Applications for Food and Drug Administration Application Approval to Market a New Drug; Revision of Postmarketing Reporting Requirements, 58993-59000 [E7-20510]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 72, Number 201 (Thursday, October 18, 2007)]
[Rules and Regulations]
[Pages 58993-59000]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: E7-20510]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 314

[Docket No. 2000N-1545] (formerly 00N-1545)


Applications for Food and Drug Administration Application 
Approval to Market a New Drug; Revision of Postmarketing Reporting 
Requirements

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending its 
regulations describing postmarketing reporting requirements to 
implement certain provisions of the Food and Drug Administration 
Modernization Act of 1997 (the Modernization Act). The changes apply to 
drug products that are life supporting, life sustaining, or intended 
for use in the prevention of a serious disease or condition and that 
were not originally derived from human tissue and replaced by a 
recombinant product. The final rule implements provisions of the 
Modernization Act by requiring an applicant who is the sole 
manufacturer of one of these products to notify FDA at least 6 months 
before discontinuing manufacture of the drug product.

DATES: This rule is effective December 17, 2007.

FOR FURTHER INFORMATION CONTACT:
    S. Mitchell Weitzman, Center for Drug Evaluation and Research (HFD-
7), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 
20857, 301-443-5535, or
    Stephen Ripley, Center for Biologics Evaluation and Research (HFM-
17), Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 
20852-1448, 301-827-6210.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of November 7, 2000 (65 FR 66665), we (FDA) 
issued a proposed rule to revise our postmarketing reporting 
requirements to implement section 506C of the Federal Food, Drug, and 
Cosmetic Act (the act) (21 U.S.C. 356c). Section 506C of the act

[[Page 58994]]

requires manufacturers who are the sole manufacturers of certain drug 
products to notify us at least 6 months before discontinuing 
manufacture of the products. Section 506C(a) applies to sole 
manufacturers of products that meet the following three criteria:
    (1) The products are life supporting, life sustaining, or intended 
for use in the prevention of a debilitating disease or condition;
    (2) The products must have been approved under section 505(b) or 
(j) of the act (21 U.S.C. 355(b) or (j)); and
    (3) The products are not originally derived from human tissue and 
replaced by a recombinant product.
    Under section 506C of the act, we may reduce the 6-month 
notification period if good cause exists for the reduction, and we must 
provide information to the public about the product discontinuance.

II. Overview of the Final Rule Including Changes to the Proposed Rule

    This final rule amends the postmarketing provisions of FDA 
regulations in Sec.  314.81 (21 CFR 314.81) to require applicants who 
are sole manufacturers of certain drug products to notify us at least 6 
months before discontinuing manufacture of the products. The 6-month 
notification period required by these regulations will give certain 
individuals who are currently taking affected medications that will be 
discontinued an opportunity to evaluate alternative therapeutic 
options, and will provide additional time for FDA to evaluate 
replacement products when available. Under Sec.  314.91 (21 CFR 
314.91), we may reduce the 6-month notification period when we find 
good cause exists for the reduction.
    In this rulemaking, the agency finalizes all of the substantive 
provisions in the proposed rule. In addition, we have made some 
revisions, none of which changed the substantive requirements. One 
revision reflects a relatively minor change in administrative process. 
In that instance, for administrative efficiency, we have revised 
proposed Sec. Sec.  314.81(b)(3)(iii)(b) and 314.91(c)(3) to make the 
notification procedures for manufacturers planning to submit a notice 
of discontinuance (or a request for reduction in the discontinuance 
notification period) the same for drugs regulated by the Center for 
Drug Evaluation and Research (CDER) or the Center for Biologics 
Evaluation and Research (CBER). As revised, manufacturers are to send 
notifications of discontinuance or requests for reduction in 
notification periods for all drugs subject to this rule, whether 
regulated by CDER or CBER, to the following designated offices:
    (1) The Drug Shortage Coordinator at the address of Director of 
CDER;
    (2) The Drug Registration and Listing Team, Division of Compliance 
Risk Management in CDER; and
    (3) The director in the review division in CDER or CBER that is 
responsible for reviewing the application.
    The final rule eliminates the proposed requirement to notify the 
Director of CBER.
    We have also revised the proposed rule to change the manner in 
which the agency publicly discloses a list of all drug products to be 
discontinued under Sec.  314.81(b)(3)(iii)(a), as described in 
paragraph (b)(3)(iii)(c) of Sec.  314.81. In the preamble to the 
proposed rule, we stated that we would provide discontinuance 
information both on the Internet and in notices in the Federal 
Register. Since the proposed rule was published in November 2000, 
access to the Internet has dramatically increased. As a result, we 
believe that posting on the Internet is an effective means to 
distribute the discontinuance information to appropriate physician and 
patient organizations, as required by section 506C(c) of the act, and 
to the public. Therefore, we no longer plan to publish the 
discontinuance information in the Federal Register. This information 
will be distributed through posting on the Internet (www.fda.gov/cder/
drug/shortages/default.htm).

A. Notification Requirements

    As described in section I of this document, we are amending our 
postmarketing reporting requirements inSec.  314.81 to implement new 
statutory requirements under section 506C of the act. Section 
314.81(b)(3)(iii) requires an applicant who is the sole manufacturer of 
an approved drug product to notify us in writing at least 6 months 
before discontinuing manufacture of the drug product if the drug 
product meets the following criteria:
    (1) The product is life supporting, life sustaining, or intended 
for use in the prevention of a serious disease or condition; and
    (2) The product was not originally derived from human tissue and 
replaced by a recombinant product.
    A life supporting or life sustaining drug is a drug product that is 
essential to, or that yields information that is essential to, the 
restoration or continuation of a bodily function important to the 
continuation of human life. The phrase ``debilitating disease or 
condition,'' as stated in section 506C(a) of the act, means serious 
disease or condition.

B. Reduction in the Discontinuance Notification Period

    Under section 506C(b) of the act, we may reduce the 6-month 
notification period if the manufacturer certifies that good cause 
exists for the reduction. We are adding Sec.  314.91 to implement 
section 506C(b) of the act. Section 314.91 allows for a reduction in 
the 6-month discontinuance notification period, as required under Sec.  
314.81(b)(3)(iii)(a), when we find good cause exists for the reduction. 
We may find good cause exists based on information certified by an 
applicant in a written request for a reduction of the discontinuance 
notification period. In limited circumstances, we may find good cause 
exists based on information already known to us (e.g., withdrawal of 
the drug from the market based upon formal regulatory action or 
resulting from consultations between the applicant and us).
    To assist a manufacturer that is requesting a reduction in the 
notification period, Sec.  314.91(c)(1) provides a template for 
certification that good cause exists. The following circumstances can 
establish good cause for a reduction in the discontinuance notification 
period:
     A public health problem may result from continuation of 
manufacturing for the 6-month period;
     A biomaterials shortage prevents the continuation of the 
manufacturing for the 6-month period;
     A liability problem may exist for the manufacturer if the 
manufacturing is continued for the 6-month period;
     Continuation of manufacturing for the 6-month period may 
cause substantial economic hardship for the manufacturer;
     The manufacturer has filed for bankruptcy under chapter 7 
or 11 of title 11, United States Code (11 U.S.C. 701 et seq. and 1101 
et seq.); or
     The manufacturer can stop making the product but still 
distribute it to satisfy existing market need for 6 months.
     Other good cause exists for the reduction.

C. Disclosure of Discontinuance Information to the Public

    Section 506C(c) of the act states that, to the maximum extent 
practicable, we are to distribute information to appropriate physician 
and patient organizations about the discontinuation of products 
described in section 506C(a). To implement section 506C(c) of the act, 
we will, in accordance with Sec.  314.81(b)(3)(iii)(c), publicly 
disclose a list of all drug products to be

[[Page 58995]]

discontinued under paragraph (b)(3)(iii)(a) of Sec.  314.81. If the 
notification period is reduced under Sec.  314.91, we will state the 
reason(s) for the reduction and the anticipated date that manufacturing 
will cease. As described in the preamble to the proposed rule (65 FR 
66665 at 66667), the listing of discontinued products will include the 
following information:
     The brand and generic name, the manufacturer, and 
indication(s) of the drug product;
     Whether a reduction in the notification period was granted 
by the agency under Sec.  314.91;
     The reason(s) for a notification period of less than 6 
months, if applicable; and
     Any additional information the agency may have regarding 
anticipated product availability.
    We will post the discontinuance information on the Internet at 
www.fda.gov/cder/drug/shortages/default.htm.

III. Comments on the Proposed Rule

    We received written comments from three pharmaceutical companies 
and a patient advocacy organization. The comments generally sought 
clarification of terms and procedures described in the proposed rule. 
Comments from the patient advocacy organization included suggestions 
for ensuring that patients affected by the withdrawal of a drug product 
covered by this rule had sufficient opportunity to prepare for 
alternative treatment options as needed. A summary of the comments 
received and our responses follow.

A. General Comments

    (Comment 1) One comment urged companies to voluntarily give notice 
to the agency 1 year before discontinuing manufacture of a product, 
even though the act requires notification only 6 months before 
discontinuance.
    Although we are retaining the 6-month notification period in the 
final rule, we agree that it would be beneficial if companies could, 
when possible, provide more than the 6-month notice required by 
statute. Section 506C of the act and Sec.  314.81(b)(3)(iii) are clear 
that this is the minimum notification period, given that they require 
``at least 6-months'' notification (emphasis added). Earlier 
notification is permitted, and FDA encourages companies to provide us 
with as much advance notification as possible.
    (Comment 2) One comment asked FDA to urge companies that intend to 
discontinue the manufacture of products to license the products to 
other pharmaceutical firms.
    We agree that it could be in the interest of public health for 
manufacturers of products covered by this final rule to find 
alternative means of making these products available to patients, 
including the possibility of transferring the new drug application 
(NDA) or abbreviated new drug application (ANDA) for these products to 
other manufacturers. However, the act does not require an applicant 
covered by this rule to transfer an NDA or ANDA, or use any other means 
to ensure product availability. The act merely requires applicants to 
meet the notice requirements implemented by this rule. Therefore, while 
we agree that it would be preferable for manufacturers to find 
alternative ways to make these products available to patients, this 
regulation will not require such measures.

B. Scope and Terminology

    Proposed Sec.  314.81(b)(3)(iii)(a) states that an applicant who is 
the sole manufacturer of an approved drug product must notify FDA in 
writing at least 6 months before discontinuing manufacture of the drug 
product if that drug product meets the following criteria: (1) The drug 
product is life supporting, life sustaining, or intended for use in the 
prevention of a serious disease or condition; and (2) the drug product 
was not originally derived from human tissue and replaced by a 
recombinant product.
    (Comment 3) One comment expressed concern that while the ``Orange 
Book'' (FDA's publication on ``Approved Drug Products with Therapeutic 
Equivalence Evaluations'') lists all drug products with approved NDAs 
and ANDAs, it is not possible to determine whether the listed approved 
products are, in fact, being manufactured. The comment therefore 
requested that we define sole manufacturer as ``an applicant listed in 
the Orange Book who is the holder of the only listed approved 
application under section 505(b) or (j) of the act.''
    We decline to adopt this definition of ``sole manufacturer'' for 
three reasons. First, agency experience indicates that sole 
manufacturers generally know that they are a sole manufacturer. Second, 
while the Orange Book is routinely updated, there may be, on occasion, 
delays in updating it because, for example, the agency may not always 
be notified about discontinuance of drug products in a timely fashion. 
Thus, the Orange Book would not be an appropriate singular source to 
determine which applicants are sole manufacturers. The comment's 
suggestion could also create potential confusion because some drugs are 
approved but not marketed, and are therefore placed in the 
``discontinued'' section of the Orange Book. Finally, we note that 
there are other generally reliable sources for obtaining commercial 
manufacturing information that can adequately provide information on 
sole manufacturers, rendering the comment's suggestion unduly 
restrictive.
    (Comment 4) One comment requested that we clarify the phrase 
``discontinuing manufacture.'' The comment indicated that 
discontinuance and the 6-month notification period should apply when a 
manufacturer is ceasing production of a product with the intent of 
withdrawing the product from the market, not when there is a temporary 
cessation of manufacturing resulting, for example, from technical 
production difficulties.
    We agree with the comment that the phrase ``discontinuing 
manufacture'' does not refer to temporary cessations of manufacturing. 
We intend to apply the provisions of final Sec.  314.81(b)(3)(iii) to 
those instances where a manufacturer has made a decision to no longer 
market a drug product that is life supporting, life sustaining, or 
intended for use in the prevention of a serious disease or condition. 
The provisions of Sec.  314.81(b)(3)(iii) would not apply to situations 
described in the comment, such as temporary or intermittent 
manufacturing cessations due to planned or unplanned circumstances. 
Manufacturers who schedule a planned temporary manufacturing cessation 
but do not intend to permanently discontinue product manufacture are 
not subject to the provisions of this regulation. Normally, the supply 
of drug product available to patients under these circumstances would 
not be affected during the period of the planned manufacturing 
cessation. Similarly, manufacturers who experience an unplanned 
temporary manufacturing interruption but intend to continue 
manufacturing over the long term are not subject to this rule. We 
request that manufacturers who experience such an unplanned temporary 
manufacturing cessation keep the agency informed about the status of 
the shutdown because the duration of an unplanned shutdown may be 
unpredictable and could affect the availability of needed therapy for 
patients.
    (Comment 5) In the preamble to the proposed rule, we interpreted 
the phrase ``life supporting or life sustaining'' drug as one that is 
essential to, or that yields information that is

[[Page 58996]]

essential to, the restoration or continuation of a bodily function 
important to the continuation of human life (65 FR 66665 at 66666). One 
comment suggested that we incorporate this interpretation into Sec.  
314.81(b)(3)(iii).
    We decline to incorporate this interpretative language into the 
codified language in Sec.  314.81(b)(3)(iii). The codified language 
parallels the statutory provision of section 506C(a) of the act. As the 
comment notes, the preamble to the proposed rule defined the term 
``life supporting or life sustaining drug'' as a ``drug product that is 
essential to, or that yields information that is essential to, the 
restoration or continuation of a bodily function important to the 
continuation of human life'' and explained the definition's origins. 
Rather than incorporating that language into the codified language, we 
intend to rely on the interpretation described in the preamble to the 
proposed rule for guidance in applying that language.
    (Comment 6) One comment contended that the scope of the language 
``intended for use in the prevention of a serious disease or 
condition'' in proposed Sec.  314.81(b)(3)(iii)(a)(1) is too broad and 
ambiguous. The comment expressed concern that the phrase ``intended for 
use in prevention'' could sweep into the rule's ambit drugs approved to 
treat less serious conditions where the less serious conditions are 
themselves a contributing factor or risk factor in the development of a 
serious disease or condition. The comment suggested that the phrase 
should be amended to apply only to products that are ``specifically 
indicated in approved labeling for prevention or prophylaxis of a 
disease or condition that is, or has the potential in its fullest 
manifestation to be, chronically debilitating.''
    We disagree with the comment's assertion that the phrase ``intended 
for use in the prevention of a serious disease or condition'' is 
ambiguous or overly broad. In general, we do not expect that drug 
products used to treat relatively minor diseases or conditions will 
fall within the scope of this rule solely because there is a 
prophylactic connection to a more serious disease or illness--however 
tenuous. For instance, antihistamines that treat allergic rhinitis 
would not generally fall under this rule, even though allergic rhinitis 
may be a trigger for asthma, a more serious disease or condition. In 
contrast, products that are intended for use in treating or preventing 
asthma would potentially fall under the scope of this rule. 
Accordingly, we have not adopted the comment's suggestion.

C. Procedures

    (Comment 7) One comment stated that a decision to discontinue 
manufacturing a product could occur ``long after'' the manufacturer 
produces the last lot. The comment requested that we clarify when the 
applicant should notify us in this situation. The comment does not 
provide any specific instances where a decision to discontinue 
manufacturing a product has occurred long after an applicant produced 
the last lot.
    As we stated in response to comment 4, we intend to apply the 
provisions of Sec.  314.81(b)(3)(iii) to those instances where a 
manufacturer has made a decision to no longer market a drug product 
that is life supporting, life sustaining, or intended for use in the 
prevention of a serious disease or condition. If the decision to 
discontinue manufacturing is not a temporary or intermittent 
manufacturing cessation, we would expect manufacturers covered by this 
rule to notify the agency as soon as the decision has been made. We 
would expect that manufacturers would ordinarily have notified the 
agency before they had produced the last lot and that they will file a 
request for a reduction of the 6-month notification period if good 
cause exists for the reduction.
    Under the scenario posed by the comment, the rule would require 
notification as soon as a decision not to resume manufacturing the drug 
has been made (i.e., to convert a temporary shutdown to a permanent 
one). In addition, the agency would expect manufacturers in such 
circumstances to be able to demonstrate that the shutdown was 
originally believed to be only temporary and to explain the change in 
circumstances.
    (Comment 8) One comment requested that we clarify whether the 6-
month notification period for discontinuing the manufacture of a 
product covered by this regulation (under Sec.  314.81(b)(3)(iii)(a)) 
would run consecutively with the 6 months of continued marketing under 
new Sec.  314.91(d)(6). Under Sec.  314.91(d)(6), an applicant can 
establish good cause for a reduction in the notification period by 
certifying that it can stop manufacturing, but continue to distribute 
the drug product to satisfy existing market need for 6 months. The 
comment asked whether, in this ``special instance,'' the manufacturer 
would be ``allowed 1 year of marketing after making the decision to 
withdraw the product.''
    We believe the comment has misconstrued the nature of the statutory 
and regulatory scheme. These provisions do not operate to limit the 
period of continued marketing of the product. They simply require 
notification to FDA at least 6 months before cessation of 
manufacturing. Manufacturers may elect to give FDA notice of 
discontinuance more than 6 months before manufacturing ceases. 
Moreover, the length of time that a product remains on the market may 
vary with the amount of product in the supply chain at the time 
manufacturing is discontinued. The statute and Sec.  314.91(d)(6) 
provide that demonstration of a manufacturer's ability to continue 
distribution of a drug product to satisfy existing market need for 6 
months can be good cause for a reduction in the 6-month notification 
period. Section 314.91(d)(6) may shorten the minimum notification 
period, but only in situations where the applicant can continue 
distribution of the drug product to satisfy existing market need for at 
least 6 months. In this circumstance, the product would likely continue 
to be marketed for less than 12 months, i.e., the 6 months of continued 
marketing plus some reduced portion of the 6-month discontinuance 
notification period.
    (Comment 9) One comment urged FDA to put the onus on manufacturers 
to prove that reduction of the 6-month notification period will not 
cause substantial physical and emotional harm to the patients who rely 
on the drug. The same comment stated the agency should create the 
highest hurdles for reducing the discontinuance notification period if 
the health and welfare of patients are at stake.
    As reflected in the good cause provisions in Sec.  314.91(d)(7), 
the statute provides several specific circumstances that may be 
considered good cause for reduction of the notification period, such as 
a public health problem that may result from continuation of 
manufacturing for the 6-month period; a biomaterials shortage; a 
liability problem; economic hardship; bankruptcy; or a manufacturer 
being able to continue distribution for 6 months. We agree that there 
should be a public health focus to establish good cause when requesting 
a reduction in the discontinuance notification period. Accordingly, we 
intend to apply the provisions in Sec.  314.91(d)(7), a broad provision 
permitting reduction in the notification period for ``other good 
cause,'' consistent with the public health concerns expressed in the 
comment. Manufacturers seeking to establish good cause for reasons 
other than those specifically enumerated under Sec.  314.91(d)(1) 
through (d)(6) will

[[Page 58997]]

be expected to demonstrate that reducing the discontinuance 
notification period will not result in increased risk of harm to the 
health of patients who use the drug.
    (Comment 10) One comment asked about the relationship between 
notification of discontinuance of manufacturing under this rule and 
removing a withdrawn product from the list of drugs submitted for 
purposes of drug registration and listing. Under current Sec.  
314.81(b)(3)(iii) (redesignated as Sec.  314.81(b)(3)(iv) by this 
rulemaking), an applicant must submit Form FDA 2657 (Drug Product 
Listing) to the Drug Registration and Listing Team, Division of 
Compliance Risk Management and Surveillance (formerly the Drug Listing 
Branch\1\), in CDER within 15 working days of the withdrawal from sale 
of a drug product.\2\ The submission of this form notifies us that the 
drug product is no longer being marketed. The comment requested that we 
clarify whether sending the notice of discontinuation of manufacturing 
to the Drug Listing Branch will result in the delisting of the product, 
or whether additional correspondence with the Drug Listing Branch will 
be required.
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    \1\ The former Drug Listing Branch has been reorganized as the 
Drug Registration and Listing Team, Division of Compliance Risk 
Management and Surveillance, in CDER's Office of Compliance.
    \2\ In the Federal Register of August 29, 2006 (71 FR 51276), we 
published a proposed rule that would amend Sec.  314.81(b)(3)(iii) 
to provide 30-days for submission of Form FDA 2657.
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    The delisting process is separate from the notification of 
discontinuance process described in this rule. The notification of 
discontinuance is submitted under this rule at least 6 months before 
cessation of manufacturing. The notice of discontinuance does not take 
the place of a listing update submitted on a Form FDA 2657. In most 
cases where manufacturing is discontinued, the drug will continue to be 
marketed for at least 6 months or more and should remain listed during 
that time. The Form 2657 would need to be submitted later, within 15 
days of withdrawal from the market of the drug, under current Sec.  
314.81(b)(3)(iii) (redesignated as Sec.  314.81(b)(3)(iv) in this 
rule). In addition, while all drugs are subject to the listing 
requirements, the discontinuance provision applies only to those 
instances where the manufacturing of a single-source drug product that 
is life supporting, life sustaining, or intended for use in the 
prevention of a serious disease or condition, will be discontinued.
    (Comment 11) One comment asked why, under Sec. Sec.  
314.81(b)(3)(iii)(b) and 314.91(c)(3) of the proposed rule, 
manufacturers of drugs regulated by CBER are not required to send the 
notification of discontinuance to the Drug Listing Branch, as are 
manufacturers of drugs regulated by CDER.
    We agree that the requirement should be the same for drugs 
regulated by CBER and CDER. For administrative efficiency, we have 
revised Sec. Sec.  314.81(b)(3)(iii)(b) and 314.91(c)(3) to make the 
procedures for manufacturers to submit a notice of discontinuance (or a 
request for reduction in the discontinuance notification period) the 
same for drugs, whether they are regulated by CDER or CBER. As revised, 
for all drugs subject to this rule, manufacturers must send 
notifications of discontinuance or requests for reduction in 
notification periods, to the following designated CDER and CBER 
offices: (1) The CDER Drug Shortage Coordinator, at the address of the 
Director of CDER; (2) the CDER Drug Registration and Listing Team, 
Division of Compliance Risk Management and Surveillance; and (3) either 
the director of the review division in CDER that is responsible for 
reviewing the application or the director of the office in CBER that is 
responsible for reviewing the application. This final rule eliminates 
the proposed requirement to notify the Director of CBER for drug 
products regulated by CBER.
    We encourage manufacturers who have questions about these processes 
to contact the Drug Shortage Coordinator at CDER.

IV. Analysis of Impacts

    We have examined the impacts of the final rule under Executive 
Order 12866 and 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). We believe that this 
final rule is not a significant regulatory action under the Executive 
order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because the final rule will result in minimal 
additional costs in about one instance per year to one manufacturer, we 
certify 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. We do not expect this 
final rule to result in any 1-year expenditure that would meet or 
exceed this amount.
    The final rule requires that manufacturers of certain drug products 
notify the agency at least 6 months before discontinuing their 
manufacture. As explained in section V of this document, the regulatory 
conditions that trigger this requirement occur only infrequently. Based 
on agency experience, we estimate that such circumstances occur no more 
than once per year. Moreover, the notification requirement will impose 
a significant burden only when market conditions deteriorate so quickly 
that firms could not foresee the desired action 6 months in advance. 
Most pharmaceutical firms rely on established long-term marketing 
plans.
    Under certain specified circumstances, the rule permits us to 
reduce the notification period for good cause. Manufacturers can 
request a reduced notification period by submitting a written 
certification, based on considerations such as public health, legal 
liability, biomaterial shortage, or substantial economic hardship. A 
certification of substantial economic hardship will need to be 
supported by evidence demonstrating that the reduced notification 
period is necessary to avoid substantial economic hardship to the 
manufacturer.

V. Paperwork Reduction Act of 1995

    This final rule contains information collection provisions that are 
subject to review by the Office of Management and Budget (OMB) under 
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The title, 
description, and respondent description of the information collection 
provisions are shown in the following paragraphs with an estimate of 
the annual reporting burden. Included in the estimate is the

[[Page 58998]]

time for reviewing instructions, searching existing data sources, 
gathering and maintaining the data needed, and completing and reviewing 
each collection of information. OMB and FDA received no comments 
concerning the information collection provisions of the proposed rule.
    Title: Applications for FDA Approval to Market a New Drug; Revision 
of Postmarketing Reporting Requirements
    Description: The final rule implements section 506C of the act and 
requires applicants who are the sole manufacturers of certain drug or 
biologic products to notify us at least 6 months before discontinuing 
the manufacture of the product. For the rule to apply, a product needs 
to meet the following three criteria:
    (1) The product must be life supporting, life sustaining, or 
intended for use in the prevention of a serious disease or condition;
    (2) The product must have been approved by FDA under section 505(b) 
or 505(j) of the act; and
    (3) The product must not have been originally derived from human 
tissue and replaced by a recombinant product.
    The rule allows us to reduce the 6-month notification period if we 
find good cause for the reduction. An applicant may request that we 
reduce the notification period by certifying that good cause for the 
reduction exists. Under the rule, we will also publicly disclose 
information about the drugs that are discontinued under the rule. 
Existing regulations, which appear in part 314, establish postmarketing 
reporting requirements for approved drugs. Current Sec.  
314.81(b)(3)(iii) (OMB control no. 0910-0001), which is redesignated as 
Sec.  314.81(b)(3)(iv) in this rule, requires an applicant to notify us 
within 15 working days of withdrawing a drug product from sale. This 
rule adds two new reporting requirements.

A. Notification of Discontinuance

    Under this rule, at least 6 months before an applicant intends to 
discontinue manufacture of a product, the applicant must send us 
written notification of the discontinuance. For drugs regulated by CDER 
or CBER, manufacturers must send notifications of discontinuance to the 
following designated offices: (1) The CDER Drug Shortage Coordinator at 
the address of the Director of CDER; (2) the CDER Drug Registration and 
Listing Team, Division of Compliance Risk Management and Surveillance 
in CDER; and (3) the director of either the CDER division or the CBER 
office that is responsible for reviewing the application. We require 
that the notification be sent to these offices to ensure that our 
efforts regarding the discontinuation of the product are commenced in a 
timely manner. We will work with members of the industry and with the 
applicant during the 6-month notification period to ease patient 
transition from the drug that will be discontinued to alternate 
therapy.

B. Certification of Good Cause

    We may reduce the 6-month notification period if we find good cause 
for the reduction. As described in section 506C(b) of the act and new 
Sec.  314.91, an applicant can request a reduction in the notification 
period for good cause by submitting written certification to the 
following designated offices: (1) The CDER Drug Shortage Coordinator at 
the address of the Director of CDER; (2) the CDER Drug Registration and 
Listing Team, Division of Compliance Risk Management and Surveillance 
in CDER; and (3) the director of either the CDER division or the CBER 
office that is responsible for reviewing the application, that good 
cause exists as follows:
     A public health problem may result from continuation of 
manufacturing for the 6-month period (Sec.  314.91(d)(1));
     A biomaterials shortage prevents the continuation of 
manufacturing for the 6-month period (Sec.  314.91(d)(2));
     A liability problem may exist for the manufacturer if the 
manufacturing is continued for the 6-month period (Sec.  314.91(d)(3));
     Continuation of the manufacturing for the 6-month period 
may cause substantial economic hardship for the manufacturer (Sec.  
314.91(d)(4));
     The manufacturer has filed for bankruptcy under chapter 7 
or 11 of title 11, United States Code (Sec.  314.91(d)(5));
     The manufacturer can stop making the product but still 
distribute it to satisfy existing market need for 6 months (Sec.  
314.91(d)(6)); or
     Other good cause exists for a reduction in the 
notification period (Sec.  314.91(d)(7)).
    With each certification described previously, the applicant must 
describe in detail the basis for the applicant's conclusion that such 
circumstances exist. We require that the written certification that 
good cause exists be submitted to the offices identified previously to 
ensure that our efforts regarding the discontinuation take place in a 
timely manner.
    Description of Respondents: An applicant who is the sole 
manufacturer and who intends to discontinue marketing of a drug product 
that meets the following criteria: (1) Is life supporting, life 
sustaining, or intended for use in the prevention of a serious disease 
or condition; (2) was approved by FDA under section 505(b) or (j) of 
the act; and (3) was not originally derived from human tissue and 
replaced by recombinant product.
    Burden Estimate: Table 1 of this document provides an estimate of 
the annual reporting burden for notification of product discontinuance 
and certification of good cause under this rule.
    Notification of Discontinuance: Based on data collected from the 
CDER drug shortage coordinator, CDER review divisions, and CBER review 
offices during 2003 through 2006, one applicant during each year 
discontinued the manufacture of one product meeting the criteria of 
section 506C of the act. Each applicant meeting the criteria is 
required under final Sec.  314.81(b)(3)(iii) to notify the agency of 
the discontinuance at least 6 months before manufacturing ceased. 
Although the procedures for notifying the agency that are set forth in 
the final rule were not in place during 2003 through 2006, we estimate 
that the number of manufacturers who would be required to notify us of 
discontinuance would remain the same. Therefore, the number of 
respondents is estimated to be one. The total annual responses are the 
total number of notifications of discontinuance that are expected to be 
submitted to CDER or CBER in a year. During 2003 through 2006, an 
applicant would have been required to notify us annually of one product 
discontinuance under the procedures. We estimate that the total annual 
responses will remain the same, averaging one response per respondent. 
The hours per response is the estimated number of hours that a 
respondent would spend preparing the information to be submitted with a 
notification of product discontinuance, including the time it takes to 
gather and copy the statement. Based on experience in working with 
applicants regarding similar collections of information, we estimate 
that approximately 2 hours on average are needed per response. 
Therefore, we estimate that 2 hours will be spent per year by 
respondents notifying us of a product discontinuance under these 
regulations.
    Certification of Good Cause: Based on data collected from the CDER 
drug shortage coordinator, CDER review divisions, and CBER review 
offices during 2003 through 2006, one applicant discontinued during 
each year the manufacture of one product meeting the criteria of 
section 506C of the act. Each applicant has the opportunity under Sec.  
314.91 to request a reduction in the 6-month notification period by 
certifying to us that good cause exists

[[Page 58999]]

for the reduction. We do not expect that each eligible applicant will 
certify that good cause exists for a reduction. Furthermore, the number 
of applicants who are in a position to request a reduction is quite 
small. Therefore, the number of respondents is estimated to be one. The 
total annual responses are the total number of notifications of 
discontinuance that are expected to be submitted to us in a year. We 
estimate that the total annual responses will remain small, averaging 
one response per respondent. The hours per response is the estimated 
number of hours that a respondent spends preparing the detailed 
information certifying that good cause exists for a reduction in the 
notification period, including the time it takes to gather and copy the 
documents. Based on experience in working with applicants regarding 
similar collections of information, we estimate that approximately 16 
hours on average are needed per response. Therefore, we estimate that 
16 hours will be spent per year by respondents certifying that good 
cause exists for a reduction in the 6-month notification period under 
Sec.  314.91.

                                 Table 1.--Estimated Annual Reporting Burden\1\
----------------------------------------------------------------------------------------------------------------
                         No. of        No. of Responses     Total Annual        Hours per
  21 CFR Section      Respondents       per Respondent       Responses           Response         Total Hours
----------------------------------------------------------------------------------------------------------------
Notification of                    1                  1                  1                  2                  2
 Discontinuance
(Sec.
 314.81(b)(3)(iii
 ))
----------------------------------------------------------------------------------------------------------------
Certification of                  10                  1                  1                 16                 16
 Good Cause
(Sec.   314.91)
----------------------------------------------------------------------------------------------------------------
Total              .................  .................  .................  .................                 18
----------------------------------------------------------------------------------------------------------------
\1\There are no capital costs or operating and maintenance costs associated with this collection of information.

    The information collection provisions of this final rule have been 
submitted to OMB for review.
    Prior to the effective date of this final rule, FDA will publish a 
notice in the Federal Register announcing OMB's decision to approve, 
modify, or disapprove the information collection provisions of this 
final rule. An agency may not conduct or sponsor, and a person is not 
required to respond to, a collection of information unless it displays 
a currently valid OMB control number.

VI. Federalism

    We have analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. We have determined that the rule 
does not contain policies that have substantial direct effects on the 
States, on the relationship between National Government and the States, 
or on the distribution of power and responsibilities among the various 
levels of government. Accordingly, we have concluded that the rule does 
not contain policies that have federalism implications as defined in 
the Executive order, and, consequently, a federalism summary impact 
statement is not required.

VII. Environmental Impact

    We have determined under 21 CFR 25.30(h) that this action is of a 
type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

List of Subjects in 21 CFR Part 314

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

0
Therefore, under the Federal Food, Drug, and Cosmetic Act, the Public 
Health Service Act, and under authority delegated to the Commissioner 
of Food and Drugs, 21 CFR part 314 is amended as follows:

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

0
1. The authority citation for 21 CFR part 314 is revised 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 314.81 is amended as follows:
0
a. Redesignate paragraph (b)(3)(iii) as (b)(3)(iv);
0
b. Remove from newly redesignated paragraph (b)(3)(iv)(c) the phrase 
``(b)(3)(iii)'' and add in its place the phrase ``(b)(3)(iv)''; and
0
c. Add new paragraph (b)(3)(iii) to read as follows:
    The addition reads as follows:


Sec.  314.81  Other postmarketing reports.

* * * * *
    (b) * * *
    (3) * * *
    (iii) Notification of discontinuance. (a) An applicant who is the 
sole manufacturer of an approved drug product must notify FDA in 
writing at least 6 months prior to discontinuing manufacture of the 
drug product if:
    (1) The drug product is life supporting, life sustaining, or 
intended for use in the prevention of a serious disease or condition; 
and
    (2) The drug product was not originally derived from human tissue 
and replaced by a recombinant product.
    (b) For drugs regulated by the Center for Drug Evaluation and 
Research (CDER) or the Center for Biologics Evaluation and Research 
(CBER), one copy of the notification required by paragraph 
(b)(3)(iii)(a) of this section must be sent to the CDER Drug Shortage 
Coordinator, at the address of the Director of CDER; one copy to the 
CDER Drug Registration and Listing Team, Division of Compliance Risk 
Management and Surveillance; and one copy to either the director of the 
review division in CDER that is responsible for reviewing the 
application, or the director of the office in CBER that is responsible 
for reviewing the application.
    (c) FDA will publicly disclose a list of all drug products to be 
discontinued under paragraph (b)(3)(iii)(a) of this section. If the 
notification period is reduced under Sec.  314.91, the list will state 
the reason(s) for such reduction and the anticipated date that 
manufacturing will cease.
* * * * *

0
3. Section 314.91 is added to subpart B to read as follows:


Sec.  314.91  Obtaining a reduction in the discontinuance notification 
period.

    (a) What is the discontinuance notification period? The 
discontinuance notification period is the 6-month period required under 
Sec.  314.81(b)(3)(iii)(a). The discontinuance notification period 
begins when an applicant who is the

[[Page 59000]]

sole manufacturer of certain products notifies FDA that it will 
discontinue manufacturing the product. The discontinuance notification 
period ends when manufacturing ceases.
    (b) When can FDA reduce the discontinuance notification period? FDA 
can reduce the 6-month discontinuance notification period when it finds 
good cause exists for the reduction. FDA may find good cause exists 
based on information certified by an applicant in a request for a 
reduction of the discontinuance notification period. In limited 
circumstances, FDA may find good cause exists based on information 
already known to the agency. These circumstances can include the 
withdrawal of the drug from the market based upon formal FDA regulatory 
action (e.g., under the procedures described in Sec.  314.150 for the 
publication of a notice of opportunity for a hearing describing the 
basis for the proposed withdrawal of a drug from the market) or 
resulting from the applicant's consultations with the agency.
    (c) How can an applicant request a reduction in the discontinuance 
notification period? (1) The applicant must certify in a written 
request that, in its opinion and to the best of its knowledge, good 
cause exists for the reduction. The applicant must submit the following 
certification:
    The undersigned certifies that good cause exists for a reduction 
in the 6-month notification period required in Sec.  
314.81(b)(3)(iii)(a) for discontinuing the manufacture of (name of 
the drug product). The following circumstances establish good cause 
(one or more of the circumstances in paragraph (d) of this section).
    (2) The certification must be signed by the applicant or the 
applicant's attorney, agent (representative), or other authorized 
official. If the person signing the certification does not reside or 
have a place of business within the United States, the certification 
must contain the name and address of, and must also be signed by, an 
attorney, agent, or other authorized official who resides or maintains 
a place of business within the United States.
    (3) For drugs regulated by the Center for Drug Evaluation and 
Research (CDER) or the Center for Biologics Evaluation and Research 
(CBER), one copy of the certification must be submitted to the Drug 
Shortage Coordinator at the address of the Director of CDER, one copy 
to the CDER Drug Registration and Listing Team, Division of Compliance 
Risk Management and Surveillance in CDER, and one copy to either the 
director of the review division in CDER responsible for reviewing the 
application, or the director of the office in CBER responsible for 
reviewing the application.
    (d) What circumstances and information can establish good cause for 
a reduction in the discontinuance notification period? (1) A public 
health problem may result from continuation of manufacturing for the 6-
month period. This certification must include a detailed description of 
the potential threat to the public health.
    (2) A biomaterials shortage prevents the continuation of the 
manufacturing for the 6-month period. This certification must include a 
detailed description of the steps taken by the applicant in an attempt 
to secure an adequate supply of biomaterials to enable manufacturing to 
continue for the 6-month period and an explanation of why the 
biomaterials could not be secured.
    (3) A liability problem may exist for the manufacturer if the 
manufacturing is continued for the 6-month period. This certification 
must include a detailed description of the potential liability problem.
    (4) Continuation of the manufacturing for the 6-month period may 
cause substantial economic hardship for the manufacturer. This 
certification must include a detailed description of the financial 
impact of continuing to manufacture the drug product over the 6-month 
period.
    (5) The manufacturer has filed for bankruptcy under chapter 7 or 11 
of title 11, United States Code (11 U.S.C. 701 et seq. and 1101 et 
seq.). This certification must be accompanied by documentation of the 
filing or proof that the filing occurred.
    (6) The manufacturer can continue distribution of the drug product 
to satisfy existing market need for 6 months. This certification must 
include a detailed description of the manufacturer's processes to 
ensure such distribution for the 6-month period.
    (7) Other good cause exists for the reduction. This certification 
must include a detailed description of the need for a reduction.

    Dated: October 5, 2007.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. E7-20510 Filed 10-17-07; 8:45 am]
BILLING CODE 4160-01-S