So, Your NDA Was Approved – Now What?!
Post-approval Responsibilities and Obligations
Lawrence Allan
Project Manager
Business Process Analysis Staff
Office of Program Operations, Office of New Drugs
CDER | US FDA
Regulatory Education for Industry (REdI) Annual Conference
August 25 - 28, 2020
FDA Disclaimer
The views and opinions presented here represent those
of the speaker and should not be considered to represent
official advice or guidance on behalf of the Food and Drug
Administration.
www.fda.gov 2
Learning Objectives
Postmarketing Regulatory Requirements
• Postmarketing safety reports, other post-approval reports,
waivers, and change of NDA ownership
Additional Post-Approval Activities
• Changes to an approved NDA (including pediatric assessments
and efficacy supplements), PMRs/PMCs, REMS, and SLCs
www.fda.gov 3
CME Challenge Question #1
True or False? US-based applicants only need to submit
Postmarketing 15-day ‘Alert reports’ for adverse drug
experiences that occur within the US.
A. True
B. False
www.fda.gov 4
CME Challenge Question #2
Which of the following information does NOT need to be
included in the NDA annual report?
A. The quantity of the drug product distributed
B. PMR/PMC status reports
C. Summaries of completed unpublished clinical trials
D. Current pricing data
www.fda.gov 5
CME Challenge Question #3
Once a CBE 30 labeling supplement has been approved,
how long does an applicant have to implement the
changes to the promotional labeling and advertising?
A. It must be updated promptly
B. 15 Days
C. One month
D. Prior to submitting the next NDA annual report
www.fda.gov 6
Postmarketing Regulatory
Requirements
www.fda.gov 7
21 CFR 314.80(b)
Review of adverse drug experiences
• Must review any adverse drug experience (ADE) information
obtained/received, regardless of the source
• Must also develop written procedures for the surveillance,
receipt, evaluation, and reporting of postmarketing ADEs to the
FDA
www.fda.gov 8
21 CFR 314.80 (c)(1)
Postmarketing 15-day ‘Alert reports’
• Must report all serious AND unexpected ADEs, whether foreign or
domestic, within 15 calendar days of receipt as an initial Alert
Report
• If new information becomes available concerning a previously
reported ADE, must submit a follow up Alert Report within 15
calendar days
• Also applies to nonapplicants (e.g., manufacturers, packers, or
distributors) that appear in the approved product labeling
www.fda.gov 9
21 CFR 314.80 (c)(2)
Periodic adverse drug experience reports
• Applicants must provide PADERs on a quarterly basis for 3 years
post-approval and then annually afterwards
• Includes narrative summaries and analyses of the ADEs, history of
any actions taken as a result of ADEs (e.g., labeling changes, ‘Dear
Doctor’ letters), and a status update on clinical trials
• Applicants may request to submit a Periodic Benefit-Risk
Evaluation Report (PBRER) in lieu of PADER
www.fda.gov 10
21 CFR 314.81
Other Postmarketing Reports
• NDA field alert report – 21 CFR 314.81(b)(1)
• Annual report – 21 CFR 314.81(b)(2)
• Advertisements and promotional labeling – 21 CFR 314.81(b)(3)(i)
• Special reports – 21 CFR 314.81(b)(3)(ii)
• Notification of a permanent discontinuance or an interruption in
manufacturing – 314.81(b)(3)(iii)
www.fda.gov 11
21 CFR 314.90
Waivers
• Can request a waiver from any of the requirements outlined in
314.50 through 314.81
• May also request a waiver from any of the criteria of “…an
adequate and well-controlled study…”
• Must contain sufficient justification why compliance with the
requirement is unnecessary or cannot be achieved, OR a
description of any alternative(s) to satisfy the purpose of the
requirement, OR any other info supporting the waiver request
www.fda.gov 12
21 CFR 314.72
Change in ownership of an application
• Former owner provides documentation that states that all rights
to the application have been transferred to the new owner
• New owner agrees to adhere to any agreements, promises, and
conditions contained in the approved application and verifies the
effective date of ownership
• Confirms receipt of a complete copy of the approved application
• Informs the FDA about any changes in conditions of the approved
application as per 314.70
www.fda.gov 13
Additional Post-approval Activities
www.fda.gov 14
21 CFR 314.70(a)
Changes to an approved NDA
• Must notify FDA of any change(s) to an approved NDA and any
revisions must be described “fully”
• For manufacturing changes, must also assess the effects of the
proposed alteration(s) before distribution of the product
• For labeling changes, must promptly revise all promotional
labeling and advertising to ensure consistency with the updates
• Confirmation that a field copy has been provided to the
applicable FDA district office (except for labeling changes)
www.fda.gov 15
21 CFR 314.70(b)
Changes requiring supplement submission and approval
prior to distribution of the product made using the change
(major changes)
• AKA – Prior Approval Supplement (PAS)
• Any proposed changes that have the potential to substantially
impact the safety/effectiveness of the product
• Review timelines depend on the supplement type (PDUFA goal)
• Can request a expedited review, if circumstances warrant
www.fda.gov 16
21 CFR 314.70(c)
Changes requiring supplement submission at least 30 days
prior to distribution of the drug product made using the
change (moderate changes)
• AKA – Changes Being Effected in 30 Days (CBE 30) supplement
• Submitted at least 30 days prior to distribution of modified product and
includes appropriate information to assess the effects of the change
• Product cannot be distributed if the applicant is informed within 30
days of receipt that a PAS is required or if information is missing
• 21 CFR 314.70(c)(6) - Changes Being Effected (CBE 0) supplement
www.fda.gov 17
21 CFR 314.70(d)
Changes to be described in an annual report (minor
changes)
• Does NOT require a separate submission to the FDA; only need to
be included in the NDA annual report
• Refer to the relevant sections of 314.70 and the Guidance for
Industry – Changes to an Approved NDA or ANDA – Apr 2004 for
additional examples
• FDA makes final determination on reporting category (PAS vs. CBE
vs. AR changes)
www.fda.gov 18
Efficacy Supplement
A supplement to an approved NDA proposing to make
one or more related changes from among the following
changes to product labeling:
• Add or modify an indication or claim; revise the dose or dose
regimen; provide for a new route of administration; make a
comparative efficacy claim naming another drug product;
significantly alter the intended patient population; change the
marketing status from prescription to over-the-counter use;
provide for, or provide evidence of effectiveness necessary for,
the traditional approval of a product originally approved under
subpart H of this part; or incorporate other information based on
at least one adequate and well-controlled clinical study
www.fda.gov 19
Section 505(B) of the FD&C Act
Pediatric Assessments
• Each application for a new active ingredient, new indication, new
dosage form, new dosing regimen, or new route of administration
shall contain data that are adequate to assess the safety and
effectiveness of the product for the claimed indication(s), and to
support dosing and administration for relevant pediatric
subpopulations
• Applicants may request a deferral or waiver (full or partial) from
these requirements
www.fda.gov 20
Section 505(O)(3) of the FD&C Act
Postmarketing Studies/Clinical Trials
• FDA can require at the time of approval that an applicant conduct
further postmarketing studies/clinical trials, and may also require
the applicant to initiate studies/clinical trials for an approved
product if new safety/serious risk information becomes available
• FDA must determine that adverse event reporting under section
505(k)(1) and the active postmarketing risk identification and
analysis system per section 505(k)(3) would be insufficient before
requiring postmarketing studies/clinical trials be conducted
www.fda.gov 21
Postmarketing Requirement (PMR)
• Postmarketing studies or clinical trials to assess a serious risk that
the applicant is required to conduct either following initial
product approval, or if a serious risk is identified post-approval
• PMR describes the study/clinical trial to be conducted to ensure
that the study/clinical trial is well designed and adequate, and
provides a milestone timetable for completion
• PMRs can be applied to products approved under the Animal
Efficacy Rule or accelerated approval, studies required under the
PREA, and for safety studies/clinical trials required under FDAAA
www.fda.gov 22
Postmarketing Commitment (PMC)
• Postmarketing studies or clinical trials that the applicant has
agreed to conduct following initial product approval
• These are studies or clinical trials concerning issues related to
clinical safety or efficacy, clinical pharmacology, nonclinical
toxicology, and/or product quality that don’t meet the statutory
purposes for PMRs
• Applicant is required to provide updates on the status of ALL
PMRs and certain PMCs in their annual report
• FDA maintains a publicly available webpage of these PMRs/PMCs
www.fda.gov 23
Section 505-1 of the FD&C Act
Risk Evaluation and Mitigation Strategies (REMS)
• Designed to focus on preventing, monitoring and/or managing a
specific serious risk by informing, educating and/or reinforcing
actions to reduce the frequency and/or severity of the event
• A required risk management plan can include one or more
elements to ensure that the benefits of using a product outweigh
the risks associated with it
• REMS may be released or modified if it’s subsequently
determined that the extra measures are no longer necessary
www.fda.gov 24
Section 505(O)(4) of the FD&C Act
Safety Labeling Changes
• Can require applicants to make safety labeling changes (SLC)
based on new safety information that becomes available after
approval of the product; must notify applicant in writing
• May include (but not limited to) updates to the BOXED
WARNINGS, CONTRAINDICATIONS, WARNINGS AND
PRECAUTIONS, DRUG INTERACTIONS, and ADVERSE REACTIONS
labeling sections
• If the labeling is changed, any REMS may need to be modified
www.fda.gov 25
Summary
Postmarketing Regulatory Requirements
• Postmarketing safety reports, other post-approval reports,
waivers, and change of NDA ownership
Additional Post-Approval Activities
• Changes to an approved NDA (including pediatric assessments
and efficacy supplements), PMRs/PMCs, REMS, and SLCs
www.fda.gov 26
CME Challenge Question #1
True or False? US-based applicants only need to submit
Postmarketing 15-day "Alert reports“ for events that
occur within the US.
A. True
B. False
www.fda.gov 27
CME Challenge Question #2
Which of the following information does NOT need to be
included in the NDA annual report?
A. The quantity of the drug product distributed
B. PMR/PMC status reports
C. Summaries of completed unpublished clinical trials
D. Current pricing data
www.fda.gov 28
CME Challenge Question #3
Once a CBE 30 labeling supplement has been approved,
how long does an applicant have to implement the
changes to the promotional labeling and advertising?
A. It must be updated promptly
B. 15 Days
C. One month
D. Prior to submitting the next NDA annual report
www.fda.gov 29
Resources
• Electronic Code of Federal Regulations (eCFR) webpage
• FDA Guidance Documents webpage
• CDER Manual of Policies & Procedures (MaPPs) webpage
• Guidance for Industry: Providing Postmarketing Periodic Safety Reports in the ICH
E2C(R2) Format (Periodic Benefit-Risk Evaluation Report) – Nov 2016
• Pediatric Product Development webpage
• Guidance for Industry: Changes to an Approved NDA or ANDA – Apr 2004
• Guidance for Industry: Submitting Separate Marketing Applications and Clinical Data
for Purposes of Assessing User Fees – Jan 2005
• Guidance for Industry: Postmarketing Studies and Clinical Trials – Implementation of
Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act – Oct 2019
www.fda.gov 30
Resources
• Guidance for Industry: Reports on the Status of Postmarketing Study Commitments –
Implementation of Section 130 of the Food and Drug Administration Modernization
Act of 1997 – Feb 2006
• Postmarket Requirements and Commitments webpage
• Guidance for Industry: FDA’s Application of Statutory Factors in Determining When a
REMS Is Necessary – Apr 2019
• Guidance for Industry: Format and Content of a REMS Document – Oct 2017
• Risk Evaluation and Mitigation Strategies (REMS) webpage
• Approved Risk Evaluation and Mitigation Strategies (REMS) webpage
• Guidance for Industry: Safety Labeling Changes – Implementation of Section
505(o)(4) of the FD&C Act – Jul 2013
• Drug Safety-related Labeling Changes (SrLC) webpage
www.fda.gov 31
Thank you!
Questions?
Lawrence Allan
Project Manager
Business Process Analysis Staff
Office of Program Operations, Office of New Drugs
CDER | US FDA
Regulatory Education for Industry (REdI) Annual Conference
August 25 - 28, 2020
