AER under 314.80 (marketing applications) - quarterly reports

Providing Postmarketing Periodic Safety
Reports in the ICH E2C(R2) Format
(Periodic Benefit-Risk Evaluation Report)
Guidance for Industry

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
November 2016
Drug Safety

Providing Postmarketing Periodic Safety
Reports in the ICH E2C(R2) Format
(Periodic Benefit-Risk Evaluation Report)
Guidance for Industry

Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: [email protected]
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
and/or
Office of Communication, Outreach and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 71, Room 3128
Silver Spring, MD 20993-0002
Phone: 800-835-4709 or 240-402-8010
Email: [email protected]
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
November 2016
Drug Safety

TABLE OF CONTENTS

I.

INTRODUCTION............................................................................................................. 1

II.

BACKGROUND ............................................................................................................... 2

A.

Postmarketing Periodic Safety Reporting Regulations .............................................................. 2

B.

The PSUR (ICH E2C)(R1) and the PBRER (ICH E2C(R2))..................................................... 2

C.

Precedence for Granting PSUR Waivers ..................................................................................... 3

III.
A.

PROCEDURES APPLICANTS SHOULD FOLLOW TO SUBMIT A PBRER ....... 4
Applicants With a PSUR Waiver ................................................................................................. 4

1. Change in the Date of the DLP for the PBRER – Submit Notification ............................................ 4
2. Longer PBRER Reporting Intervals But No Change in Frequency – Submit Notification .............. 5
3. Other Changes to the PSUR Waiver – Submit New Waiver ............................................................ 5
B. Applicants Without a PSUR Waiver ............................................................................................ 5

IV.

SUBMITTING WAIVER REQUESTS .......................................................................... 6

V.

FORMAT, CONTENT, AND TIMING OF THE PBRER ........................................... 7

Contains Nonbinding Recommendations

Providing Postmarketing Periodic Safety Reports in the ICH
E2C(R2) Format (Periodic Benefit-Risk Evaluation Report)
Guidance for Industry 1
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on
this topic. It does not establish any rights for any person and is not binding on FDA or the public. You
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the
title page.

I.

INTRODUCTION

This guidance describes the conditions under which applicants 2 can use an alternative reporting
format, the International Council for Harmonisation (ICH) 3 E2C(R2) Periodic Benefit-Risk
Evaluation Report (PBRER), in place of the U.S. periodic adverse drug experience report
(PADER), U.S. periodic adverse experience report (PAER), or ICH E2C Periodic Safety Update
Report (PSUR), to satisfy the periodic postmarketing safety reporting requirements in §§
314.80(c)(2) and 600.80(c)(2) (21 CFR 314.80(c)(2) and 600.80(c)(2)). This guidance also
describes the procedures applicants should follow if they wish to submit a PBRER in place of a
PADER, PAER, or PSUR. 4 The steps will differ, depending on whether or not the applicant has
an approved waiver in place to substitute the PSUR for the PADER/PAER.

1

This guidance has been prepared by the Office of Surveillance and Epidemiology in the Center for Drug
Evaluation and Research (CDER) in cooperation with the Center for Biologics Evaluation and Research (CBER) at
the Food and Drug Administration.

2

This guidance uses the term applicant to mean the holder of an approved new drug application (NDA), abbreviated
new drug application (ANDA), or biologics license application (BLA), which are referred to collectively in this
guidance as applications.

3

Formerly the International Conference on Harmonisation. The ICH was organized to provide an opportunity for
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 for human
use among regulators around the world (for more information about the ICH and the procedures for adopting
harmonized guidelines, see http://www.ich.org/). Guidelines that have been formally endorsed by the ICH are
implemented by the FDA in the form of FDA guidance documents whose development follows the procedures
outlined in FDA’s good guidance practices regulation (21 CFR 10.115).
4

FDA accepts all three formats, the PADER/PAER, PSUR, and PBRER, to fulfill the postmarketing periodic safety
reporting requirements under §§ 314.80(c)(2) and 600.80(c)(2). Each format must be submitted according to the
content and timelines specified in the regulations (PADER/PAER) or by ICH (PSUR and PBRER).

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Contains Nonbinding Recommendations
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
as recommendations, unless specific regulatory or statutory requirements are cited. The use of
the word should in Agency guidances means that something is suggested or recommended, but
not required.

II.

BACKGROUND
A.

Postmarketing Periodic Safety Reporting Regulations

FDA regulations in §§ 314.80(c)(2) and 600.80(c)(2) require applicants to submit postmarketing
periodic safety reports in the PADER/PAER format for each approved application. The reports
must be submitted quarterly for the first 3 years following the U.S. approval date and annually
thereafter (see §§ 314.80(c)(2)(i) and 600.80(c)(2)(i)), and must contain the information
described in §§ 314.80(c)(2)(ii) and 600.80(c)(2)(ii).
B.

The PSUR and the PBRER

In November 1996, the ICH endorsed the ICH E2C Periodic Safety Update Report Guideline
(ICH E2C(R1) guideline), which established the PSUR as a harmonized format for
postmarketing periodic safety reports for approved drugs and biologic products, and described
the format, content, and timing of PSUR submissions. FDA adopted that guideline and, in May
1997, published it as FDA guidance for industry E2C Clinical Safety Data Management:
Periodic Safety Update Reports for Marketed Drugs. 5 In February 2003, ICH endorsed and
made final an addendum that further clarified some aspects of the ICH E2C(R1) guideline. In
February 2004, FDA published the addendum as FDA guidance for industry Addendum to E2C
Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs. 6
On April 11, 2012, FDA announced the availability of a draft guidance for industry entitled E2C
(R2) Periodic Benefit-Risk Evaluation Report, 7 which reflected revisions by ICH and described
the format, content, and timing of the updated version, the PBRER, as presented in the ICH
EC2(R2) 8 step 2 guideline. 9 ICH subsequently endorsed a final version of that guideline on
5

62 FR 27470 (May 19, 1997). We update guidances periodically. To make sure you have the most recent version
of a guidance, check the FDA Drugs guidance Web page at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

6

69 FR 5551 (Feb. 5, 2004). When final, this guidance will represent FDA’s current thinking on this topic.

7

77 FR 21782 (April 11, 2012).

8

The terms R1 and R2 refer to successive revisions in ICH E2C.

9

The term step 2 refers to the point in the ICH process where the draft guideline is agreed and signed by the Expert
Working Group and the ICH Assembly, which signifies acceptance for consultation by the Members of the ICH
Association.

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Contains Nonbinding Recommendations
November 15, 2012, and published the ICH guideline Periodic Benefit-Risk Evaluation Report
(PBRER) E2C(R2) 10 (ICH E2C(R2) step 4 guideline). 11 The step 4 guideline updates and
combines the E2C(R1) guideline and the addendum to the E2C(R1) guideline. The step 4
guideline replaces the PSUR with the PBRER for postmarketing periodic safety reporting, and
describes the recommended format, content, and timing of PBRER submissions. Like the PSUR,
the harmonized PBRER is intended to promote a consistent approach to periodic postmarketing
safety reporting among the ICH regions and to enhance efficiency by reducing the number of
reports generated for submission to regulatory authorities. FDA adopted the step 4 guideline
and, on July 19, 2016, published it as FDA guidance for industry E2C(R2) Periodic Benefit-Risk
Evaluation Report (PBRER) (ICH E2C(R2) PBRER guidance). 12
In addition to adopting ICH guidelines as described above, on April 28, 2013, FDA made
available a draft guidance for industry Providing Postmarket Periodic Safety Reports in the ICH
E2C(R2) Format (Periodic Benefit-Risk Evaluation Report), 13 which FDA is now finalizing in
this current guidance. This current guidance describes the procedures that applicants should
follow to submit a PBRER in place of a PADER, PAER, or PSUR.
C.

Precedence for Granting PSUR Waivers

Since the introduction of the PSUR reporting format, FDA has granted waivers under §§
314.90(b) and 600.90(b) (21 CFR 314.90(b) and 600.90(b)) to allow applicants to substitute the
PSUR for the PADER/PAER (PSUR waiver). FDA has routinely granted PSUR waivers on the
condition that applicants provide the following information:
•

The nonexpedited individual case safety reports (ICSRs) received during the reporting
interval, as required under §§ 314.80(c)(2)(ii)(B) and 600.80(c)(2)(ii)(B), excluding any
previously submitted nonexpedited ICSRs. All ICSRs must be submitted electronically
in a format FDA can process, review, and archive as described §§ 314.80(g) and
600.80(h) .

•

A list of all ICSRs submitted during the reporting interval and their submission dates.

•

A narrative that identifies any changes made to the approved U.S. labeling based on new
information in the PSUR, as required under §§ 314.80(c)(2)(ii)(A)(3) and

________________________
10

Available at http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html.

11

The term step 4 refers to the point in the ICH process at which consensus is reached and the guideline is
recommended for adoption by the regulatory agencies.
12

81 FR 17009

13

78 FR 20926 (April 8, 2013).

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Contains Nonbinding Recommendations
600.80(c)(2)(ii)(A)(3), along with a copy of the U.S. labeling in effect on the data lock
point (DLP) 14 date.
FDA has routinely granted waivers to permit applicants to change the date of the DLP from the
U.S. approval date, as required under §§ 314.80(c)(2)(i) and 600.80(c)(2)(i), to a different date
for harmonization purposes. These waivers have been granted on the condition that the applicant
ensures that there are no gaps in reporting resulting from the date change. FDA has also
permitted applicants to include multiple products with the same active moiety or active
ingredient in a single report as recommended in the ICH E2C(R1) guidance.
Generally, FDA has not waived the reporting frequencies required under §§ 314.80(c)(2)(i) and
600.80(c)(2)(i). However, FDA has permitted applicants to submit PSURs at longer intervals,
consistent with the ICH guidelines, on the condition that the applicant submit a periodic safety
report as needed to fulfill the reporting frequency requirements.
Example: FDA granted an applicant a waiver to submit a PSUR for its drug product
every 3 years. FDA granted this waiver on the condition that the applicant also submit
an annual PADER for years 1 and 2 of the 3-year PSUR cycle.
III.

PROCEDURES APPLICANTS SHOULD FOLLOW TO SUBMIT A PBRER
A.

Applicants With a PSUR Waiver

If applicants already have a PSUR waiver for an approved application, FDA will consider the
existing PSUR waiver to permit applicants to submit a PBRER instead of a PSUR under the
conditions described below, because the PBRER replaces the PSUR for postmarketing periodic
safety reporting. If applicants wish to substitute the PBRER for the PSUR with no changes in
the DLP or frequency of reporting, applicants can do so without submitting a new waiver
request. However, if applicants wish to change any conditions of their PSUR waiver other than
the format, applicants should submit either a notification or new waiver request, depending on
the circumstances described below.
1.

Change in the Date of the DLP for the PBRER – Submit Notification

If applicants wish to use a DLP date for the PBRER that is different than the DLP date used
for the PSUR, applicants should ensure there are no gaps in reporting intervals resulting from
the change in DLP. Examples of appropriate alternatives include the following:
•
•
•

Submit overlapping reports to cover the gap.
Submit a one-time PADER/PAER to cover the gap.
Extend the reporting interval of the applicant’s upcoming PADER/PAER by up
to 3 months to cover the gap.

14

The term data lock point refers to the date designated as the cut-off for data to be included in the PSUR or
PBRER.

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Contains Nonbinding Recommendations

Applicants should submit written notification to the application(s), indicating the change in
DLP date and describing the measures taken to ensure that there are no resulting gaps in
reporting.
2.

Longer PBRER Reporting Intervals But No Change in Frequency – Submit
Notification

If applicants wish to submit the PBRER less frequently than is permitted under their PSUR
waiver, the continued validity of the applicant’s waiver will be conditioned on the applicant’s
submission of a PADER/PAER as needed to fulfill the reporting frequency requirement under
our regulations.
Applicants should submit written notification to the application, indicating this change and
describing the measures taken to ensure that the periodicity requirements are being met.
Example: If the applicant’s PSUR waiver specifies annual PSUR submission but the
applicant wishes to submit a PBRER every 3 years, the applicant can substitute the
PBRER for the PSUR, provided the applicant submits a PADER/PAER for years 1
and 2 of the 3-year PBRER cycle to maintain the annual reporting frequency
required under the regulations and as specified in its PSUR waiver.
3.

Other Changes to the PSUR Waiver – Submit New Waiver

If applicants wish to change any other condition of their PSUR waiver beyond what is
described in sections III.A.1 and III.A.2 above, then applicants should submit a new waiver
request. For example, a new waiver request should be submitted to change the overall
reporting frequency or to add or remove products covered by the report.
B.

Applicants Without a PSUR Waiver

If applicants do not already have a PSUR waiver and wish to submit in the PBRER format, a
waiver request must be submitted under § 314.90(a) or 600.90(a) in order to submit a PBRER
instead of the PADER/PAER (PBRER waiver). In accordance with the ICH E2C(R2) PBRER
guidance, applicants can prepare a single PBRER for multiple products with the same active
moiety or ingredient.
If the applicant’s waiver request is for several products, the applicant can submit a single waiver
request letter that references multiple applications.
Each PBRER waiver request should include the following information:
1. The product name(s) and application number(s).
2. Email address and telephone number for the individual FDA may contact should the Agency
need additional information regarding the waiver request.
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Contains Nonbinding Recommendations
3. A brief description of the justification for the request.
4. The U.S. approval date for the product(s) and current reporting interval used.
5. The reporting interval of the last PADER/PAER submitted for the product(s).
6. The date of the DLP that applicants intend to use for each PBRER. If applicants propose a
DLP date other than one aligned to the U.S. approval date, applicants should describe their
plan to ensure there are no gaps in reporting intervals. Examples of appropriate alternatives
include:
•
•
•

Submitting overlapping reports to cover the gap;
Submitting a one-time PADER/PAER to cover the gap; or
Extending the reporting interval of the applicant’s final PADER/PAER by up to 3
months to close the gap.

7. The frequency with which applicants intend to submit reports.
The time period from the product’s U.S. approval date is less than or equal to 3 years:
Applicants can ask FDA to consider waiving the quarterly reporting requirement under §§
314.80(c)(2)(i) and 600.80(c)(2)(i), and instead propose to submit the PBRER less frequently
during this period (e.g., every 6 or 12 months). FDA will grant or deny the request on an
application-specific basis.
The time period from the product’s U.S. approval date is greater than 3 years:
Applicants must submit a postmarketing periodic safety report annually, as required under §§
314.80(c)(2)(i) and 600.80(c)(2)(i). Alternatively, applicants can submit a PBRER less
frequently on the condition that applicants also submit an annual periodic safety report in one
of the other acceptable formats (i.e., PADER/PAER or PSUR) as needed to fulfill the annual
requirement. See the example in section II.C.
IV.

SUBMITTING WAIVER REQUESTS

The applicant’s waiver request letter should be submitted to each of the applications for which a
waiver is being requested. Requests submitted electronically should be sent via FDA’s
Electronic Submissions Gateway (ESG) to the electronic common technical document (eCTD) 15
for the applications for which a waiver is being requested.
Requests submitted on paper should be sent to the appropriate address below:
For CDER-regulated drug and biological products:
Central Document Room
Center for Drug Evaluation and Research
Food and Drug Administration
15

Guidance for industry, Providing Regulatory Submissions in Electronic Format —Certain Human Pharmaceutical
Product Applications and Related Submissions Using the eCTD Specifications (May 2015).

6

Contains Nonbinding Recommendations
5901-B Ammendale Rd.
Beltsville, MD 20705-1266
For CBER-regulated biological products:
U.S. Food and Drug Administration
Center for Biologics Evaluation and Research
Office of Biostatistics and Epidemiology
Document Control Center
10903 New Hampshire Ave.
Bldg. 71, Rm. G112
Silver Spring, MD 20993-0002

V.

FORMAT, CONTENT, AND TIMING OF THE PBRER

When preparing and submitting the PBRER, the applicant should follow the format, content, and
timing recommendations described in the ICH E2C(R2) PBRER guidance.
As part of the applicant’s PBRER submission to FDA, the applicant should provide a list of all
ICSRs submitted during the reporting interval, a narrative that identifies any changes made to the
approved U.S. labeling, and a copy of the U.S. labeling in effect on the DLP, as specified in the
bulleted list in section II.C. Applicants must also electronically submit nonexpedited ICSRs
received during the reporting interval, as required under §§ 314.80(c)(2)(ii)(B) and
600.80(c)(2)(ii)(B), excluding any previously submitted nonexpedited ICSRs. 16,17
The applicant can submit 6-month and 12-month PBRERs within 70 calendar days following the
DLP, and the applicant can submit PBRERs covering a longer reporting interval within 90
calendar days following the DLP.

16

Draft guidance for industry, Providing Submissions in Electronic Format — Postmarketing Safety Reports
(June 2014). When final, this guidance will represent FDA’s current thinking on this topic.
17

Guidance for industry, Providing Submissions in Electronic Format — Postmarketing Safety Reports for Vaccines
(August 2015).

7