
[Federal Register: August 22, 2008 (Volume 73, Number 164)]
[Rules and Regulations]               
[Page 49603-49610]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr22au08-3]                         

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 314, 601, and 814

[Docket No. FDA-2008-N-0032] (formerly Docket No. 2008N-0021)
RIN 0910-ZA32

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

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending its 
regulations regarding changes to an approved new drug application 
(NDA), biologics license application (BLA), or medical device premarket 
approval application (PMA). This final rule provides that a 
supplemental application submitted under certain FDA regulations is 
appropriate to amend the labeling for an approved product to reflect 
newly acquired information and to add or strengthen a contraindication, 
warning, precaution, or adverse reaction if there is sufficient 
evidence of a causal association with the drug, biologic, or device, as 
defined in other FDA regulations and guidance documents.

DATES: This rule is effective September 22, 2008.

FOR FURTHER INFORMATION CONTACT:
    For information regarding devices: Nicole Wolanski, Center for 
Devices and Radiological Health (HFZ-402), Food and Drug 
Administration, 9200 Corporate Blvd., Rockville, MD 20850, 240-276-
4010.
    For information regarding biologics: Christopher Joneckis, Center 
for Biologics Evaluation and Research (HFM-1), Food and Drug 
Administration, 1401 Rockville Pike, Rockville MD 20852, 301-827-0373.
    For information regarding drugs: Laurie Burke, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 22, rm. 6462, Silver Spring, MD 20933, 301-796-
0900.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of January 16, 2008 (73 FR 2848), FDA 
proposed amending its regulations regarding changes to an NDA, BLA, or 
PMA to codify the agency's longstanding view concerning 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 (the 
January 2008 proposed rule). With respect to drugs, Sec.  
314.70(c)(6)(iii) (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. The corresponding regulation for biological 
products, Sec.  601.12(f)(2) (21 CFR 601.12(f)(2)), provides that 
products with certain labeling changes may be distributed before FDA 
approval. Similarly, with respect to devices, Sec.  814.39(d) (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''

[[Page 49604]]

or ``CBE supplements.''\1\ FDA proposed amending these provisions to 
affirm that a CBE supplement is appropriate to amend the labeling for 
an approved product only to reflect newly acquired information and to 
make it clear 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. The phrase ``sufficient evidence of a 
causal association'' refers to the standards for drugs and biologics 
described in Sec.  201.57(c)(6) (21 CFR 201.57(c)(6)) (for Warnings and 
Precautions--``reasonable evidence''), and in Sec.  201.57(c)(7) (21 
CFR 201.57(c)(7)) (for Adverse Reactions--``some basis to believe'') 
and to the standard for devices in the Device Labeling Guidance, 
General Program Memorandum G91-1 (March 8, 1991) (http://www.fda.gov/
cdrh/g91-1.html) (``reasonable evidence'') for the level of evidence 
needed to support a causal association with these medical products.
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    \1\ For devices, such supplements are also referred to as 
Special PMA Supplements. This document will use the term ``CBE 
supplement.''
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    As described in the January 2008 proposed rule, FDA believes that 
amending FDA's CBE regulations is consistent with the agency's role in 
protecting the public health. Before approving an NDA, BLA, or PMA, FDA 
undertakes a detailed review of the proposed labeling, allowing only 
information for which there is a scientific basis to be included in the 
FDA-approved labeling. Under the Federal Food, Drug, and Cosmetic Act 
(the act), the Public Health Service Act (the 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 scientific evaluation 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. Expressly requiring that a CBE supplement reflect newly 
acquired information and be based on sufficient evidence of a causal 
association will help to ensure that scientifically accurate 
information appears in the approved labeling for such products.

II. Changes to the January 2008 Proposed Rule

    FDA has made the following changes to the January 2008 proposed 
rule:
    The definition of ``newly acquired information'' has been revised 
to clarify that data, whether derived from new clinical studies, 
reports of adverse events, or new analyses of previously submitted data 
(e.g., meta-analyses) needs to be of a ``different type or greater 
severity or frequency than previously included in submissions to FDA''. 
The codified section of the January 2008 proposed rule suggested that 
this limitation applied only to data derived from reports of adverse 
events. Instead, it applies to data derived from new clinical studies, 
reports of adverse events, and new analyses of previously submitted 
data.
    In addition, FDA has made one technical correction to the January 
2008 proposed rule. The technical correction is in Sec.  601.12, where 
an amendment was proposed adding paragraph (f)(5), containing the 
definition of ``newly acquired information.'' In fact, the amendment 
should have proposed adding this definition to paragraph (f)(6) of 
Sec.  601.12 rather than to paragraph (f)(5) of Sec.  601.12.

III. Comments

    FDA received approximately 20 comments to the January 2008 proposed 
rule. The comments were submitted by consumer advocacy groups, 
individuals, law firms, law professors, pharmaceutical companies, trade 
associations, and Members of Congress.
    (Comment 1) Several comments stated that this proposed amendment 
would make it more difficult for sponsors to warn about new risks. Most 
of these comments were focused on the aspect of the rule that imposed a 
requirement that sponsors have a sufficient amount of causal evidence 
before a CBE should be used.
    In addition, comments argued that FDA should distinguish between 
situations when sponsors are obligated to warn of a new risk, and 
situations when the sponsor is permitted to warn. For example, some 
comments stated that the requirement in Sec.  201.57(c)(6) that there 
be some evidence of a causal relationship should apply to situations 
when a manufacturer must warn, but should not apply to when 
manufacturers may warn. These comments argue that public policy should 
not discourage sponsors from warning, even when the regulations do not 
require it.
    Similarly, one comment argued that causation is not a binary issue 
(i.e., causation is either present or not). Rather, the causal 
relationship between a product and an adverse effect is often difficult 
to establish and may require large trials, often specifically designed 
to assess the risk. One comment argued that because of this difficulty, 
drug and device sponsors may delay warning and delay making labeling 
changes by asserting that the CBE regulation (if finalized as proposed) 
would not permit them to amend their labeling.
    FDA does not agree that this rule will make it more difficult to 
provide appropriate warnings regarding hazards associated with medical 
products. This rule is intended to describe FDA's existing labeling 
standards and policies, but does not amend the standards under which 
sponsors must provide warnings regarding risks (Sec.  201.57(c)(6)). 
Nor is the rule intended to suggest that there is a mathematically 
precise distinction between whether there is, or is not, sufficient 
evidence of a causal relation between a drug and an adverse effect to 
support its inclusion in the labeling. The rule is, nevertheless, 
sufficiently clear and objective to allow sponsors to determine whether 
a medical product's labeling should be amended. If new safety 
information meets the requirements of Sec.  201.57(c)(6), it is 
appropriate for inclusion in the labeling of a drug or biologic and a 
sponsor must update its labeling ``as soon as'' such information 
becomes available. That section states that causation need not have 
been ``definitely established'' for a warning to be required to appear 
in labeling, but rather that there need only be ``reasonable'' evidence 
of a causal association with the drug, a standard that could be met by 
a wide range of evidence. A CBE submission may be made when the 
evidence meets the standard set forth in this rule, even if that 
evidence would not also support a higher evidentiary standard, such as 
a finding that there is a ``preponderance'' of evidence that a product 
actually causes a particular kind of adverse event. A sponsor's 
submission or FDA's acceptance of a CBE supplement does not necessarily 
mean that a drug product actually has caused any particular adverse 
event or type of adverse event.
    Through Sec.  201.57 (and the predecessor regulation, now codified 
at Sec.  201.80 (21 CFR 201.80)), the agency set uniform standards for 
drug labeling, seeking to ensure that scientifically sound information 
is provided in the labeling of the drug. There is no reason the 
standard for adding new information to labeling should be different 
from the

[[Page 49605]]

standard for the initial labeling. If new information about a drug 
comes to light, a sponsor must make a decision as to whether the 
requirements of Sec.  201.57 are met, and whether to submit a CBE 
supplement or other type of supplemental application. Failure to update 
labeling as required could result in regulatory actions or criminal 
penalties. If there is doubt as to whether the standard of Sec.  
201.57(c)(6) has been met, a sponsor should confer with FDA. The agency 
has clarified by regulation and guidance the types of supplements that 
should be filed to satisfy a sponsor's obligations to change a drug's 
labeling, and sponsors can consult with FDA on that question as well. 
See 21 CFR 314.70; Guidance for Industry: Changes to an Approved NDA or 
ANDA (November 1999) (http://www.fda.gov/cder/guidance/2766fnl.pdf).
    This rule does not undermine a sponsor's responsibility to maintain 
its label--rather, it clarifies FDA's longstanding practice of 
requiring that sponsors must have sufficient evidence that the 
standards are met (Sec.  201.57(c) and Device Labeling Guidance).
    With respect to comments suggesting that Sec.  201.57 sets the 
standard for when sponsors must warn, but that a lower standard should 
be used under Sec.  314.70(c)(6) for when a sponsor may warn, FDA has 
previously stated and reiterates here that it ``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'' (71 FR 3922 at 3935, January 24, 2006) 
(the 2006 Physician Labeling Rule). FDA, therefore, declines to set 
different standards for when a sponsor must warn, as opposed to when it 
may warn of a particular risk or adverse event.
    (Comment 2) Several comments stated that the rule would conflict 
with the intent of Congress. FDA in no way believes that this rule 
conflicts with Congressional intent. Another, comment stated that 
Congress did not intend for the act to preempt State law because there 
is no express preemption provision with respect to drugs. Several 
comments referred to the recently enacted Food and Drug Administration 
Amendments Act of 2007 (FDAAA) in support of this position. These 
comments suggest that for FDA to change the circumstances when sponsors 
could update their labeling by a CBE would conflict with congressional 
intent. FDAAA provided additional authority for FDA to require sponsors 
to make safety related changes to their labeling. The statute also 
included a rule of construction as part of a paragraph providing new 
authority to the Secretary to require labeling changes for drug 
products: ``This paragraph shall not be construed to affect the 
responsibility of the responsible person or the holder of the approved 
application under section 505(j) to maintain its label in accordance 
with existing requirements, including subpart B of part 201 and 
sections 314.70 and 601.12 of title 21, Code of Federal Regulations (or 
any successor regulations).'' (Section 505(o)(4)(I) of the act (21 
U.S.C. 355(o)(4)(I))).
    FDA does not believe that the absence of an express preemption 
provision with respect to drugs affects the application of the doctrine 
of implied preemption. Furthermore, FDA does not agree that the rule of 
construction affects FDA's ability to finalize the January 2008 
proposed rule for several, independent reasons.\2\ The January 2008 
proposed regulation is consistent with the rule of construction. First, 
the rule of construction, by its terms, contemplates amendments to 
applicable regulations by its reference to ``successor regulations'' 
governing a sponsor's obligation to change product labeling. Congress, 
therefore, expressly acknowledged that FDA's regulations are not static 
and may be subsequently amended by the agency, as FDA is doing here. 
Second, the rule of construction operates to preserve Federal labeling 
obligations only in the face of an argument that ``this paragraph''--21 
U.S.C. 355(o)(4), the new statutory provision permitting the Secretary 
of Health and Human Services (the Secretary) to impose labeling changes 
after meeting certain procedural requirements--``affects'' those 
responsibilities. Third, the rule of construction refers to, and 
therefore preserves only a sponsor's Federal-law (as opposed to State-
law) ``responsibility[ies] * * * to maintain its label.'' As was noted 
in the U.S. Government's amicus brief at the merits stage in Wyeth v. 
Levine, No. 06-1249 (June 2008) (http://www.justice.gov/osg/briefs/
2007/3mer/1ami/2006-1249.mer.ami.pdf), the rule of construction 
``simply means that the relevant amendments do not affect obligations 
under other federal laws. It does not manifest any intent to depart 
from the application of ordinary principles governing the preemption of 
conflicting state laws. * * * [T]he text of the rule of construction 
that Congress actually enacted, which is limited to the effect of 
Section 901, itself preserves complementary federal requirements 
without evincing any intent to protect conflicting state laws.'' Id. at 
32 (emphases in original).
    (FDA has verified the Web site addresses in this document, but FDA 
is not responsible for subsequent changes after this document publishes 
in the Federal Register).
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    \2\ FDA notes that the rule of construction in 21 U.S.C. 
355(o)(4) on its face does not relate to medical devices.
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    In other words, the rule of construction makes it clear that a 
sponsor cannot contend that, because the Secretary has the power to 
order new labeling changes, the sponsor no longer has an obligation to 
monitor post-marketing experiences and maintain its labeling under 
applicable Federal regulations. Indeed, it can maintain its labeling by 
using all existing tools, including through prior approval supplements, 
CBE-30 day supplements (Sec. Sec.  314.70(c), 601.12(c) and 814.39(e)), 
and CBE supplements, along with other changes that may be reported in 
an annual report. Under both the rule of construction and this final 
rule, a sponsor still must update its labeling under Federal law ``to 
include a warning about a clinically significant hazard as soon as 
there is reasonable evidence of a causal association with a drug'' 
(Sec.  201.57(c)(6)), and add other risk information as required by the 
regulations (Sec.  201.57(c)).
    If FDA were to interpret section 505(o)(4) of the act as 
eliminating the ability or obligation under Federal law of a sponsor to 
``maintain'' its label, this would conflict with the rule of 
construction. But this final rule does not take away a sponsor's 
obligation to maintain its labeling under Federal law under appropriate 
circumstances. FDA is amending the text of the rules at issue here not 
because of the new powers in section 505(o)(4) of the act, but to 
clarify a sponsor's responsibilities and to make the text of the 
regulations match FDA's practice regarding CBE labeling changes, which 
predate FDAAA. Manufacturers continue to have a responsibility under 
Federal law, including the amended regulations under this rulemaking, 
to maintain their labeling and update the labeling with new safety 
information.
    (Comment 3) One comment asserted that this rule could undermine 
consumer confidence in medical products and FDA. Consumer confidence in 
medical products and in FDA itself is critically important. This 
amendment is intended to clarify FDA's existing policies and is 
intended to ensure that scientifically valid and appropriately worded 
warnings will be provided in the approved labeling for medical 
products, and to prevent overwarning, which may deter

[[Page 49606]]

appropriate use of medical products, or overshadow more important 
warnings. Accordingly, FDA does not agree that the rule will undermine 
confidence in medical products or the agency.
    (Comment 4) One comment stated that the January 2008 proposed 
rule's reference to ``newly acquired information'' might undermine 
warnings in situations where a sponsor warns about a particular risk, 
but then later information demonstrates that the warning was 
insufficient.
    FDA believes that the final rule addresses this concern. First, if 
later data or analyses demonstrate that prior warnings were 
insufficient, such data would clearly qualify as newly acquired 
information under the rule. Indeed, the rule expressly provides that 
new analyses of previously submitted information are considered new 
information that could be submitted by a CBE supplement (provided that 
other requirements for a CBE supplement are met). Therefore, if a 
sponsor determined that existing warnings were insufficient based on 
newly acquired information such as a new analysis of previously 
submitted data, the sponsor could still submit a CBE based on its new 
analysis of the previous data, provided the other requirements of the 
rule are met. Moreover, FDA now has new tools to address this 
situation, including its authority to require labeling changes under 
section 505(o) of the act.
    (Comment 5) Several comments asserted that sponsors, not FDA, have 
the most information about their products and should have authority to 
revise their labeling as soon as new information comes to light.
    Sponsors are still required to act promptly to add risk information 
to labeling (Sec.  201.57(c)(6)). This rule describes the standard for 
one type of change to the labeling. It is intended to clarify the 
circumstances in which sponsors are required to update labeling, not to 
undermine or remove a sponsor's obligation to modify labeling to 
reflect appropriate new information. Under FDA's regulations and this 
final rule, sponsors are required to warn as soon as appropriate new 
information comes to light (Sec.  201.57(c)(6)).
    (Comment 6) Several comments stated that FDA did not have 
sufficient resources to review all potential warnings before labeling 
may be updated. As stated in the January 2008 proposed rule, FDA does 
not consider this amendment to substantively change the standards for 
submission of CBE or prior review supplements. The agency does not 
expect that it will increase the number of prior approval supplements 
or otherwise increase agency workloads.
    (Comment 7) One comment requested that FDA clarify the relationship 
between the January 2008 proposed rule and statements made by FDA in 
the preamble to the 2006 Physician Labeling Rule (71 FR 3922). The 
comment inquired whether these changes ``supersede'' certain statements 
in the preamble to the 2006 Physician Labeling Rule. The agency 
believes that these amendments are consistent with prior statements by 
FDA, including those in the 2006 Physician Labeling Rule. The preamble 
to the 2006 Physician Labeling Rule set forth a number of principles 
regarding FDA's regulation of drug labeling. See, e.g. 71 FR 3922 at 
3935 (``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'' * * *); ibid. 
(``State-law attempts to impose additional warnings can lead to 
labeling that does not accurately portray a product's risks, thereby 
potentially discouraging safe and effective use of approved products * 
* *''). That preamble also set forth some non-exclusive examples of 
instances of preemption. Id. at 3935-3936 (stating that ``at least'' 
the enumerated cases are preempted). In a proposed rule that published 
in the Federal Register of May 29, 2008 (73 FR 30831 at 30861), FDA 
reiterated its support for the general principles underlying preemption 
set forth in the 2006 Physician Labeling Rule. In briefs recently filed 
in the Supreme Court of the United States and in testimony before 
Congress, FDA has also stated a more generally applicable rule that is 
consistent with the examples of preempted cases and the principles set 
forth in the preamble to the 2006 Physician Labeling Rule that: (1) The 
labeling requirements are not a mere minimum safety standard, but 
rather strike a balance between risks and benefits, and (2) FDA's 
regulations permit changes in labeling without prior approval only in 
narrow circumstances. Specifically, FDA has explained that State law 
claims that ``challenge labeling that FDA approved after being informed 
of the relevant risk'' are preempted. Brief of the United States as 
Amicus Curiae Supporting Petitioner, Wyeth v. Levine, No. 06-1249; 
Testimony of Deputy FDA Commissioner Randall Lutter before The House 
Committee on Oversight and Government Reform 5 (2008) http://
oversight.house.gov/documents/20080514142253.pdf (``* * * State law 
claims are preempted if they challenge a design or labeling that FDA 
approved, after being informed of the relevant health risk * * *''). 
FDA reiterates and reaffirms here the positions set forth in those 
documents. FDA further notes that FDA there explained the interplay 
between this CBE regulation and preemption. FDA believes that this 
explanation sufficiently describes the relationship between this CBE 
regulation and the 2006 Physician Labeling Rule preamble.
    (Comment 8) One comment requested that FDA make it clear that 
information previously known to the manufacturer, but not submitted to 
FDA, can be eligible for inclusion in a CBE amendment.
    The term ``newly acquired information'' is defined in the final 
rule as ``information not previously submitted to FDA * * *.'' 
Accordingly, if information was previously known to the manufacturer, 
but not submitted to FDA, it would be ``newly acquired information'' 
that may qualify for inclusion in a CBE supplement (provided other 
requirements for a CBE supplement have been met).
    (Comment 9) Several comments requested that FDA clarify the effect 
of this amendment on State tort liability and preemption, and one 
comment stated that this rule lacked a sufficient statement of 
irreconcilable conflict to justify the agency's assertion of implied 
preemption of ``all [S]tate law''. This rule does not preempt all State 
tort law and, furthermore, an ``irreconcilable conflict'' (i.e., an 
impossibility of compliance with both Federal and State law) is not the 
only basis for preemption of State law. Under implied preemption 
principles, if a State law frustrates Federal objectives, the State law 
is preempted. As a result, FDA's views on preemption, as explained 
elsewhere in this preamble, are amply justified by well-established 
principles of preemption. See Geier v. American Honda Co., 529 U.S. 861 
(2000); 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). Moreover, liability 
imposed under State tort law constitutes a State ``requirement'' within 
the meaning of 21 U.S.C. 360k(a). See Reigel v. Medtronic, 128 S.Ct. 
999, 1008-09 (2008). For further discussion of the scope of preemption, 
see the response to comment 7 of this document and section VIII. 
Federalism of this document.
    (Comment 10) One comment requested that FDA develop an alternative 
mechanism to address proposed labeling changes. FDA believes that its 
regulations (as modified

[[Page 49607]]

in this final rule) provide appropriate and adequate regulatory 
pathways for updating and modifying labeling of drugs, biological 
products, and medical devices. See Sec.  314.70(c) (for drugs), Sec.  
601.12(f)(2) (for biological products) and Sec.  814.39(d) (for medical 
devices).
    (Comment 11) One comment requested that FDA clarify the degree of 
certainty that is required for demonstrating causation under FDA's 
regulations. FDA does not believe that additional clarification of its 
labeling rules is necessary. The regulations set forth in Sec.  201.57 
provide relevant standards for when information is appropriate for 
inclusion in labeling, including causation standards. FDA believes that 
standard is sufficiently clear and objective.
    (Comment 12) One comment noted that the preamble to the January 
2008 proposed rule stated that ``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 * * *.'' (73 FR 2848 
at 2850) (emphasis added). The comment requested that FDA clarify the 
temporal relationship between the submission of new information to FDA 
and a subsequent CBE supplement. FDA agrees that this issue should be 
clarified here so as to provide greater guidance to sponsors in 
determining their regulatory obligations. Newly acquired information 
includes information not previously submitted to FDA. If a sponsor 
submits data or analysis to FDA as part of a discussion of the kind of 
labeling change that would be appropriate and decides as a result of 
that discussion to prepare and submit a CBE supplement, then the 
supporting data or analysis will not be considered ``previously 
submitted to FDA''--even if it was not first submitted on the same day 
as the CBE supplement. This allows for a labeling change when a sponsor 
submits data or analysis to FDA before the sponsor has completed its 
CBE supplement, and is also designed so as not to deter the sponsor 
from submitting the information for fear that such a submission would 
preclude the sponsor from making a CBE change. This clarification is 
designed to address the situation where a sponsor submits data or 
analyses to FDA as part of the process of determining what labeling 
change is appropriate, and then diligently and promptly prepares a CBE 
supplement.
    Moreover, FDA also notes that the definition of ``newly acquired 
information'' includes ``new analyses'' of previously submitted 
information. If a sponsor submits information to FDA, then later 
conducts a new analysis that demonstrates that labeling should be 
revised to account for that information, a CBE would be appropriate. 
For example, if the sponsor submits adverse event information to FDA, 
and then later conducts a new analysis of data showing risks of a 
different type or of greater severity or frequency than did reports 
previously submitted to FDA, the sponsor meets the requirement for 
``newly acquired information''.
    (Comment 13) One comment requested that FDA clarify the 
relationship between the CBE regulations and risk evaluation and 
mitigation strategies (REMS) for drugs and biological products.
    Under the new authority provided in FDAAA, FDA may require the 
submission of a proposed REMS if FDA believes that such a strategy is 
necessary to ensure that the benefits of the drug outweigh its risks. A 
REMS must be approved by FDA (21 U.S.C. 355-1(h)), as must proposed 
modifications to a REMS (21 U.S.C. 355-1(g)). Accordingly, if the 
labeling for a drug describes an element of an approved REMS, the 
sponsor must receive prior approval of any labeling changes that would 
necessitate a change to the sponsor's REMS. For example, if a REMS 
included elements to assure safe use under section 505-1(f) of the act, 
some of those elements might be described in the approved labeling for 
the drug or biologic. If the sponsor became aware of newly acquired 
safety information that would otherwise be appropriate for a CBE, but 
would require the sponsor to modify an element to assure safe use that 
is required under a REMS, the sponsor would need to receive prior 
approval of the labeling change. However, if the newly acquired 
information is related to the concern leading to a REMS but the 
proposed change to labeling could be made without requiring a 
modification of the REMS, the approved labeling for the product could 
be strengthened without prior approval. For example, if a REMS was 
imposed requiring periodic monitoring of liver enzymes to ensure the 
risk of liver toxicity for a drug was outweighed by the benefits of the 
drug, strengthening warnings related to that risk may be made by a CBE 
supplement (provided that other requirements for a CBE supplement are 
met and that the change can be made without modifying the REMS).
    (Comment 14) One comment requested that FDA clarify that any change 
to the Highlights section of the labeling of a drug or biologic must be 
made by a prior approval supplement.
    The agency agrees that this issue should be clarified, but does not 
agree that changes to Highlights can never be accomplished by a CBE 
supplement. Under existing regulations, changes to the Highlights are 
classified as a ``major change,'' requiring a prior approval supplement 
(Sec.  314.70(b)(2)(v)(C)). Accordingly, in most cases, changes to 
Highlights will require a prior approval supplement. However, in the 
preamble to the January 2008 proposed rule, we noted that FDA could 
waive this limitation under Sec.  314.90 or request that a sponsor make 
a change to Highlights under Sec.  314.70(c)(6)(iii)(E) or Sec.  
601.12(f)(2)(E). These provisions authorize FDA to waive the Highlights 
limitation or otherwise ask the sponsor to submit a CBE supplement in 
appropriate circumstances.
    (Comment 15) One comment requested that FDA clarify that sponsors 
may not use the CBE process to submit labeling changes for drugs or 
biological products under section 505(o) of the act.
    FDA disagrees with this comment. Under section 505(o) of the act, 
FDA must notify the sponsor if the agency becomes aware of new safety 
information that should be included in the labeling for a particular 
drug or biologic. Following that notification, the sponsor must submit 
a ``supplement'' proposing changes to the labeling or submit a 
statement explaining the reasons why the sponsor believes the labeling 
change is not warranted. Nothing in section 505(o) limits this 
``supplement'' to a prior approval supplement. In fact, to effect the 
change most rapidly, FDA may request that the sponsor file a CBE 
supplement under these circumstances.
    (Comment 16) One comment requested that FDA provide a 
comprehensive, written response to every CBE supplement submitted to 
the agency by a sponsor, describing FDA's grounds for approval, 
disapproval, or, as the case may be, request for modification to the 
submitted CBE supplement. FDA disagrees with this comment. The comment 
failed to provide a compelling justification for this proposal.
    (Comment 17) One comment asserted that if FDA finalizes this rule, 
it will create a disincentive for sponsors to conduct additional trials 
of their products because the sponsors would have to provide additional 
warnings if causation is shown. Under current regulations, sponsors 
must warn about risks of approved products if the requirements for 
updating labeling are triggered. This rule does not change those 
standards. FDA therefore does not believe that it will change the 
incentives

[[Page 49608]]

for sponsors to conduct new clinical trials.
    (Comment 18) One comment stated that the rule would unjustifiably 
impose an added regulatory burden. FDA disagrees with this comment, as 
this rule does not add to the existing regulatory burden. Rather, as 
previously stated, the rule simply affirms that a CBE supplement is 
appropriate to amend the labeling for an approved product only to 
reflect newly acquired information and makes it clear 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. For further discussion of the regulatory burden, see sections 
V. Analysis of Impacts and VI. Paperwork Reduction Act of this 
document.

IV. Legal Authority

    As explained in the January 2008 proposed rule, 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. 
The Federal Food, Drug, and Cosmetic Act (21 U.S.C. 301 et seq.) and 
the Public Health Service Act (42 U.S.C. 201 et seq.) provide FDA with 
authority over the labeling for drugs, biological products, and medical 
devices, and authorize 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,\3\ 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.
---------------------------------------------------------------------------

    \3\ 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)).
---------------------------------------------------------------------------

    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.

V. Analysis of Impacts

    FDA has examined the impacts of the final rule under Executive 
Order 12866, 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 final 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 these amendments to existing regulations are 
intended only to codify the agency's interpretation of current policy, 
the agency certifies that the final 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 
final rule to result in any 1-year expenditure that would meet or 
exceed this amount.
    The objective of the final rule is to make explicit the agency's 
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 final rule is to clarify 
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 reasonable evidence of a causal association with the approved 
drug, biologic, or medical device. 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 this final rule does not establish any new regulatory or 
recordkeeping requirements, the agency does not expect that there will 
be any associated compliance costs. The final rule simply clarifies the 
agency's 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 these clarifications will 
promote more effective and safe use of approved drug, biologic, and 
medical device products. The agency believes that any potential impacts 
of these amendments to existing regulations will be minimal because 
this action does not represent a substantive change from current 
policy. We did not receive any comments on the January 2008 proposed 
rule that would cause us to reconsider these determinations.

VI. Paperwork Reduction Act of 1995

    This final 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. 35013520). The collections of information in 21 CFR part 314 
have been approved under OMB Control No. 0910-0001 (expires May 31, 
2011); 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,

[[Page 49609]]

clearance by OMB under the PRA is not required.

VII. 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.

VIII. Federalism

    FDA has analyzed this final 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.'' Like any Federal requirement, if a State law 
requirement makes compliance with both Federal law and State law 
impossible, or would frustrate Federal objectives, the State 
requirement would be preempted. See Geier v. American Honda Co., 529 
U.S. 861 (2000); 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). Moreover, if a 
State requirement constitutes a requirement that is different from, or 
in addition to, a Federal requirement applicable to a medical device, 
and which relates to the safety or effectiveness of the device, the 
State law requirement is preempted. See 21 U.S.C. 360k(a), Reigel v. 
Medtronic, 128 S.Ct. 999 (2008). In addition to the discussion above in 
response to comment 7 of this document, FDA notes that, at least when a 
sponsor did not meet the standard to change its labeling through a CBE 
supplement under this rule to include the warning a plaintiff alleges 
should have been added to labeling, State law liability that is 
premised on a failure to warn is preempted.
    FDA has provided the States with an opportunity to comment on the 
January 2008 proposed rule. Specifically, following publication of the 
January 2008 proposed rule in the Federal Register, FDA issued a ``Dear 
Colleague'' letter on January 17, 2008. The purpose of this letter was 
to alert officials in various organizations within the 50 States about 
the rulemaking, including officials with State pharmacy boards, State 
medical boards, health commissioners, and drug program directors. The 
letter briefly explained what the rulemaking would do when it became 
final and it encouraged the officials to review the January 2008 
proposed rule and provide FDA with any comments they may have 
concerning the impact this rule may have on the following: (1) On the 
States, (2) on the relationship between the national government and the 
States, or (3) on the distribution of power and responsibilities among 
the various levels of government. FDA received one comment that appears 
to be in response to this ``Dear Colleague'' letter. This comment is 
addressed in the final rule.

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 requirements.

0
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, 21 CFR parts 314, 601, and 814 are 
amended as follows:

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

0
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.

0
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, or new analyses of previously submitted data 
(e.g., meta-analyses) if the studies, events or analyses reveal risks 
of a different type or greater severity or frequency than previously 
included in submissions to FDA.
* * * * *

0
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 Sec.  
201.57(c) of this chapter;
* * * * *

PART 601--LICENSING

0
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).

0
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 evidence of a causal association 
satisfies the standard for inclusion in the labeling under Sec.  
201.57(c) of this chapter;
* * * * *

[[Page 49610]]

    (6) 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, or new analyses of previously 
submitted data (e.g., meta-analyses) if the studies, events or analyses 
reveal risks of a different type or greater severity or frequency than 
previously included in submissions to FDA.
* * * * *

PART 814--PREMARKET APPROVAL OF MEDICAL DEVICES

0
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.

0
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, or new analyses of previously submitted data 
(e.g., meta-analyses) if the studies, events or analyses reveal risks 
of a different type or greater severity or frequency than previously 
included in submissions to FDA.

0
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: August 19, 2008.
Jeffrey Shuren,
Associate Commissioner for Policy and Planning.
[FR Doc. E8-19572 Filed 8-21-08; 8:45 am]

BILLING CODE 4160-01-S
