[Federal Register: October 18, 2007 (Volume 72, Number 201)]
[Rules and Regulations]
[Page 58993-59000]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr18oc07-2]
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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 (http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://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
http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://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