorough FDA 
review of the pertinent scientific evidence and communicates to health 
care practitioners the agency's formal, authoritative conclusions 
regarding the conditions under which the product can be used safely and 
effectively. FDA's approval of an application is expressly conditioned 
upon the applicant incorporating the specified labeling changes exactly 
as directed. For example, Sec. Sec.  314.105(b), 814.44(d)(1). 
Moreover, after approval, FDA continuously works to evaluate the latest 
available scientific information to monitor the safety of products and 
to incorporate information into the product's labeling when 
appropriate. Allowing a sponsor, without prior FDA approval, to add 
information to the labeling for a product based solely on data 
previously submitted to the FDA would undermine FDA's approval process 
and could result in unnecessary or confusing information being placed 
in the labeling for a drug, biologic, or medical device.
    For these reasons, FDA is proposing to amend its regulations to 
make explicit the agency's longstanding position and practice regarding 
CBE supplements. FDA does not consider this amendment to be a 
substantive change, and it would not alter the agency's existing 
practices with respect to accepting or rejecting labeling changes 
proposed by a CBE supplement.

II. Legal Authority

    This rule, if finalized, would amend Sec. Sec.  314.70, 601.12, and 
814.39 in a manner consistent with the agency's current understanding 
and application of those provisions. FDA's legal authority to modify 
Sec. Sec.  314.70, 601.12, and 814.39 arises from the same authority 
under which FDA initially issued these regulations. Both the act and 
the PHS Act provide FDA with authority over the labeling for approved

[[Page 2852]]

drugs, biologics, and medical devices, and authorizes the agency to 
enact regulations to facilitate FDA's review and approval of 
applications regarding the labeling for such products.
    Section 502 of the act (21 U.S.C. 352) provides that a drug, 
biologic,\6\ or medical device will be considered misbranded if, among 
other things, the labeling for the product is false or misleading in 
any particular (21 U.S.C. 352(a)). Under section 502(f) of the act, a 
product is misbranded unless its labeling bears adequate directions for 
use, including adequate warnings against, among other things, unsafe 
dosage or methods or duration of administration or application. 
Moreover, under section 502(j) of the act, a product is misbranded if 
it is dangerous to health when used in the manner prescribed, 
recommended, or suggested in its labeling.
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    \6\ Although the language of section 502 of the act refers only 
to drugs and devices, it is also applicable to biologics. (See 42 
U.S.C. 262(j)).
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    In addition to the misbranding provisions, the premarket approval 
provisions of the act authorize FDA to require that product labeling 
provide adequate information to permit safe and effective use of the 
product. Under section 505 of the act (21 U.S.C. 355), FDA will approve 
an NDA only if the drug is shown to be both safe and effective for its 
intended use under the conditions set forth in the drug's labeling. 
Similarly, under section 515(d)(2) of the act (21 U.S.C. 360e(d)(2)), 
FDA must assess whether to approve a PMA according to the ``conditions 
of use prescribed, recommended, or suggested in the proposed labeling'' 
of the device. Section 701(a) of the act (21 U.S.C. 371(a)) authorizes 
FDA to issue regulations for the efficient enforcement of the act.
    Section 351 of the PHS Act (42 U.S.C. 262) provides additional 
legal authority for the agency to regulate the labeling of biological 
products. Licenses for biological products are to be issued only upon a 
showing that the biological product is safe, pure, and potent (42 
U.S.C. 262(a)). Section 351(b) of the PHS Act (42 U.S.C. 262(b)) 
prohibits any person from falsely labeling any package or container of 
a biological product. FDA's regulations in part 201 apply to all 
prescription drug products, including biological products.

III. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 as amended, the Regulatory Flexibility Act (5 U.S.C. 601-
612), and the Unfunded Mandates Reform Act of 1995 (Public Law 104-4). 
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; distributive impacts; and equity). The agency believes that 
this proposed rule is not a significant regulatory action as defined by 
the Executive Order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because the proposed amendments to existing 
regulations are intended only to clarify the agency's interpretation of 
current policy, the agency certifies that the proposed rule will not 
have a significant economic impact on a substantial number of small 
entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $127 million, using the most current (2006) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
proposed rule to result in any 1-year expenditure that would meet or 
exceed this amount.
    The objective of the proposed rule is to make explicit the agency's 
longstanding view of when a change to the labeling of an approved drug, 
biologic, or medical device may be made in advance of the agency's 
review of the change. More specifically, the purpose of the proposed 
rule is to codify the agency's understanding that a CBE supplement is 
appropriate to amend the labeling for an approved product only to 
reflect newly acquired information, and to clarify that a CBE 
supplement may be used to add or strengthen a contraindication, 
warning, precaution, or adverse reaction only if there is sufficient 
evidence of a causal association with the approved product. FDA does 
not consider this to be a substantive policy change, and it does not 
alter the agency's current practices with respect to accepting or 
rejecting labeling changes proposed by a CBE supplement.
    Because the proposed rule does not establish any new regulatory or 
record keeping requirements, the agency does not expect that there will 
be any associated compliance costs. The proposed rule simply codifies 
the agency's longstanding interpretation of when sponsors are allowed 
to add information regarding the risks associated with a product to the 
labeling without prior approval from FDA. It is expected that the 
proposed codifications would promote more effective and safe use of 
approved products. The agency believes that any potential impacts of 
the proposed rule would be minimal because this action does not 
represent a substantive policy change.

IV. Paperwork Reduction Act of 1995

    This proposed rule refers to previously approved collections of 
information that are subject to review by the Office of Management and 
Budget (OMB) under the Paperwork Reduction Act of 1995 (the PRA) (44 
U.S.C. 3501-3520). The collections of information in: 21 CFR part 314 
have been approved under OMB Control No. 0910-0001 (expires May 31, 
2008); 21 CFR part 601 have been approved under OMB Control No. 0910-
0338 (expires June 30, 2010); and 21 CFR part 814 have been approved 
under OMB Control No. 0910-0231 (expires November 30, 2010). Therefore, 
FDA tentatively concludes that the proposed requirements in this 
document are not subject to review by OMB because they do not 
constitute a ``new collection of information'' under the PRA.

V. Environmental Impact

    The agency has determined under 21 CFR 25.31(a) and 25.34(e) 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.

VI. Federalism

    The agency has analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. Section 4(a) of the 
Executive order requires agencies to ``construe * * * a Federal statute 
to preempt State law only where the statute contains an express 
preemption provision or there is some other clear evidence that the 
Congress intended preemption of State law, or where the exercise of 
State authority conflicts with the exercise of Federal authority under 
the Federal statute.'' Under the principles of implied conflict 
preemption, courts

[[Page 2853]]

have found state law preempted where it is impossible to comply with 
both federal and state law or where the state law ``stands as an 
obstacle to the accomplishment and execution of the full purposes and 
objectives of Congress.'' See English v. General Electric Co., 496 U.S. 
72, 79 (1990); Florida Lime & Avocado Growers, Inc., 373 U.S. 132, 142-
43 (1963); Hines v. Davidowitz, 312 U.S. 52, 67 (1941).
    If finalized as proposed, this rule codifies longstanding agency 
policy and understanding with respect to Sec. Sec.  314.70(c)(6)(iii), 
601.12(f) and 814.39(d). To the extent that state law would require a 
sponsor to add information to the labeling for an approved drug or 
biologic without advance FDA approval based on information or data as 
to risks that are similar in type or severity to those previously 
submitted to the FDA, or based on information or data that does not 
provide sufficient evidence of a causal association with the product, 
such a state requirement would conflict with federal law. In such a 
situation, it would be impossible to market a product in compliance 
with both federal and state law, and the state law would ``stand[] as 
an obstacle to the accomplishment and execution of the full purposes 
and objectives of Congress,'' Hines, 312 U.S. at 67. Moreover, such a 
state law requirement relating to a medical device would constitute a 
requirement that is different from, or in addition to, a federal 
requirement applicable to the device, and which relates to the safety 
or effectiveness of the device. 21 U.S.C. 360k(a).
    FDA believes that the proposed rule, if finalized as proposed, 
would be consistent with Executive Order 13132. Section 4(e) of the 
Executive order provides that when adjudication or rulemaking could 
have a preemptive effect on state law, ``the agency shall provide all 
affected State and local officials notice and an opportunity for 
appropriate participation in the proceedings.'' By publication of this 
proposed rule, FDA invites comments from State and local officials. FDA 
also intends to provide separate notice of this proposed rule to the 
States.

VII. Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic comments regarding this document. 
Submit a single copy of electronic comments or three paper copies of 
any mailed comments, except that individuals may submit one paper copy. 
Comments are to be identified with the docket number found in brackets 
in the heading of this document and may be accompanied by a supporting 
memorandum or brief. Received comments may be seen in the Division of 
Dockets Management between 9 a.m. and 4 p.m., Monday through Friday.
    Please note that in January 2008, the FDA Web site is expected to 
transition to the Federal Dockets Management System (FDMS). FDMS is a 
Government-wide, electronic docket management system. After the 
transition date, electronic submissions will be accepted by FDA through 
the FDMS only. When the exact date of the transition to FDMS is known, 
FDA will publish a Federal Register notice announcing that date.

VIII. Proposed Effective Date

    FDA is proposing that any final rule that may issue based on this 
proposal be effective on the date of its publication in the Federal 
Register.

List of Subjects

21 CFR Part 314

    Administrative practice and procedure, Confidential business 
information, Drugs, Reporting and recordkeeping requirements.

21 CFR Part 601

    Administrative practice and procedure, Biologics, Confidential 
business information.

21 CFR Part 814

    Administrative practice and procedure, Confidential business 
information, Medical devices, Medical research, Reporting and 
recordkeeping.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and the 
Public Health Service Act and under authority delegated to the 
Commissioner of Food and Drugs, it is proposed that 21 CFR parts 314, 
601, and 814 be amended as follows:

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG

    1. The authority citation for 21 CFR part 314 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 356a, 
356b, 356c, 371, 374, 379e.

    2. Section 314.3 is amended in paragraph (b) by alphabetically 
adding the definition for ``newly acquired information'' to read as 
follows:


Sec.  314.3  Definitions.

* * * * *
    (b) * * *
    Newly acquired information means data, analyses, or other 
information not previously submitted to the agency, which may include 
(but are not limited to) data derived from new clinical studies, 
reports of adverse events of a different type or greater severity or 
frequency than previously included in submissions to FDA, or new 
analyses of previously submitted data (e.g., meta-analyses).
* * * * *
    3. Section 314.70 is amended by revising paragraphs (c)(6)(iii) 
introductory text and (c)(6)(iii)(A) to read as follows:


Sec.  314.70  Supplements and other changes to an approved application.

* * * * *
    (c) * * *
    (6) * * *
    (iii) Changes in the labeling to reflect newly acquired 
information, except for changes to the information required in Sec.  
201.57(a) of this chapter (which must be made under paragraph 
(b)(2)(v)(C) of this section), to accomplish any of the following:
    (A) To add or strengthen a contraindication, warning, precaution, 
or adverse reaction for which the evidence of a causal association 
satisfies the standard for inclusion in the labeling under 201.57(c) of 
this chapter;
* * * * *

PART 601--LICENSING

    4. The authority citation for 21 CFR part 601 continues to read as 
follows:

    Authority: 15 U.S.C 1451-1561; 21 U.S.C. 321, 351, 352, 353, 
355, 356b, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C. 
216, 241, 262, 263, 264; sec 122 Pub. L. 105-115, 111 Stat. 2322 (21 
U.S.C. 355 note).
    5. Section 601.12 is amended by revising paragraphs (f)(2)(i) 
introductory text and (f)(2)(i)(A), and by adding paragraph (f)(6) to 
read as follows:


Sec.  601.12  Changes to an approved application.

* * * * *
    (f) * * *
    (2) Labeling changes requiring supplement submission--product with 
a labeling change that may be distributed before FDA approval. (i) An 
applicant shall submit, at the time such change is made, a supplement 
for any change in the package insert, package label, or container label 
to reflect newly acquired information, except for changes to the 
package insert required in Sec.  201.57(a) of this chapter (which must 
be made under paragraph (f)(1) of this section), to accomplish any of 
the following:
    (A) To add or strengthen a contraindication, warning, precaution, 
or adverse reaction for which the

[[Page 2854]]

evidence of a causal association satisfies the standard for inclusion 
in the labeling under Sec.  201.57(c) of this chapter;
* * * * *
    (5) For purposes of paragraph (f)(2) of this section, information 
will be considered newly acquired if it consists of data, analyses, or 
other information not previously submitted to the agency, which may 
include (but are not limited to) data derived from new clinical 
studies, reports of adverse events of a different type or greater 
severity or frequency than previously included in submissions to FDA, 
or new analyses of previously submitted data (e.g., meta-analyses).
* * * * *

PART 814--PREMARKET APPROVAL OF MEDICAL DEVICES

    6. The authority citation for 21 CFR part 814 continues to read as 
follows:

    Authority: 21 U.S.C. 351, 352, 353, 360, 360c-360j, 371, 372, 
373, 374, 375, 379, 379e, 381.

    7. Section 814.3 is amended by adding paragraph (o) to read as 
follows:


Sec.  814.3  Definitions.

* * * * *
    (o) Newly acquired information means data, analyses, or other 
information not previously submitted to the agency, which may include 
(but are not limited to) data derived from new clinical studies, 
reports of adverse events of a different type or greater severity or 
frequency than previously included in submissions to FDA, or new 
analyses of previously submitted data (e.g., meta-analyses).
    8. Section 814.39 is amended by revising paragraphs (d)(1) 
introductory text and (d)(2)(i) to read as follows:


Sec.  814.39  PMA supplements.

* * * * *
    (d)(1) After FDA approves a PMA, any change described in paragraph 
(d)(2) of this section to reflect newly acquired information that 
enhances the safety of the device or the safety in the use of the 
device may be placed into effect by the applicant prior to the receipt 
under Sec.  814.17 of a written FDA order approving the PMA supplement 
provided that:
* * * * *
    (2) * * *
    (i) Labeling changes that add or strengthen a contraindication, 
warning, precaution, or information about an adverse reaction for which 
there is reasonable evidence of a causal association.
* * * * *

    Dated: December 4, 2007.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. E8-702 Filed 1-15-08; 8:45 am]
BILLING CODE 4160-01-S