
[Federal Register Volume 78, Number 237 (Tuesday, December 10, 2013)]
[Notices]
[Pages 74151-74154]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2013-29393]


-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

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


Agency Information Collection Activities; Proposed Collection; 
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Draft Guidance for Industry on Providing Postmarket Periodic Safety 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.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is announcing an 
opportunity for public comment on the proposed collection of certain 
information by the Agency. Under the Paperwork Reduction Act of 1995 
(the PRA), Federal Agencies are required to publish notice in the 
Federal Register concerning each proposed collection of information and 
to allow 60 days for public comment in response to the notice. This 
notice solicits comments on the information collection associated with 
the submission of periodic safety reports as described in the guidance 
entitled ``Periodic Benefit-Risk Evaluation Report (PBRER) (E2C(R2)).'' 
The guidance was prepared under the auspices of the International 
Conference on Harmonisation (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use, and describes the 
format, content, and timing of a PBRER for an approved drug or 
biologic. This notice also solicits comments on the information 
collection associated with the submission of waiver-related materials 
as described in the draft guidance entitled ``Providing Postmarket 
Periodic Safety Reports in the ICH E2C(R2) Format.'' The draft guidance 
is intended to inform applicants of the conditions under which FDA will 
exercise its waiver authority to permit applicants to submit an ICH 
E2C(R2) PBRER in place of the ICH E2C(R1) Periodic Safety Update Report 
(PSUR), U.S. periodic adverse drug experience report (PADER), or U.S. 
periodic adverse experience report (PAER), to satisfy the periodic 
safety reporting requirements in FDA regulations.

DATES: Submit either electronic or written comments on the collection 
of information by February 10, 2014.

ADDRESSES: Submit electronic comments on the collection of information 
to http://www.regulations.gov. Submit written comments on the 
collection of information to the Division of Dockets Management (HFA-
305), Food and Drug Administration, 5630 Fishers Lane., Rm. 1061, 
Rockville, MD 20852. All comments should be identified with the 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, PRAStaff@fda.hhs.gov.

SUPPLEMENTARY INFORMATION: Under 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 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 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 concerning each proposed collection of information before 
submitting the collection to OMB for approval. To comply with this 
requirement, FDA is publishing notice of the proposed collection of 
information set forth in this document.
    With respect to the following collection of information, FDA 
invites comments on these topics: (1) Whether the proposed collection 
of information is necessary for the proper performance of FDA's 
functions, including whether the information will have practical 
utility; (2) the accuracy of FDA's estimate of the burden of the 
proposed collection of information, including the validity of the 
methodology and assumptions used; (3) ways to enhance the quality, 
utility, and clarity of the information to be collected; and (4) ways 
to minimize the burden of the collection of information on respondents, 
including through the use of automated collection techniques, when 
appropriate, and other forms of information technology.

Reporting in Accordance With International Conference on 
Harmonisation--Periodic Benefit-Risk Evaluation Report (E2C(R2)) 
Guidance

I. Background

    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.
    The April 11, 2012, Federal Register notice stated that the draft 
PBRER guidance includes information collection provisions that are 
subject to review by OMB under the PRA, and that before publication of 
the final guidance document, FDA intends to solicit public comment and 
obtain OMB approval for any information collections recommended in the 
guidance that are

[[Page 74152]]

new or that would represent material modifications to previously 
approved collections of information found in FDA regulations. This 
Federal Register notice begins the process of requesting public comment 
and obtaining OMB approval for collections of information associated 
with reporting in accordance with the PBRER guidance.

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 
PADERs 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 PAERs 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 
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 that 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 that would be granted for the submission of PBRERs. 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)

[[Page 74153]]

and 600.90(a), that allow applicants to prepare and submit reports 
using the 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 use a different data lock point 
or change the frequency of reporting.
    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 request a waiver to change 
the data lock point and this waiver request should include a 
description of the measures taken to ensure that there are no resulting 
gaps in reporting with the change.
    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 applicant must request a waiver. This waiver request should 
describe the measures taken to ensure that the periodicity requirements 
under Sec. Sec.  314.80(c)(2)(i) and 600.80(c)(2)(i) are being met. If 
an applicant requests to submit a PBRER less frequently than is 
permitted under the applicant's PSUR waiver, 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 draft guidance also states that if an applicant is on 
a quarterly reporting schedule but wishes to submit a PBRER every 6 
months without submitting a quarterly PADER/PAER in the intervening 
quarters, the applicant may request a waiver of the quarterly reporting 
requirement.
    FDA expects approximately 189 waiver requests to include the 
additional information and notifications 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 and 
notifications described previously would be on average approximately 1 
hour for each waiver request.
    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 1-4 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.
    FDA estimates the additional burden of this collection of 
information as follows:

                                     Table 1--Estimated Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
  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
----------------------------------------------------------------------------------------------------------------
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....................
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............  ..............  ..............             321
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.



[[Page 74154]]

    Dated: December 3, 2013.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2013-29393 Filed 12-9-13; 8:45 am]
BILLING CODE 4160-01-P


