[Federal Register Volume 79, Number 90 (Friday, May 9, 2014)]
[Notices]
[Pages 26766-26768]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2014-10658]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2013-D-1478]


Agency Information Collection Activities; Submission for Office 
of Management and Budget Review; Comment Request; Providing Waiver-
Related Materials in Accordance With Draft Guidance for Industry on 
Providing Postmarket Periodic Safety Reports in the International 
Conference on Harmonisation E2C(R2) Format

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing that a 
proposed collection of information has been submitted to the Office of 
Management and Budget (OMB) for review and clearance under the 
Paperwork Reduction Act of 1995 (the PRA).

DATES: Fax written comments on the collection of information by June 9, 
2014.

ADDRESSES: To ensure that comments on the information collection are 
received, OMB recommends that written comments be faxed to the Office 
of Information and Regulatory Affairs, OMB, Attn: FDA Desk Officer, 
FAX: 202-395-7285, or emailed to [email protected]. All 
comments should be identified with the title. Also include the FDA 
docket number found in brackets in the heading of this document.

FOR FURTHER INFORMATION CONTACT: FDA PRA Staff, Office of Operations, 
Food and Drug Administration, 1350 Piccard Dr., PI50-400B, Rockville, 
MD 20850, [email protected].

SUPPLEMENTARY INFORMATION: In compliance with 44 U.S.C. 3507, FDA has 
submitted the following proposed collection of information to OMB for 
review and clearance.

Reporting in Accordance With International Conference on 
Harmonisation--Periodic Benefit Risk Evaluation Report (E2C(R2)) 
Guidance--(OMB Control Number 0910-NEW)

I. Background

    The International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) 
was organized to provide an opportunity for tripartite harmonization 
initiatives to be developed with input from both regulatory and 
industry representatives. ICH is concerned with harmonization of 
technical requirements for the registration of pharmaceutical products 
among three regions: The European Union, Japan, and the United States. 
In January 2012, the ICH Steering Committee agreed that the ``E2C(R2) 
Periodic Benefit-Risk Evaluation Report'' draft guidance (the draft 
PBRER guidance) should be made available for public comment. The PBRER 
is intended to provide a common standard for periodic reporting on 
approved drugs or biologics among the ICH regions. The harmonized PBRER 
is intended to promote a consistent approach to periodic postmarket 
safety reporting among the ICH regions and to enhance efficiency by 
reducing the number of reports generated for submission to the 
regulatory authorities.
    The draft PBRER guidance revises an earlier version of this 
guidance issued in 1997 with an addendum issued in 2004. In the Federal 
Register of April 11, 2012 (77 FR 21782), FDA announced the 
availability of the draft PBRER guidance for public comment. FDA 
presented the comments received as part of the considerations by the 
E2C(R2) Expert Working Group for revisions of the guidance. A final 
version of the guidance was subsequently endorsed by the ICH on 
November 15, 2012, and published as the ICH harmonized tripartite 
guideline ``Periodic Benefit-Risk Evaluation Report (PBRER) E2C(R2)'' 
(the PBRER guidance), available at http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html. FDA anticipates 
issuing final guidance on this topic that is consistent with the final 
ICH document, published November 2012, and thus is seeking PRA approval 
for information collections consistent with that document.

II. Voluntary Preparation of Periodic Safety Reports in Conformance 
With the ICH E2C(R2) PBRER Guidance, in Lieu of PADERs/PAERs Required 
Under 21 CFR 314.80(c)(2) and 600.80(c)(2)

    FDA currently has OMB approval for the required submission of 
periodic adverse drug experience reports (PADER) for drugs subject to a 
new drug application (NDA) or an abbreviated new drug application 
(ANDA) (Sec.  314.80(c)(2) (21 CFR 314.80(c)(2)); OMB control number 
0910-0230), and for the required submission of periodic adverse 
experience reports (PAER) for drugs subject to a biologics license 
application (BLA) (Sec.  600.80(c)(2) (21 CFR 600.80(c)(2)); OMB 
control number 0910-0308). Such reports include, for the reporting 
interval, reports of serious, expected adverse experiences and all non-
serious adverse experiences and an index of these reports, a narrative 
summary and analysis of adverse experiences, an analysis of the 15-day 
Alert reports submitted during the reporting interval, and a history of 
actions taken because of adverse experiences. Applicants must submit 
each PADER/PAER to FDA quarterly for the first 3 years after the 
product is approved by FDA and annually thereafter. As described in the 
supporting documentation under OMB control numbers 0910-0230 and 0910-
0308, FDA currently has OMB approval for approximately 60 hours for the 
preparation and submission of each PADER under Sec.  314.80(c)(2) and 
28 hours for the preparation and submission of each PAER under Sec.  
600.80(c)(2).
    There is considerable overlap in the information required under 
Sec. Sec.  314.80(c)(2) and 600.80(c)(2) and the information requested 
in a periodic safety report using the ICH E2C(R2) PBRER format. As a 
result, and as discussed further in this document, FDA, in the Federal 
Register of April 8, 2013 (78 FR 20926), announced the availability of 
a draft guidance to indicate its willingness to accept postmarket 
periodic safety reports using the ICH PBRER format in lieu of the

[[Page 26767]]

specific reports described in FDA regulations. (As described further in 
this document, the April 2013 draft guidance also addresses waiver-
related information that should be submitted to FDA by companies who 
wish to exercise this alternative reporting.)
    Companies who submit periodic reports on the same drug to multiple 
regulators, including not only the United States, but, also the 
European Union, Japan, and regulators in other countries who have 
elected to adopt the ICH standards, may find it in their interest to 
prepare a single PBRER, rather than preparing multiple types of reports 
for multiple regulators. Companies who choose to submit a PBRER to FDA 
would include some information beyond that required by FDA regulations, 
including worldwide marketing approval status; estimated exposure and 
use patterns; information from clinical trials, non-interventional 
studies, non-clinical data, and literature; benefit evaluation, and 
benefit-risk analysis for approved indications, and should use a 
particular format described in the draft PBRER guidance.
    FDA is not proposing to require submission of the PBRER; applicants 
subject to periodic safety reporting requirements under FDA regulations 
could choose to continue to submit the reports as specified in those 
regulations, and would be permitted to alternate between submission of 
reports in the PBRER format and submission of reports as specified in 
FDA regulations with an approved waiver. Based on FDA's experience with 
submission of periodic safety reports under previous ICH periodic 
reporting guidance, FDA believes that applicants would elect to submit 
the PBRER to FDA only in cases where they are also submitting that 
report to other regulatory authorities, some of which have underlying 
legal requirements that closely parallel the elements of the PBRER. For 
this reason, FDA believes that the additional burden associated with 
preparation of a PBRER in lieu of existing PADERs/PAERs is not 
attributable to the proposed collection of information by FDA, but 
rather is a ``usual and customary'' expenditure of time, effort, and 
financial resources that would be ``incurred by persons in the normal 
course of their activities,'' and thus is excluded from the calculation 
of burden under the PRA (5 CFR 1320.5(b)(2).) Cf. 5 CFR 1320.5(b)(3) 
(permitting exclusion from Federal burden of burden incurred in 
complying with an information collection that is also conducted by a 
State or local government if the State or local requirement would be 
imposed even in the absence of a Federal requirement).
    We therefore believe that the existing estimate of burden for 
submission of periodic safety reports, approved under OMB control 
numbers 0910-0230 and 0910-0308, would be unchanged by this proposed 
collection, which would permit, but not require, the substitution of a 
PBRER for the periodic safety report otherwise required. We request 
comment on the assumption that all PBRERs submitted to FDA would be 
prepared in any event to submit to other jurisdictions, or 
alternatively, on the number of PBRERs that applicants will choose to 
prepare solely for submission to FDA, and the estimated burden for 
submitting such a report.

III. Materials Related to Waivers Permitting Submission of a PBRER To 
Satisfy the Periodic Safety Reporting Requirements in Sec. Sec.  
314.80(c)(2) and 600.80(c)(2)

    Because FDA regulations in Sec. Sec.  314.80(c)(2) and 600.80(c)(2) 
include specific requirements for periodic safety reports, in order for 
an applicant to submit an alternative report, such as the PBRER, for a 
given product, FDA must grant a waiver. Existing regulations permit 
applicants to request waivers of any postmarketing safety reporting 
requirement, and the information collections associated with such 
waiver requests generally are approved under existing control numbers. 
(See Sec.  314.90(a), waivers for drugs subject to NDAs and ANDAs 
(approved under OMB control number 0910-0001); and Sec.  600.90(a), 
waivers for products subject to BLAs (approved under OMB control number 
0910-0308).)
    In the Federal Register of April 8, 2013, FDA announced the 
availability of a draft guidance entitled ``Providing Postmarket 
Periodic Safety Reports in the ICH E2C(R2) Format'', which indicates 
that FDA will be prepared to grant waivers to enable submission of the 
PBRER in the United States in place of a PADER required under Sec.  
314.80(c)(2) or in place of a PAER required under Sec.  600.80(c)(2). 
The draft guidance both explains conditions under which applicants that 
have previously received waivers to submit reporting information in the 
format of the previous ICH guidance would be permitted to apply those 
existing waivers to the submission of PBRERs, and also advises how 
applicants that have not previously obtained a waiver may submit waiver 
requests to submit the PBRER. This Federal Register notice solicits 
comment on certain information collections proposed in the April 8, 
2013, draft guidance that are related to waivers specifically to enable 
the submission of PBRERs, and that are not already addressed under 
approved control numbers covering waiver submissions and periodic 
safety reports generally.
    FDA has previously granted waiver requests, submitted under 
Sec. Sec.  314.90(a) and 600.90(a), that allow applicants to prepare 
and submit reports using the periodic safety update report (PSUR) 
format described in the 1997 and 2004 ICH E2C guidance. In accordance 
with the recommendations of the April 8, 2013, draft guidance, if an 
applicant already has a PSUR waiver in place for a given approved 
application, FDA will consider the existing PSUR waiver to allow the 
applicant to submit a PBRER instead of a PSUR because the PBRER 
replaces the PSUR for postmarketing periodic safety reporting for that 
application. The applicant would not need to submit a new waiver 
request unless the applicant wishes to change the frequency of 
reporting. FDA will consider requests to be waived of the quarterly 
reporting requirement but will not waive applicants of the annual 
reporting requirement.
    If an applicant submits a PBRER in place of the PSUR and uses a 
different data lock point, the applicant should submit overlapping 
reports or submit a one-time PADER/PAER in order to cover the gap in 
reporting intervals. The applicant should submit notification to the 
application(s), indicating the change in data lock point and should 
include a description of the measures taken to ensure that there are no 
resulting gaps in reporting.
    If an applicant submits a PBRER in place of the PSUR and uses a 
different reporting frequency for the PBRER than was used for the PSUR, 
the continued validity of the waiver will be conditioned on the 
submission of a PADER/PAER as needed to fulfill the reporting frequency 
requirement under FDA regulations. The applicant should submit a 
notification to the application(s), describing this change and the 
measures taken to ensure that the periodicity requirements are being 
met.
    FDA expects approximately 187 waiver requests and notifications to 
include the additional information described previously in this 
document for using a different data lock point and/or for using a 
different reporting frequency when submitting a PBRER. FDA expects 
approximately 55 applicants to make these submissions, and we estimate 
that the time for submitting the additional information described 
previously would be on average approximately 1 hour for each waiver 
request or notification.

[[Page 26768]]

    If an applicant does not have a PSUR waiver in place for an 
approved application, the applicant may submit a waiver request under 
Sec.  314.90(a) or Sec.  600.90(a) to submit a PBRER instead of the 
PADER/PAER. The applicant should submit a request to FDA for each 
approved application for which a waiver is requested, and a single 
waiver request letter can include multiple applications. Waiver 
requests should be submitted to each of the application(s) in the 
request, and may be submitted electronically or by mail as described in 
the April 8, 2013, draft guidance. Each PBRER waiver request should 
include the following information:
    1. The product name(s) and application number(s);
    2. A brief description of the justification for the request;
    3. The U.S. approval date for the product(s) and current reporting 
interval used;
    4. The reporting interval of the last PADER/PAER submitted for the 
product(s);
    5. The data lock point that will be used for each PBRER. If a data 
lock point other than one aligned to the U.S. approval date is 
proposed, the applicant should describe how he/she will ensure that 
there are no gaps in reporting intervals (e.g., by submitting 
overlapping reports; submitting a one-time PADER/PAER to cover the gap 
period; or, if the gap is less than 2 months, extending the reporting 
interval of the final PADER/PAER to close the gap).
    6. The frequency for submitting the PBRER, as described in section 
IV.C of the April 8, 2013, draft guidance.
    7. The email address and telephone number for the individual who 
can provide additional information regarding the waiver request.
    As explained earlier, existing regulations at Sec. Sec.  314.90(a) 
or 600.90(a) permit applicants to request waivers of any postmarketing 
safety reporting requirement, and the information collections 
associated with such waiver requests generally are approved under OMB 
control numbers 0910-0001and 0910-0308. FDA believes that the 
information submitted under numbers 1 to 4 and number 7 in the list in 
the previous paragraph is information that is typical of any waiver 
request regarding postmarketing safety reporting and is accounted for 
in the existing approved collections of information for waiver requests 
and reports. Concerning numbers 5 and 6, FDA expects approximately 67 
waiver requests to include the additional information for using a 
different data lock point and/or for using a different reporting 
frequency when submitting a PBRER. FDA expects approximately 29 
applicants to make these submissions, and we estimate that the time for 
submitting the additional information described in the previous 
paragraph would be on average approximately 2 hours for each waiver 
request.
    In the Federal Register of December 10, 2013 (78 FR 74151), FDA 
published a 60-day notice requesting public comment on the proposed 
collection of information. No comments were received.
    FDA estimates the additional burden of this collection of 
information as follows:

                                 Table 1--Estimated Annual Reporting Burden \1\
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  Additional information and/or
   notifications for using  a        Number of       Number of     Total annual       Average
different data lock point and/or    respondents    responses per     responses      burden per      Total hours
a different  reporting frequency                    respondent                       response
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Applicants that have a PSUR                   55             3.4             187               1             187
 waiver for an approved
 application....................
Applicants that do not have a                 29             2.3              67               2             134
 PSUR waiver for an approved
 application....................
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    Total.......................  ..............  ..............  ..............  ..............             321
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.


    Dated: May 5, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014-10658 Filed 5-8-14; 8:45 am]
BILLING CODE 4160-01-P