[Federal Register Volume 77, Number 38 (Monday, February 27, 2012)]
[Notices]
[Pages 11550-11553]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2012-4439]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2012-D-0140]


Draft Guidance for Industry on Notification to Food and Drug 
Administration of Issues That May Result in a Prescription Drug 
Shortage; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice; request for comments.

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SUMMARY: The Food and Drug Administration (FDA) is announcing the 
availability of a draft guidance for industry entitled ``Notification 
to FDA of Issues that May Result in a Prescription Drug or Biological 
Product Shortage.'' This draft guidance relates to the Federal Food, 
Drug, and Cosmetic Act (FD&C Act), which requires sole manufacturers to 
notify FDA of a discontinuance of certain drug products and to the 
President's Executive Order 13588 of October 31, 2011, directing FDA to 
use all available administrative tools to expand the Agency's efforts 
to combat the problem of drug shortages. We are also requesting 
responsive comments from interested stakeholders on a specific question 
posed in this Federal Register document related to the draft guidance.

DATES: Although you can comment on any guidance at any time (see 21 CFR 
10.115(g)(5)), to ensure that the Agency considers your comment on this 
draft guidance before it begins work on the final version of the 
guidance, submit either electronic or written comments on the draft 
guidance by May 29, 2012.

[[Page 11551]]

Submit either electronic or written comments concerning the proposed 
collection of information by April 27, 2012.

ADDRESSES: Submit written requests for single copies of the draft 
guidance to the Division of Drug Information, Center for Drug 
Evaluation and Research (CDER), Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, rm. 2201, Silver Spring, MD 20993-0002 or to 
the Office of Communication, Outreach and Development (HFM-40), Center 
for Biologics Evaluation and Research (CBER), Food and Drug 
Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-
1448. Send one self-addressed adhesive label to assist the office in 
processing your request. The guidance may also be obtained by mail by 
calling CDER at 301-796-3400 or CBER at 1-800-835-4709 or 301-827-1800. 
See the SUPPLEMENTARY INFORMATION section for electronic access to the 
draft guidance document.
    Submit electronic comments to http://www.regulations.gov. Submit 
written comments on the draft guidance to the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT:

Kalah Auchincloss, Center for Drug Evaluation and Research, Food and 
Drug Administration, 10903 New Hampshire Ave., Bldg. 51, rm. 6208, 
Silver Spring, MD 20993, 301-796-0659; or
Stephen Ripley, Center for Biologics Evaluation and Research, Food and 
Drug Administration, 1401 Rockville Pike, Rockville, MD 20852-1448, 
301-827-6210.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is concerned about the rising incidence of drug shortages in 
the United States, particularly those involving drugs that are 
manufactured by a small number of firms and for which no good 
therapeutic substitutes are available. The number of drug shortages has 
been rising steadily over the last 5 years, tripling from 61 in 2005 to 
178 in 2010. In 2011, FDA tracked over 250 drug shortages. Some of 
these shortages delay or deny needed care for patients since they 
involve critical drugs used to treat cancer, to fight infectious 
diseases, to provide required nutrition, or to address other serious 
medical conditions. Other shortages force providers to prescribe 
second-line alternatives, which can be less effective and higher risk 
than first-line therapies.
    Under section 506C of the FD&C Act (21 U.S.C. 356c), sole 
manufacturers are required to report to FDA discontinuances of drug 
products that are life-supporting, life-sustaining, or intended for use 
in the prevention of a debilitating disease or condition and that are 
approved under a new drug application (NDA) or abbreviated new drug 
application (ANDA). On October 31, 2011, FDA sent a letter to 
manufacturers reminding them of their mandatory reporting requirements 
under section 506C of the FD&C Act and encouraging them to voluntarily 
notify the Agency of potential disruptions to supply of a prescription 
product that could lead to a product shortage, even beyond those 
instances that are required to be reported by statute. On the same day, 
the President issued Executive Order 13588 directing FDA to use all 
available administrative tools to expand its efforts to combat the 
problem of drug shortages.
    FDA recognizes that some shortages can be neither predicted nor 
prevented; however, we know that effective communication and early 
notification from manufacturers has a significant impact on the 
incidence and duration of shortages. Manufacturers can play a critical 
role in decreasing the impact of shortages by reporting to the FDA 
circumstances that might affect their ability to supply the market and 
potentially lead to a product shortage. Notifying FDA in advance of 
incidents that may result in a shortage helps FDA work with 
manufacturers to take early action to prevent or alleviate shortages. 
For example, in 2011, early notification by manufacturers allowed FDA 
to help prevent shortages of 195 drugs, including 86 drugs produced by 
one company. However, as the President recognized in the Executive 
Order, FDA cannot begin to work with manufacturers or use tools at our 
disposal to avoid or mitigate a shortage until we know there is a 
potential problem.
    There is no single, or simple, solution that can resolve the drug 
shortage problem, but we are committed to working with manufacturers, 
distributors, health care providers, and other stakeholders to identify 
the issues that can lead to shortages, to establish processes to avoid 
or mitigate critical shortages in the future, and to ensure continued 
patient access to vital safe and effective products. As part of this 
effort, we are issuing this guidance to help manufacturers better 
understand mandatory reporting obligations, to encourage voluntary 
reporting of additional issues that could lead to a shortage or 
disruption in supply of a drug or biological product, and to address 
other issues, such as quality control and contingency planning related 
to product shortages or potential disruption in supply.
    This draft guidance is being issued consistent with FDA's good 
guidance practices regulation (21 CFR 10.115). The draft guidance, when 
finalized, will represent the Agency's current thinking on required and 
voluntary notifications to FDA of issues related to product shortages. 
It does not create or confer any rights for or on any person and does 
not operate to bind FDA or the public. An alternative approach may be 
used if such approach satisfies the requirements of the applicable 
statutes and regulations.

II. Request for Information

    To assist us in finalizing guidance on drug shortages, FDA is 
seeking information and comments on the draft guidance from interested 
stakeholders. Although we welcome comment on any aspect of the draft 
guidance, we are particularly interested in obtaining information and 
comment regarding the appropriate scope of voluntary reporting of 
disruptions that may lead to a product shortage or potential disruption 
in supply. Specifically, please comment on whether manufacturers of all 
prescription drug and biological products should be encouraged to 
notify FDA of issues that may lead to a product shortage or potential 
disruption in supply. In your comments, please indicate whether the 
Agency should encourage voluntary reporting with regard to only a 
certain subset of prescription drug and biological products and, if so, 
please describe the products.
    The comment period for the related interim final rule (IFR) on drug 
shortages published in the Federal Register of December 19, 2011 (76 FR 
78530), and effective January 18, 2012, closed on February 17, 2012. 
Please do not submit comments on the IFR to the docket for the draft 
guidance; we will not consider comments on the IFR submitted to the 
docket for the draft guidance.

III. Paperwork Reduction Act of 1995

    Under the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 
3501-3520), Federal Agencies must obtain approval from the Office of 
Management and Budget (OMB) for each collection of information that 
they conduct or sponsor. ``Collection of information'' is defined in 44 
U.S.C. 3502(3) and 5 CFR 1320.3(c) and includes Agency requests or 
requirements that members of the public submit reports, keep records, 
or

[[Page 11552]]

provide information to a third party. Section 3506(c)(2)(A) of the PRA, 
44 U.S.C. 3506(c)(2)(A), requires Federal Agencies to provide a 60-day 
notice in the Federal Register for each proposed collection of 
information before submitting the collection to OMB for approval. To 
comply with this requirement, FDA is publishing this notice of the 
proposed collection of information set forth in this document.
    With respect to the collection of information associated with this 
draft guidance, FDA invites comments on the following topics: (1) 
Whether the proposed information collected is necessary for the proper 
performance of FDA's functions, including whether the information will 
have practical utility; (2) the accuracy of FDA's estimated burden of 
the proposed information collected, including the validity of the 
methodology and assumptions used; (3) ways to enhance the quality, 
utility, and clarity of the information collected; and (4) ways to 
minimize the burden of information collected on the respondents, 
including through the use of automated collection techniques, when 
appropriate, and other forms of information technology.
    The draft guidance provides information on the requirements for 
notification to FDA of a discontinuance of certain drug products under 
section 506C of the FD&C Act as implemented by 21 CFR 314.81(b)(3)(iii) 
and 314.91, and also reflects amendments to the implementing 
regulations published in the Federal Register as an IFR on December 19, 
2011 and effective January 18, 2012. The draft guidance also provides 
information to industry on voluntarily notifying FDA of other issues 
that may result in a shortage or disruption in supply of a prescription 
drug or biological product in the U.S. market. In addition, the draft 
guidance encourages manufacturers to make contingency plans for 
responding to situations that could lead to a drug or biological 
product shortage or potential disruption in supply. The draft guidance 
is intended for manufacturers of prescription drug and biological 
products regulated by CDER or CBER.
    The burden analysis for the information collection resulting from 
the mandatory notification requirements under section 506C of the FD&C 
Act, as implemented by Sec. Sec.  314.81(b)(3)(iii) and 314.91, and 
from the implementing regulations in the December 19, 2011, IFR, was 
submitted to OMB for emergency review under the PRA on December 21, 
2011 (see ``V. Paperwork Reduction Act of 1995'' at 76 FR 78537). OMB 
has approved this information collection under OMB control number 0910-
0699. A discussion of the scope and logistics of mandatory notification 
under section 506C of the FD&C Act and the IFR is found in section III 
of the draft guidance.
    Under section IV of the draft guidance, manufacturers of all 
prescription drug and biological products are encouraged to voluntarily 
notify FDA of issues that may result in a shortage of a product in the 
U.S. market or a potential disruption in supply. Voluntary notification 
of issues that may lead to a potential shortage or disruption in supply 
includes reporting of circumstances beyond those instances that are 
required to be reported by section 506C, and includes the following:
     Product quality problems, such as the presence of 
particulates or impurities, microbial contamination, and stability 
concerns;
     Interruptions or other adjustments in manufacturing that 
may adversely affect market supply, such as routine maintenance, that 
may temporarily halt production or renovation of manufacturing 
facilities;
     Delays in acquiring critical raw materials or components, 
or loss of raw material or components supplier (e.g. vials, stoppers, 
bottles);
     Transfer of manufacturing to an alternate facility (e.g. 
due to loss of an existing manufacturing site or to add additional 
capacity);
     Loss of a production line or production capacity (e.g., 
machinery failure or malfunction or quality issues related to a cell 
line);
     Any production problems that occur during or after 
manufacturing that could result in supply disruptions (e.g. out of 
specification test results, stability problems, or labeling and 
packaging defects);
     Import delays (e.g. shipments detained upon entry to the 
United States for any reason that may delay delivery to the 
manufacturing firm);
     Unexpected increases in demand (e.g. due to a shortage of 
an alternative product); and
     Product discontinuances (e.g. a business decision to stop 
manufacturing or marketing the product or a temporary product hold 
while investigating issues that may result in a recall), even if you 
are not a sole manufacturer or the product in question is not subject 
to section 506C.
    Based on the number of shortages we have seen during the past 12 
months, we estimate that annually a total of approximately 480 
manufacturers (``number of respondents'' in table 1 of this document) 
will voluntarily notify us of issues that may result in a shortage or 
potential disruption in supply of a drug or biological product, as 
described previously. We estimate that these manufacturers will submit 
annually a total of approximately 480 notifications (``total annual 
responses'' in table 1 of this document). We also estimate that 
preparing and submitting this information to us will take approximately 
2 hours per manufacturer (``hours per response'' in table 1 of this 
document), including the time that some manufacturers may need to 
prepare information and take remedial steps in response to follow up 
questions and other action from FDA, as described in section V of the 
draft guidance. We base this estimate on our experience with the 
reporting of similar information to FDA, including mandatory reporting 
under section 506C of the FD&C Act of discontinuance of manufacturing 
of a sole source drug that is life-supporting, life-sustaining, or 
intended for use in the prevention of a serious disease or condition, 
and from the increase in voluntary notifications received since 
publication on October 31, 2011, of the letter to manufacturers 
requesting such reports.
    Under section VI of the draft guidance, manufacturers are 
encouraged to engage in quality control, risk-management, and 
contingency planning for responding to situations that could lead to a 
drug or biological product shortage or potential disruption in supply. 
The draft guidance explains that contingency plans should cover 
additional manufacturing sites, production lines, and suppliers, such 
as building redundancy into manufacturing capabilities or providing for 
additional suppliers under the NDA, ANDA, and BLA processes. The plans 
may need to identify alternative API and component suppliers and/or 
have redundant manufacturing capacity registered and in compliance with 
current good manufacturing practices under 21 CFR parts 210 and 211.
    In table 2 of this document, we estimate that a total of 
approximately 70 manufacturers (``number of recordkeepers'' in table 2 
of this document) will prepare contingency plans for responding to 
situations that could lead to a product shortage or potential 
disruption in supply, as described above. We estimate that these 
manufacturers will prepare a total of approximately 70 contingency 
plans (``total records'' in table 2 of this document). We also estimate 
that preparing and maintaining each contingency plan will take 
approximately 500 hours per manufacturer (``average burden per 
recordkeeping'' in table 2 of this

[[Page 11553]]

document). We base this estimate on our experience with related 
contingency planning under the draft guidance for industry entitled: 
``Planning for the Effects of High Absenteeism to Ensure Availability 
of Medically Necessary Drug Products'' (Absenteeism Draft Guidance) 
published in the Federal Register of January 8, 2010 (75 FR 1060), and 
October 18, 2010 (75 FR 63832), and the public comments we received on 
our burden estimate for that guidance. The Absenteeism Draft Guidance 
recommends that drug and biological product manufacturers develop 
written plans to maintain an adequate supply of medically necessary 
products during an emergency that results in high employee absenteeism. 
Although the draft guidance that is the subject of this Federal 
Register document is not related to employee absenteeism, the two 
guidance documents apply to a similar group of manufacturers and we 
believe the contingency plans recommended in both draft guidance 
documents will include similar elements. Accordingly, we believe the 
burden estimates from the Absenteeism Draft are relevant to this draft 
guidance. However, we specifically request comment on these contingency 
plan burden hour estimates.
    FDA estimates the burden of this collection of information as 
follows:

                                     Table 1--Estimated Reporting Burden \1\
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                                                     Number of
                                     Number of     responses per   Total annual      Hours per      Total hours
                                    respondents     respondent       responses       response
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Voluntary Reporting Under                    480               1             480               2             960
 Section IV of the Draft
 Guidance.......................
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............  ..............  ..............             960
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\1\ There are no capital costs or operating and maintenance costs associated with this information collection.


                                   Table 2--Estimated Recordkeeping Burden \1\
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                                                                                      Average
                                     Number of       Number of                      burden per
                                   recordkeepers    records per   Total  records   recordkeeping    Total hours
                                                   recordkeeper                     (in hours)
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Voluntary Contingency Plans                   70               1              70             500          35,000
 Under Section VI of the Draft
 Guidance.......................
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............  ..............  ..............          35,000
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\1\ There are no capital costs or operating and maintenance costs associated with this information collection.

IV. Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) either written or electronic comments regarding this 
document. It is only necessary to send one set of comments. Identify 
comments with the docket number found in brackets in the heading of 
this document. Received comments may be seen in the Division of Dockets 
Management between 9 a.m. and 4 p.m., Monday through Friday.

V. Electronic Access

    Persons with access to the Internet may obtain the document at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm121568.htm, http://www.fda.gov/cber/guidelines.htm, or 
http://www.regulations.gov.

    Dated: February 22, 2012.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2012-4439 Filed 2-24-12; 8:45 am]
BILLING CODE 4160-01-P