[Federal Register Volume 77, Number 24 (Monday, February 6, 2012)]
[Rules and Regulations]
[Pages 5696-5699]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2012-2558]



[[Page 5696]]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 201, 312, 314, 601, 610, 801, 807, 809, 812, and 814

[Docket No. FDA-2006-N-0364]


Exceptions or Alternatives to Labeling Requirements for Products 
Held by the Strategic National Stockpile

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is adopting as a final 
rule, without change, the interim final rule that issued regulations 
permitting FDA Center Directors to grant exceptions or alternatives to 
certain regulatory labeling requirements applicable to human drugs, 
biological products, or medical devices that are or will be included in 
the Strategic National Stockpile (SNS). FDA is taking this action to 
complete the rulemaking initiated with the interim final rule.

DATES: This rule is effective February 6, 2012.

FOR FURTHER INFORMATION CONTACT:
    For information concerning biological products:

Melissa Reisman, Center for Biologics Evaluation and Research (HFM-17), 
Food and Drug Administration, 1401 Rockville Pike, suite 200N, 
Rockville, MD 20852-1448, (301) 827-6210.

    For information concerning drug products:

Brad G. Leissa, Center for Drug Evaluation and Research, Food and Drug 
Administration, 10001 New Hampshire Ave., Hillandale Building, rm. 
2170, Silver Spring, MD 20993, (301) 796-1693.

    For information concerning medical devices:

Larry Spears, Center for Devices and Radiological Health, Food and Drug 
Administration, 10903 New Hampshire Ave., Bldg. 66, rm. 3412, Silver 
Spring, MD 20993, (301) 796-5517.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of December 28, 2007 (72 FR 73589), FDA 
issued an interim final rule entitled ``Exceptions or Alternatives to 
Labeling Requirements for Products Held by the Strategic National 
Stockpile'' (hereinafter referred to as the interim final rule).\1\ 
This rule became effective upon the date of publication in the Federal 
Register.
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    \1\ In the Federal Register of November 18, 2008 (73 FR 68332), 
FDA issued a technical amendment to reincorporate a regulation that 
was inadvertently revised by the interim final rule.
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    We issued the interim final rule to facilitate the safety, 
effectiveness, and availability of appropriate medical countermeasures 
stored in the SNS in the event of a public health emergency. We also 
recognized that it may be appropriate for certain human drugs, 
biological products, or medical devices (hereinafter referred to 
collectively as medical products) that are or will be held in the SNS 
to be labeled in a manner that would not comply with certain FDA 
labeling requirements. However, noncompliance with these labeling 
requirements could render such products misbranded under section 502 of 
the Federal Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 
352). Under this rule, the appropriate FDA Center Director may grant 
exceptions or alternatives to certain regulatory labeling requirements 
applicable to medical products that are or will be included in the SNS 
if he or she determines that compliance with the labeling requirements 
could adversely affect the safety, effectiveness, or availability of 
specified lots, batches, or other units of medical products that are or 
will be included in the SNS. An exception or alternative granted under 
this rule may include conditions or safeguards deemed appropriate by 
the FDA Center Director to ensure that the labeling for such products 
includes information necessary for the safe and effective use of the 
product given the product's anticipated circumstances of use.
    For example, this rule applies to certain medical products that 
enter the SNS as investigational products in addition to medical 
products in the SNS that are approved, licensed, or cleared for 
marketing.\2\ Labels on investigational products ordinarily would not 
contain all elements required on licensed, approved, or cleared product 
labels. Certain information, such as expiration dates, warnings for 
users, license numbers of manufacturers and other information, may not 
be available or finalized for an investigational product, and thus 
could not be included on a container label if the investigational 
product was added to the SNS. Prior to the implementation of this rule, 
when investigational products were ultimately approved for marketing, 
the products would have been returned to the manufacturer or sent to 
relabelers for relabeling, a potentially time-consuming, costly, and 
labor-intensive process. Further, requiring relabeling of such 
investigational products after approval, licensure or clearance could 
adversely affect the safety, effectiveness, or availability of the 
products. This rule allows the appropriate FDA Center Director to grant 
an exception or alternative to the relevant labeling requirements to 
enable the immediate use of a product in the event of a public health 
emergency.
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    \2\ As noted in the preamble to the interim final rule, medical 
products stockpiled in the SNS may also include products that will 
ultimately be used in an emergency under section 564 of the FD&C Act 
(21 U.S.C. 360bbb-3).
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    For these reasons, as explained in the interim final rule and the 
following section of this document, this rule allows FDA Center 
Directors to grant exceptions or alternatives to certain labeling 
requirements not explicitly required by statute for medical products 
that are or will be included in the SNS.

II. Comments on the Interim Final Rule and FDA Responses

    We received 7 comments on the proposed rule. These comments were 
received from hospitals, biologics manufacturers, law firms, other 
government agencies, and other interested persons. To make it easier to 
identify comments and our responses, the word ``Comment,'' in 
parentheses, will appear before the comment's description, and the word 
``Response,'' in parentheses, will appear before our response. We have 
also numbered each comment to help distinguish between different 
comments. The number assigned to each comment is purely for 
organizational purposes and does not signify the comment's value or 
importance or the order in which it was received. Certain comments were 
grouped together because the subject matter of the comments was 
similar.
    (Comment 1) One comment applauded the efforts put forth by the 
Agency to provide industry with the opportunity for exceptions or 
alternatives to FDA labeling requirements for products held by the SNS. 
The comment also recognized the importance of facilitating rapid access 
to large quantities of medical products in the event of an act of 
terrorism or natural disaster. Another comment expressed general 
agreement with the interim final rule.
    (Response) We appreciate these comments in support of the rule. 
Congress mandated the development of a SNS to provide for the emergency

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health security of the United States in the event of a bioterrorist 
attack or other public health emergency (section 319F-2(a) of the 
Public Health Service Act (the PHS Act) (42 U.S.C. 247d-6(b))). By 
providing a legal mechanism for addressing certain labeling issues 
associated with medical products in the SNS without compromising their 
safety, effectiveness, or availability for use in an emergency, this 
rule is designed to help enable the rapid deployment of medical 
countermeasures stored in the SNS in the event of such an emergency.
    (Comment 2) A number of comments responded to FDA's solicitation 
for comments as to whether the scope of the rule should be amended to 
include medical products in other Federal, State, and local stockpiles. 
One comment suggested that FDA expand the rule to include medical 
products stored in hospitals. Another comment suggested that the 
interim final rule should be extended to medical products stored in the 
Department of Defense stockpiles. Yet another comment requested that 
the scope of the rule not be extended to medical products in other 
Federal, State, or local stockpiles because extending the scope of the 
rule would most likely result in manufacturers seeing a high influx of 
requests for exceptions or alternatives to labeling requirements under 
the rule. Finally, a comment expressed general concern that the interim 
final rule is flawed and therefore should not be extended to other 
stockpiles.
    (Response) We appreciate the comments received in response to our 
solicitation. We have considered the issue, including the points raised 
in these comments, and have decided not to extend the rule to other 
Federal, State, and local stockpiles. With respect to the comment that 
the scope of the rule should be extended to medications stored in 
hospitals, we note that the SNS was created by statute to maintain 
medical products under centralized control. Centralized control of the 
stockpile assures that appropriate products are selected for inclusion 
in the SNS and that they are then stored under appropriate conditions. 
Centralized control also provides for efficient distribution in the 
event of a public health emergency.
    In response to the comment expressing concern that extending the 
rule to include additional medical products in other Federal, State, or 
local stockpiles would cause a high influx of requests for exceptions 
or alternatives to the labeling requirements specified in the rule, we 
recognize that extending the rule to other stockpiles may result in a 
high influx of requests and further note our concern that such requests 
would relate to products outside the control of SNS oversight. We 
reiterate that medical products are stockpiled in the SNS under 
centralized control to provide for efficient distribution in the event 
of a bioterrorist attack or other public health emergency, and this 
centralized control helps ensure that adequate procedures are followed 
for inventory management and accounting, and for the physical security 
of the stockpile. Accordingly, at this time, we decline to expand the 
scope of the final rule to apply to medical products in other Federal, 
State, and local stockpiles. Additionally, we note our disagreement 
with the comment that the interim final rule is generally flawed. As 
mandated by Congress, the SNS was created to provide for the emergency 
health security of the United States in the event of a public health 
emergency such as a bioterrorist attack. The interim final rule is 
necessary to give FDA Center Directors the ability to grant exceptions 
or alternatives to certain regulatory labeling requirements that could 
adversely affect the safety, effectiveness, or availability of medical 
products that are or will be included in the SNS in the event of a 
public health emergency.
    (Comment 3) There were two comments regarding those provisions of 
the interim final rule which allow SNS officials, or any entity that 
manufactures (including labeling, packing, repackaging, or relabeling), 
distributes, or stores the medical products to submit a request for an 
exception or alternative to the labeling requirements specified in the 
rule. One comment expressed concern that the rule permitted a SNS 
official to apply for alternative labeling without the consent of the 
product license holder. The comment acknowledged that there may be 
situations that could require a SNS official to apply for a labeling 
change without the license holder's consent, such as if a license 
holder went out of business, but stated that in all other cases only 
the product license holder (or, in the case of an investigational 
product, the anticipated biologics license application (BLA) or new 
drug application (NDA) holder) should be permitted to request an 
exception or alternative to the labeling requirements specified in the 
rule. The comment further suggested that any request by a SNS official 
for an exception or alternative to the labeling requirements specified 
in the rule should be accompanied by the written concurrence of the 
product license holder.
    Similarly, another comment requested that the rule be amended to 
allow only the product license holder or the sponsor of the 
investigational new drug application (IND) to submit a request for a 
labeling exception or alternative. The comment further requested that 
the rule be amended to require SNS officials to first submit a request 
for an alternative or exception to the labeling requirements specified 
in the rule to the product license holder or IND sponsor for its 
concurrence prior to submitting the request to FDA, and that the 
license holder or IND sponsor be required to concur with the request 
prior to SNS officials forwarding the request to FDA.
    (Response) The interim final rule allows for drug, biologic, and 
device application holders, or sponsors of INDs or investigational 
device exemptions (IDEs), to submit requests for labeling exceptions or 
alternatives. Our experience to date with respect to the interim final 
rule has been that BLA holders or applicants or sponsors of INDs have 
submitted all of the requests received for labeling exceptions or 
alternatives with the concurrence of SNS officials. We continue to 
anticipate that many, if not all, of the requests submitted under this 
rule will be submitted by manufacturers with the concurrence of SNS 
officials prior to or at the time a specified lot, batch, or other unit 
of the product is procured by the SNS, or when an investigational 
product held in the SNS has been approved, licensed, or cleared. 
Nonetheless, we also continue to recognize the need for additional 
flexibility regarding products stored in the SNS to ensure their 
availability in the event of a public health emergency. For example, in 
order to prepare for an emergency, an SNS official or FDA Center 
Director could determine there is a need for labeling exceptions or 
alternatives to facilitate the use of a medical countermeasure during 
an emergency. We note that in this example we anticipate that the 
exception or alternative required would not result in any actual change 
to the product labeling, but rather would allow for the use of the 
product regardless of the current labeling.
    Thus, we continue to recognize that it may be necessary to allow 
government officials, as well as any entity that manufactures 
(including labeling, packing, repackaging, or relabeling), distributes, 
or stores the medical product, to request exceptions or alternatives to 
the labeling requirements specified in this rule to ensure that medical 
products stored in the SNS are rapidly available for public use.

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    (Comment 4) A comment suggested that FDA grant or deny a request 
for an exception or alternative within 30 days from the receipt of any 
request because such situations may call for rapid turnaround.
    (Response) We agree that there may be situations that could call 
for a rapid turnaround in responding to a request for an exception or 
alternative. The intent of this rule is to ensure the rapid 
availability of medical countermeasures in the event of a public health 
emergency, and FDA will respond to all requests regarding the SNS as 
rapidly as possible. However, we do not believe that requiring FDA to 
respond within a set timeframe without accounting for the variability 
and complexity of each request would necessarily serve the public 
health.
    (Comment 5) One comment asked what documentation would be provided 
to the Department of Homeland Security's Customs and Border Protection 
Agency (CBP) to allow importation of medical products that are the 
subject of grants of exceptions or alternatives to labeling 
requirements.
    (Response) This rule has no effect on the information that must be 
submitted to CBP for imported medical products. That documentation 
remains unchanged. FDA and CBP will be able to make appropriate 
determinations regarding products for which exceptions or alternatives 
have been granted without additional information at the time of entry.
    (Comment 6) A comment stated that while the rule appears to permit 
only minor and technical labeling changes, it appears to be intended to 
permit FDA to make additional labeling changes based on information 
that becomes available to FDA after the initial label approval. The 
comment argued that a change to previously approved labels based on 
information not previously available alters the conditions under which 
a product may be sold and may affect the product's value without 
appropriate compensation to the manufacturer. Furthermore, the comment 
expressed a general concern that such actions by the government may 
violate the Constitution's Due Process and Takings provisions. The 
comment further argued that even if such actions did not rise to the 
level of Constitutional violations, they would be disincentives to 
industry developing products with uses covered by the SNS. Finally, the 
commenter was concerned that FDA may require a manufacturer of 
investigational products to add language to the outer package labeling 
of its product in the SNS after the product is licensed, approved, or 
cleared.
    (Response) The concerns expressed in the comment are unfounded. We 
do not agree that FDA's grant of an exception or alternative to certain 
FDA labeling requirements under the rule would adversely affect a 
product's value. This rule applies to medical products that are or will 
be held in the SNS only. The purpose of the rule is to provide for 
exceptions or alternatives to certain regulatory requirements if 
compliance with the requirements could adversely affect the safety, 
effectiveness, or availability of these products. Therefore, we would 
anticipate that this rule could encourage, as opposed to discourage, 
the procurement of medical products by the SNS.
    We reiterate that this rule is narrowly drafted to create necessary 
exceptions or alternatives to specified labeling requirements to ensure 
that medical products stored in the SNS are available for public use in 
the event of an emergency. To date, we have received six requests for 
exceptions or alternatives to labeling requirements, all of which have 
been initiated by BLA holders or applicants or sponsors of IND 
applications, with the concurrence of SNS officials. Our experience to 
date is that this rule does not create disincentives to participation 
in the SNS, and we note that the comment did not contain any data or 
information to substantiate this concern. Furthermore, to the extent 
that the comment is arguing that this rule violates the Due Process and 
Takings clauses of the Constitution by affecting a product's value 
without appropriate compensation to the manufacturer, as discussed 
previously, we disagree. As we have explained, this rule will not 
adversely affect the value of a product. We do not believe that this 
rule in any way violates the Constitution.
    (Comment 7) One comment expressed concern that relabeling a product 
suggests product manipulation. The comment stated that over labeling or 
relabeling creates the possibility for error, damage to the product and 
potential confusion by the SNS and, ultimately, for the user for whom 
the product is intended. Further, any of these possibilities may 
increase product liability exposure for the manufacturer.
    (Response) The concerns expressed in the comment are unfounded. As 
stated in the preamble to the interim final rule, we recognize that 
relabeling is a potentially time-consuming, costly, and labor-intensive 
process that could possibly cause product mishandling, sabotage or 
diversion, or could cause products to be unavailable for dispensing in 
the event of an emergency. Accordingly, this rule is specifically 
designed to allow FDA Center Directors to grant exceptions or 
alternatives to certain labeling requirements for medical products in 
the SNS to mitigate the need for relabeling. We also note that since 
the development of the SNS, manufacturers, in conjunction with FDA, the 
Centers for Disease Control and Prevention/SNS officials and the 
Department of Health and Human Services/Biomedical Advanced Research 
and Development Authority, have developed innovative labeling 
mechanisms for certain products through which relabeling an 
investigative product requires minimal manipulation post-licensure 
(e.g., ``zipper'' labels or ``tear-off'' labels on the actual product 
container).
    Regarding the product liability concern, this rule does not 
authorize the use of unapproved products, or of approved products for 
unapproved uses in an emergency. This rule instead permits a Center 
Director to authorize an exception or alternative from certain labeling 
requirements. Notably, with regard to other product liability concerns 
the commenter may have, the Public Readiness and Emergency Preparedness 
(PREP) Act is intended to address tort liability for manufacturers in 
such circumstances (42 U.S.C. 247d-6(d)).
    (Comment 8) A comment stated that the rule would appear to place 
burdens on a manufacturer. For example, the comment states that the 
rule does not exempt a sponsor from the requirement that it include in 
the company's annual report to FDA changes in labeling even when the 
government initiated the change without input from the manufacturer. 
The comment suggests that therefore, the company will need to track the 
activities of the SNS after the product has been distributed.
    (Response) FDA clarifies that under 21 CFR 201.26(e), a sponsor or 
applicant would only have to report a grant of a request for an 
exception or alternative of labeling requirements if the sponsor or 
applicant requested the change. We also note that we expect that in the 
majority of cases, this exception or alternative would be granted 
during the product approval process. Accordingly, FDA does not expect 
this rule to impose burdensome reporting requirements on manufacturers.

III. Legal Authority

    In this final rule, FDA is amending regulations pertaining to the 
content and format of medical product labeling. The provisions of this 
rule allow FDA to grant exceptions or alternatives to certain of those 
labeling requirements. The labeling regulations to which

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exceptions or alternatives are permitted under this rule were issued by 
FDA under authority of the FD&C Act and the PHS Act to mandate 
particular ways that firms must satisfy the broad requirements and 
prohibitions in those statutes, such as the prohibition on false and 
misleading drug and device labeling. As described in section II of this 
document, and in the interim final rule, FDA has determined that 
circumstances may arise in which compliance with those regulatory 
mandates could adversely affect the safety, effectiveness, or 
availability of certain medical products that are or will be included 
in the SNS. Moreover, due to the unique nature of the SNS, those 
products could deviate from particular mandates of existing labeling 
regulations without violating the broad statutory requirements and 
prohibitions in the FD&C Act and the PHS Act. For those reasons, FDA is 
exercising its authority to regulate labeling by modifying the existing 
regulations in a way that allows exceptions or alternatives for medical 
products that are or will be included in the SNS.
    As explained in the interim final rule, FDA has various sources of 
authority to issue labeling regulations, including, for example, 
sections 201(n), 502(a), and 701(a) of the FD&C Act (21 U.S.C. 321(n), 
352(a), and 371(a)) for drugs (including biological products) and 
devices, and sections 351(a)(1)(A) and 351(a)(2)(A) of the PHS Act (42 
U.S.C. 262(a)(1)(A) and (a)(2)(A)) for biological products. In 
addition, as more fully discussed in the interim final rule, FDA has 
concluded that exceptions or alternatives granted under this rule will 
not render products misbranded due to the additional safeguards and 
conditions that may be required when an exception or alternative is 
granted, as well as the unique storage, deployment and distribution 
considerations essential to the SNS.

IV. Analysis of Impacts

    FDA has examined the impacts of the final rule under Executive 
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5 
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 
104-4). Executive Orders 12866 and 13563 direct 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 analysis of costs and benefits of available regulatory 
alternatives contained in the interim final rule (72 FR 73589 at 73596) 
is adopted without change in this final rule. By now reaffirming that 
interim final rule, FDA has not imposed any new requirements. 
Therefore, there are no additional costs and benefits associated with 
this final rule.
    The Regulatory Flexibility Act requires Agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because this final rule does not make any changes to 
the interim final rule or our analysis included therein, 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 issuing ``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 $136 million, using the most current (2010) 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.

V. The Paperwork Reduction Act

    Sections 201.26(b), 610.68(b), 801.128(b), and 809.11(b) of this 
final rule contain information collection requirements that were 
submitted for review and approval to the Director of the Office of 
Management and Budget (OMB), as required by section 3507(d) of the 
Paperwork Reduction Act of 1995. The information collection 
requirements were approved and assigned OMB control number 0910-0614 
(expires August 31, 2014).

VI. Environmental Impact

    The Agency has determined under 21 CFR 25.30(k) 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.

VII. Federalism

    In the Federal Register of October 5, 2011 (76 FR 61565), FDA 
published a notification of preemption review, which was conducted in 
response to a memorandum from the President that directed Federal 
Agencies to review recently issued regulations to ensure that any 
statements concerning preemption can be justified under legal 
principles governing preemption, including those outlined in Executive 
Order 13132. In this notification, FDA announced its determination that 
the preamble to the interim final rule referred to statements 
concerning preemption that are not justified under legal principles 
governing preemption. FDA has analyzed this final rule in accordance 
with the principles set forth in Executive Order 13132 and has 
determined that this rule is consistent with the Executive Order. 
Section 4(a) of this 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.'' In this rule, FDA is adopting as 
a final rule regulations permitting FDA Center Directors to grant 
exceptions or alternatives to certain regulatory labeling requirements 
applicable to medical products that are or will be included in the SNS. 
Certain State requirements regarding the format and content of 
nonprescription drug labeling and/or labeling of approved medical 
devices may be subject to the express preemption provisions in section 
751 of the FD&C Act (21 U.S.C. 379r) (nonprescription drugs) and 
section 521 of the FD&C Act (21 U.S.C. 360k) (approved medical 
devices). We also note that even where an express preemption provision 
is not applicable, implied preemption may arise.
    Accordingly, the interim final rule amending 21 CFR parts 201, 312, 
314, 601, 610, 801, 807, 809, 812, and 814 which was published at 72 FR 
73589 on December 28, 2007, is adopted as a final rule without change.

    Dated: February 1, 2012.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2012-2558 Filed 2-3-12; 8:45 am]
BILLING CODE 4160-01-P