Federal Register / Vol. 73, No. 164 / Friday, August 22, 2008 / Rules and Regulations 49603 

Escherichia coli O157:H7,’’ Journal of Food 

Protection, 65:1388–1393, 2002. 

*53. Niemira, B.A., ‘‘Radiation Sensitivity 

and Recoverability of Listeria monocytogenes 

and Salmonella on 4 Lettuce Types,’’ Journal 

of Food Science, 68: 2784–2787, 2003. 

*54. Niemira, B.A., ‘‘Relative Efficacy of 

Sodium Hypochlorite Wash Versus 

Irradiation to Inactivate Escherichia coli 

O157:H7 Internalized in Leaves of Romaine 

Lettuce and Baby Spinach,’’ Journal of Food 

Protection, 70:2526–2532, 2007. 

*55. Zhang, L., Z. Lu, and H. Wang, ‘‘Effect 

of Gamma Irradiation on Microbial Growth 

and Sensory Quality of Fresh-Cut Lettuce,’’

International Journal of Food Microbiology, 

106:348–351, 2006. 

*56. Zhang, L., Z. Lu, F. Lu, and X. Bie, 

‘‘Effect of Gamma Irradiation on Quality 

Maintaining of Fresh-Cut Lettuce,’’ Food 

Control, 17:225–228, 2006. 

*57. Fan, X. and K.J. Sokorai, ‘‘Sensorial 

and Chemical Quality of Gamma-Irradiated 

Fresh-Cut Iceberg Lettuce in Modified 

Atmosphere Packages,’’ Journal of Food 

Protection, 65:1760–1765, 2002. 

*58. Fan, X. and K.J. Sokorai, ‘‘Assessment 

of Radiation Sensitivity of Fresh-Cut 

Vegetables Using Electrolyte Leakage 

Measurement,’’ Postharvest Biology and 

Technology, 36:191–197, 2005. 

*59. Fan, X., B.A. Niemira, and K.J. 

Sokorai, ‘‘Use of Ionizing Radiation to 

Improve Sensory and Microbial Quality of 

Fresh-cut Green Onion Leaves,’’ Journal of 

Food Science, 68:1478–1483, 2003. 

*60. Petran, R.L., W.H. Sperber, and A.B. 

Davis, ’’Clostridium botulinum Toxin 

Formation in Romaine Lettuce and Shredded 

Cabbage: Effect of Storage and Packaging 

Conditions,’’ Journal of Food Protection, 58, 

624–627, 1995. 

*61. Renner, H. W., U. Graf, F.E. Wurgler, 

H. Altmann, J.C. Asquith, and P.S. Elias, ‘‘An 

Investigation of the Genetic Toxicology of 

Irradiated Foodstuffs Using Short-Term Test 

Systems, III—in vivo Tests in Small Rodents 

and in Drosophila melangaster,’’ Food 

Chemistry and Toxicology, 30:867–878, 1982. 

List of Subjects in 21 CFR Part 179 

Food additives, Food labeling, Food 

packaging, Radiation protection, 

Reporting and record keeping 

requirements, Signs and symbols. 

■ Therefore, under the Federal Food, 

Drug, and Cosmetic Act and under 

authority delegated to the Commissioner 

of Food and Drugs, 21 CFR part 179 is 

amended as follows: 

PART 179—IRRADIATION IN THE 

PRODUCTION, PROCESSING AND 

HANDLING OF FOOD 

■ 1. The authority citation for 21 CFR 

part 179 continues to read as follows: 

Authority: 21 U.S.C. 321, 342, 343, 348, 

373, 374. 

■ 2. Section 179.26 is amended in the 

table in paragraph (b) by adding a new 

item ‘‘12.’’ under the headings ‘‘Use’’

and ‘‘Limitations’’ to read as follows: 

§ 179.26 Ionizing radiation for the 

treatment of food. 

* * * * * 

(b) * * * 

Use Limitations 

* * * * * * * 

12. For control of food-borne pathogens and extension of shelf-life in 

fresh iceberg lettuce and fresh spinach. 

Not to exceed 4.0 kGy. 

* * * * * 

Dated: August 19, 2008. 

Jeffrey Shuren, 

Associate Commissioner for Policy and 

Planning. 

[FR Doc. E8–19573 Filed 8–21–08; 8:45 am] 

BILLING CODE 4160–01–S 

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. 

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, § 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, 

§ 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, § 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 §§ 314.70(c), 601.12(f)(2), and 

814.39(d) are commonly referred to as 

‘‘changes being effected supplements’’


yshivers on PROD1PC62 with RULES
49604 Federal Register / Vol. 73, No. 164 / Friday, August 22, 2008 / Rules and Regulations 

1For devices, such supplements are also referred 

to as Special PMA Supplements. This document 

will use the term ‘‘CBE supplement.’’

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 § 201.57(c)(6) (21 CFR 

201.57(c)(6)) (for Warnings and 

Precautions—‘‘reasonable evidence’’), 

and in § 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. 

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 § 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 § 601.12 rather than to paragraph 

(f)(5) of § 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 § 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 (§ 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 § 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 § 201.57 (and the 

predecessor regulation, now codified at 

§ 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 


yshivers on PROD1PC62 with RULES
Federal Register / Vol. 73, No. 164 / Friday, August 22, 2008 / Rules and Regulations 49605 

2FDA notes that the rule of construction in 21 

U.S.C. 355(o)(4) on its face does not relate to 

medical devices. 

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 § 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 § 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 (§ 201.57(c) 

and Device Labeling Guidance). 

With respect to comments suggesting 

that § 201.57 sets the standard for when 

sponsors must warn, but that a lower 

standard should be used under 

§ 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). 

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 postmarketing 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 

(§§ 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’’ (§ 201.57(c)(6)), and add other 

risk information as required by the 

regulations (§ 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 


yshivers on PROD1PC62 with RULES
49606 Federal Register / Vol. 73, No. 164 / Friday, August 22, 2008 / Rules and Regulations 

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 (§ 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 (§ 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 nonexclusive 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 


yshivers on PROD1PC62 with RULES
Federal Register / Vol. 73, No. 164 / Friday, August 22, 2008 / Rules and Regulations 49607 

in this final rule) provide appropriate 

and adequate regulatory pathways for 

updating and modifying labeling of 

drugs, biological products, and medical 

devices. See § 314.70(c) (for drugs), 

§ 601.12(f)(2) (for biological products) 

and § 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 § 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 (§ 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 § 314.90 or request that 

a sponsor make a change to Highlights 

under § 314.70(c)(6)(iii)(E) or 

§ 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 


yshivers on PROD1PC62 with RULES
49608 Federal Register / Vol. 73, No. 164 / Friday, August 22, 2008 / Rules and Regulations 

3Although 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)). 

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 §§ 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. 

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, 


yshivers on PROD1PC62 with RULES
Federal Register / Vol. 73, No. 164 / Friday, August 22, 2008 / Rules and Regulations 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. 

■ 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 

■ 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: 

§ 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. 

* * * * * 

■ 3. Section 314.70 is amended by 

revising paragraphs (c)(6)(iii) 

introductory text and (c)(6)(iii)(A) to 

read as follows: 

§ 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 

§ 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: 

§ 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 § 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 § 201.57(c) of this 

chapter; 

* * * * * 


yshivers on PROD1PC62 with RULES
49610 Federal Register / Vol. 73, No. 164 / Friday, August 22, 2008 / Rules and Regulations 

(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 

■ 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: 

§ 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. 

■ 8. Section 814.39 is amended by 

revising paragraphs (d)(1) introductory 

text and (d)(2)(i) to read as follows: 

§ 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 

§ 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 

DEPARTMENT OF HOMELAND 

SECURITY 

Coast Guard 

33 CFR Part 100 

[Docket No. USCG–2008–0424] 

Special Local Regulation; U.S. 

Nationals Waterski Racing 

Championship; Mission Bay, San 

Diego, CA 

AGENCY: Coast Guard, DHS. 

ACTION: Notice of enforcement of 

regulation. 

SUMMARY: The Coast Guard will enforce 

the U.S. Nationals Waterski Racing 

Championship special local regulation 

on Mission Bay from 8 a.m. on October 

10, 2008 through 5 p.m. on October 12, 

2008. This action is necessary to 

provide for the safety of the 

participants, crew, spectators, 

participating vessels, and other vessels 

and users of the waterway. During the 

enforcement period, no person or vessel 

may enter the special local regulation 

without permission of the Captain of the 

Port. 

DATES: The regulations in 33 CFR 

100.1101 will be enforced from 8 a.m. 

on October 10, 2008 through 5 p.m. on 

October 12, 2008. 

FOR FURTHER INFORMATION CONTACT: 

Petty Officer Kristen Beer, USCG, 

Waterways Management, U.S. Coast 

Guard Sector San Diego at (619) 278–

7233. 

SUPPLEMENTARY INFORMATION: The Coast 

Guard will enforce the special local 

regulation for the U.S. Nationals 

Waterski Racing Championship in 33 

CFR 100.1101 on October 10, 2008, from 

8 a.m. to 7 p.m., October 11, 2008, from 

8 a.m. to 7 p.m., and October 12, 2008, 

from 8 a.m. to 7 p.m. 

Under the provisions of 33 CFR 

100.1101, a vessel may not enter the 

regulated area, unless it receives 

permission from the COTP. Spectator 

vessels may safely transit outside the 

regulated area but may not anchor, 

block, loiter in, or impede the transit of 

participants or official patrol vessels. 

The Coast Guard may be assisted by 

other Federal, State, or local law 

enforcement agencies in enforcing this 

regulation. 

This notice is issued under authority 

of 33 CFR 100.1101(a) and 5 U.S.C. 

552(a). In addition to this notice in the 

Federal Register, the Coast Guard will 

provide the maritime community with 

extensive advance notification of this 

enforcement period via the Local Notice 

to Mariners, marine information 

broadcasts, local radio stations and area 

newspapers. If the COTP or his 

designated representative determines 

that the regulated area need not be 

enforced for the full duration stated in 

this notice, he or she may use a 

Broadcast Notice to Mariners to grant 

general permission to enter the 

regulated area. 

Dated: August 8, 2008. 

T.H. Farris, 

Captain, U.S. Coast Guard, Captain of the 

Port Sector San Diego. 

[FR Doc. E8–19532 Filed 8–21–08; 8:45 am] 

BILLING CODE 4910–15–P 

DEPARTMENT OF HOMELAND 

SECURITY 

Coast Guard 

33 CFR Part 165 

[Docket Number USCG–2008–0769] 

Oregon Symphony Celebration 

Fireworks Display, Portland, OR 

AGENCY: Coast Guard, DHS. 

ACTION: Notice of enforcement of 

regulation. 

SUMMARY: The Coast Guard will enforce 

the ‘‘Oregon Symphony Celebration 

Fireworks Display safety zone on the 

Willamette River’’; from 8:30 p.m. 

through 11:30 p.m. on August 28, 2008. 

This action is necessary to provide a 

safe display for the public and to keep 

them clear of the fall out area of the 

fireworks. During the enforcement 

period, no person or vessel may enter 

the safety zone without permission of 

the Captain of the Port Portland or his 

designated representative. 

DATES: The regulations in 33 CFR 

165.1315(a)(7) will be enforced from 

8:30 p.m. through 11:30 p.m. on August 

28, 2008. 

FOR FURTHER INFORMATION CONTACT: BM2 

Joshua Lehner, Sector Portland 

Waterways Management at (503) 247–

4015. 

SUPPLEMENTARY INFORMATION: The Coast 

Guard will enforce the safety zone for 

the Oregon Symphony Celebration 

Fireworks Display in 33 CFR 

165.1315(a)(7) on August 28, 2008 from 

8:30 p.m. to 11:30 p.m. 


yshivers on PROD1PC62 with RULES