Office of Generic Drugs
Division of Project Management (DPM): Things
That Make You Go Hmmmm
1.
2.
3.
4.
5.
Form FDA 356h: Joe Shin, PharmD
Secure Email: Mandy Kwong, PharmD
Transfer of Ownership (TOO): Megan Tychinski, PharmD, CAPM
ANDA Consolidation: Kathleen Melendez, RPh
Endorsement/Clearance Phase: CDR Lakeeta Carr, MSN/MHA,
BSN, RN, NE-BC
6. Withdrawal Process: Tre Ferguson, PharmD
1
DPM: Things That Make You Go
Hmmmm
----Form FDA 356h--Joe Shin, Pharm.D.
Regulatory Project Manager
Division of Project Management
Office of Regulatory Operations
Office of Generic Drugs, FDA
Form FDA 356h
3
Purpose of Form FDA 356h
• Accompanies regulatory submissions to new drug
applications (NDAs), biologic license applications
(BLAs), abbreviated new drug applications (ANDAs),
and supplements
• Describes the reason for, and content of, the
submission
• Captures information used to populate FDA
systems
4
Regulation
21 CFR 314.94 (a)(1):
The applicant shall submit a completed and signed
application form that contains the information described
under CFR 314.50(a)(1), (a)(3), (a)(4), and (a)(5). The
applicant shall state whether the submission is an
abbreviated application under this section or a
supplement to an abbreviated application under CFR
314.97.
5
Sections of Form FDA 356h
• There are 4 sections to the FDA 356h form
– Applicant Information
– Product Description
– Application Information
– Certification
6
Applicant Information
• Applicant
Information section:
– Fields 2-6
7
Applicant Information
•
Common Issues:
– Field 2: Name of Applicant
• Inconsistency of Applicant
name (e.g. Acme Drugs and
Acme Drugs, Inc. are
considered separate companies
by our Document Room)
– Field 6: Authorized U.S. Agent
• Required for non-U.S.
applicants. See 21 CFR 314.50
(a)(5)
• Include the name of the
individual along with their
company name.
• Provide a secure email address
• Phone number (should include
extension if applicable)
8
Product Description
• Product Description
section:
– Fields 7-15
9
Product Description
• Common Issues:
– Field 9: Established Name
• Ensure proper use of the USP
name
– Field 11:
Chemical/Biochemical/Blood Product
Name (If any)
• Provide chemical name (e.g. 2[(2,6-dichlorophenyl)amino]benzeneacetic, monosodium
salt)
– Field 13: Strengths
• “Injections” or “for Injection”
drug products, include total
strength and fill volume in
addition to mg/ml
10
Application Information
• Application
Information section:
– Fields 16-31
11
Application Information
• Common Issues:
– Field 20: Identify the listed
drug product that is the basis
for the submission
• Fill in the name of the RLD
and its application number
• Ensure that the patent
certification checkboxes
are complete and accurate.
This should match
information found in
Module 1.3.5.
12
Application Information
• Common Issues cont.:
– Field 29: Establishment Information
• List all facilities associated with
the manufacturing, packaging,
and control sites for both drug
substance and drug product
• Provide accurate address
information for all establishments.
• Provide accurate FEI and DUNS
numbers
13
Application Information
• Common Issues cont.:
– Field 29: Establishment Information
• Select appropriate checkbox for
establishment status
– Pending: New
establishments at time of
submission
– If not a new establishment,
indicate current status (e.g.
active, inactive, or
withdrawn).
14
Application Information
• Common Issues cont.:
– Field 29: Establishment Information
• Establishment contact person
should be an individual at the site,
not a corporate office or the U.S.
Agent.
• Provide accurate telephone
number for the contact person.
• Provide a brief description of the
manufacturing steps and/or types
of testing conducted at the site.
– Field 30: Cross References
• Should include all cross
references, including all DMFs
15
Certification
• Certification section:
– Fields 32-39
16
Certification
•
Common Issues:
– Field 32: Name & Title of Applicant’s
Responsible Official
• This individual is responsible for
certifying compliance with
applicable laws and regulations.
• U.S. Agent from Field 6 may also act
as the applicant’s Responsible
Official.
– Field 38 & 39: Signature &
Countersignature
• If the applicant’s Responsible Official
does not reside or have a place of
business within the U.S. then Field
39 must be countersigned by an
attorney, agent, or authorized
official who does reside or have
business within the U.S.
17
Possible Consequences
1. For Initial ANDA submissions, failure to include a
complete and signed Form FDA 356h may result in a
refuse-to-receive notification.
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Possible Consequences – Cont. 2
2. If FDA discovers during technical review that the
applicant failed to identify all facilities on the
Form FDA 356h, the applicant will be asked to
update the Form FDA 356h in an IR or CRL.
– If the facility requires an inspection, a 10-month
review goal may be added to the review of the IR
or CR amendment.
19
Possible Consequences – Cont. 3
3. For amendments and resubmissions, an
incomplete Form FDA 356h may require
further communication with the applicant to
provide updated and complete Form FDA 356h
forms leading to delays in review.
20
Takeaways
• Clearly complete and update the Form FDA 356h
with every submission
• Follow the Instructional Supplement for proper
completion of the Form FDA 356h
• Ensure that the most up-to-date version of the
Form FDA 356h is being utilized.
21
Takeaways – Cont.
• Provide accurate contact information for the
applicant’s Responsible Official and/or U.S. Agent
• Include complete information on the locations of
all manufacturing, packaging, and control sites for
both drug substance and drug product
22
References
•
•
•
Regulations:
– 21 CFR 314.94(a)(1)
– 21 CFR 314.50 (a)(1), (a)(2), (a)(3), (a)(4), & (a)(5)
– 21 CFR 314.101 (d)(1)
Forms:
– Form FDA 356h
(http://inside.fda.gov:9003/downloads/administrative/forms/fda/ucm00820
9.pdf)
– Form FDA 356h Supplement
(http://inside.fda.gov:9003/downloads/administrative/forms/fda/ucm32189
8.pdf)
Guidances:
– ANDA Submission-Refuse-to-Receive Standards: Guidance for Industry
(http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformati
on/guidances/ucm370352.pdf)
23
DPM: Things That Make You Go
Hmmm
----Secure Email--Lt. Mandy C. Kwong, PharmD
Regulatory Project Manager- Team Leader
Division of Project Management
What is Secure E-mail?
• FDA uses Secure E-mail Technology to safeguard
confidential information, and help protect our
machines against incoming e-mail threats or
otherwise harmful, unsolicited e-mail.
www.fda.gov
25
FDA Secure Email Partners
• You are strongly encouraged to become a
Secure Email Partner
• Why?
– Ensure that our messages will not be readable by a
third-party
– E-mails are only secure if they are sent to a Secure
E-mail partner
www.fda.gov
26
FDA Secure Email Partners
• Allows for TIMELY informal communications
that may include commercial confidential
information (CCI)
– If we are unable to confirm that your email is
secure, we will send the communication containing
any CCI via mail or fax
27
FDA Secure Email Partners
Must be a business email address
We cannot secure internet service provider
accounts such as:
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Options for Setting Up Secure Email
1) S/MIME (Secure/Multipurpose Internet Mail
Extension) Encryption
2) Secure SMTP (Simple Mail Text Protocol) over
TLS (Transport Layer Security) Encryption
29
Options for Setting Up Secure Email
1) S/MIME Encryption
- More secure but more complex to set up
- Done at workstation-level (without e-mail administrators)
- Certificate will need to be repurchased/renewed once-a-year
- One year Digital ID costs $20.00 per person
- For each FDA user or mailbox you wish to securely
communicate with, a one-time setup process is required to
create an FDA Outlook contact and corresponding FDA proxy
certificate
- Set up time is as little as a few hours
- To set up, email [email protected]
www.fda.gov
30
Options for Setting Up Secure Email
2) Secure SMTP over TLS encryption
- A one year Digicert SSL certificate is $144. A three year
certificate is $345
- Configuration involves your email administrator
- Everyone at your organization will be able to send email
securely to the FDA
- Set up time can be a few days or longer, especially if your
email system is outsourced.
- To set up, email [email protected]
www.fda.gov
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S/MIME vs TLS
User
Computer
User
Mailbox
Company
Email
Server
Cloud /3rd
Party
Email
Internet
FDA
Server
S/MIME protection
TLS protection
User
Computer
User
Mailbox
Company
Email
Server
Internet
FDA
S/MIME protection
For additional questions, email
[email protected]
TLS protection
32
Things That Make You Go Hmmm…
Transfer of Ownership
Megan Tychinski, PharmD, CAPM
Regulatory Project Manager
Division of Project Management
Office of Generic Drugs, FDA
What is a Transfer of Ownership (TOO)?
• The Code of Federal Regulations section 314.99(a)
states that:
An applicant shall comply with the requirements of
314.65 regarding withdrawal by the applicant of an
unapproved abbreviated application and 314.72 regarding
a change in ownership of an abbreviated application.
• TOO: Change in ownership of an application
– Applicant A  Applicant B
– Subsidiaries
• Parent company  Subsidiary
• Subsidiary 1  Subsidiary 2
34
I have submitted my TOO…
What happens next?
• FDA Process
(1) Ensure all required information has been
submitted to the application
(2) Issue TOO Acknowledgement Letter to applicant
35
FDA Obstacle
• Ensuring all required information has been submitted
• 356h form(s)
• Transfer of ownership from former owner
• Acceptance of ownership from new owner
36
21 CFR 314.72
Change in ownership of an application
• (a) An applicant may transfer ownership of its
application. At the time of transfer the new and
former owners are required to submit
information to the Food and Drug
Administration as follows:
– (1) The former owner shall submit a letter or other
document that states that all rights to the
application have been transferred to the new owner.
37
21 CFR 314.72
Change in ownership of an application
• (2) The new owner shall submit an application form
signed by the new owner and a letter or other
document containing the following:
– (i) The new owner's commitment to agreements, promises, and
conditions made by the former owner and contained in the
application;
– (ii) The date that the change in ownership is effective; and
– (iii) Either a statement that the new owner has a complete copy of
the approved application, including supplements and records that
are required to be kept under 314.81, or a request for a copy of
the application from FDA's files. FDA will provide a copy of the
application to the new owner under the fee schedule in 20.45 of
FDA's public information regulations.
www.fda.gov
38
21 CFR 314.72
Change in ownership of an application
• (b) The new owner shall advise FDA about any change in the
conditions in the approved application under 314.70, except
the new owner may advise FDA in the next annual report
about a change in the drug product's label or labeling to
change the product's brand or the name of its manufacturer,
packer, or distributor.
39
To be noted…
• If the new owner requests a copy of the application, they
must make a Freedom of Information Act request.
– Directions found at:
http://www.fda.gov/RegulatoryInformation/FOI/HowtoMake
aFOIARequest/ucm2007229.htm
• If former and new owners provide separate submissions
for the transfer, a 356h form should be included with
each submission.
• If one submission is sent for the transfer that includes all
requirements, only one 356h form with the new owner’s
information is needed.
40
Withdrawn ANDAs
• An applicant’s decision to withdraw an ANDA
pursuant to 21 CFR 314.150(c) is without
prejudice to refiling.
• Once notice of withdrawal is published in the
Federal Register, withdrawal is final.
41
OGD Recommendations
• Submit TOO Amendment in a separate submission
– i.e. Do not combine with CR responses, other administrative
changes, etc.
• When submitting multiple TOOs:
– Ensure accuracy of information submitted to reduce processing
delays
– Please include a list of all ANDAs being transferred on each of the
cover letters
• List the ANDA # and the established name
– Ex. Atenolol Tablets USP, 25 mg, 50 mg, and 100 mg
• Contact RPM for all ANDA-specific questions
42
ANDA Consolidation
Kathleen Melendez, Pharmacist
Primary Filing Reviewer, ORO/DFR
Center for Drug Evaluation and Research
Office of Generic Drugs
U.S. Food and Drug Administration
43
Information needed to process the
request
• Submit a separate copy of the request for
consolidation to each ANDA applicable.
• Request submitted to the parent ANDA should
be identified as a “Correspondence.”
• Request submitted to the child ANDAs should
each be identified as “Request for
Consolidation.”
44
Identify all formulations and ANDAs
• Indicate that all inactive ingredients are
proportional for all formulations identified in
the request by including a chart of all
ingredients, quantity of the ingredient per
dosage form, and the weight to weight
percentage.
45
Submit a chart like this in the Cover Letter for each
ANDA submitted.
46
Provide BE documentation
• Provide documentation that BE studies were
performed.
• Provide documentation of any BE waivers
received.
47
Denial of the Request
The most common reasons for holds or denials:
• Pending supplements such as an open issue or
pending review.
• Consolidation requests should not be submitted
as a CBE-30. They should be submitted as a
Correspondence/Request for Consolidation.
48
Approval
• If all the information has been provided, and
there are no open issues or pending reviews
associated with the ANDAs, then the request for
consolidation will be approved.
49
For more information
• FDA MAPP 5241.2 describes FDA’s process for
reviewing and approving or denying requests to
consolidate previously approved ANDAs:
– http://www.fda.gov/aboutfda/centersoffices/officeofme
dicalproductsandtobacco/cder/manualofpoliciesproced
ures/default.htm
• MAPP stands for Manual of Policies and
Procedures.
• MAPPs describe internal policies and procedures
and are made available to the public to increase
transparency.
www.fda.gov
50
Endorsement/Clearance Phase
Lakeeta Carr, MSN/MHA, BSN, RN, NE-BC
Commander, United States Public Health Service
Regulatory Project Manager
Introduction
Endorsement/Clearance Phase
Divisions/Personnel Involved
Communication from FDA to You
52
Endorsement/Clearance Phase
What does
endorsement/clearance
phase mean?
www.fda.gov
53
Endorsement Phase
Final Decision
Division of
Legal &
Regulatory
Support
Labeling
Bioequivalence
(BE)
www.fda.gov
REMS
Quality
54
Division of Legal & Regulatory Support
Addressed all listed patents &
exclusivities
All grants of 180 day
exclusivity consistently
applied/compliant with
“Forfeiture Provisions” of
505(j)(5)(D)(I)-(VI) of FD&C
Act
Required documentation
related to patents &
exclusivities have been
provided
Consistent application of
Hatch Waxman policy &
precedents across applicants
Certifications/statements to
newly listed patents
All information required by
314.95(e)-notice
requirements and 314.107(e)court actions
Changes to certifications and
impact on labeling/timing of
approval
55
OGD Discipline Final Reviews
REMS
Labeling
Quality
BE
DMF &
Facilities
Statuses
Updated
BE
Guidance
* Applicant expected to keep all information updated
RLD
Labeling
Updates
56
Communication to Industry
On track to
provide
action
RPM May
request
assurance re:
labeling,
patent, Type II
DMF and
inspections if
applicable
Courtesy copy
to secure
email
Hard copy via
mail
Please note: Communication regarding action is not a guarantee of approval.
57
Conclusion
Endorsement/Clearance Phase
Divisions/Personnel Involved
Communication from FDA to You
58
DPM: Things that Make You Go Hmmm
Voluntary Withdrawal of Approved and
Unapproved ANDAs by Applicants
Presented by:
Wilbert (Tre’) Ferguson III, PharmD
Regulatory Project Manager
Food & Drug Administration
Office Of Generic Drugs
59
So you’ve decided to withdraw
your unapproved ANDA..what now?
www.fda.gov
60
What does the Code of Federal
Regulations have to say?
21 CFR 314.65 to be precise
• An applicant may at any time withdraw an
unapproved application by notifying the FDA in
writing.
• You may refile without prejudice.
• The agency will retain the application and will
provide a copy on request under the fee
schedule in 21 CFR 20.45.
61
Withdrawal of an unapproved ANDA
• The application is considered withdrawn on the
date of the request.
• Upon receipt of the request to withdraw an
unapproved ANDA from an applicant a
withdrawal acknowledgment letter will be
issued to the applicant.
• All pending reviews will be discontinued.
www.fda.gov
62
But what about approved ANDAs?
63
Back to the Code of Federal Regulations
this time its 21 CFR 314.150(c)
1. FDA will withdraw approval of an application if the
application is being withdrawn because the
product is no longer marketed, provided none of
the conditions in 314.150 (a) and (b) apply to the
drug.
2. If there are safety or efficacy issues please contact
the regulatory project manager for details. If there
are safety or efficacy issues, 21 CFR 314.150(c)
does not apply!
www.fda.gov
64
Back to the Code of Federal Regulations
this time its 21 CFR 314.150(c) – Cont’d
3. FDA will consider a written request for a
withdrawal to be a waiver of an opportunity for
hearing otherwise provided for in this section.
4. The applicant may refile without prejudice.
65
What else do we need to know about
withdrawing approval under 21 CFR
314.150(c)?
1. The withdrawal request should specify the products are
no longer marketed and request that FDA withdraw
approval of the application, including any supplements.
2. If the request does not include the withdrawal of any
pending supplements, the RPM will call the applicant to
confirm. If the applicant wishes to withdraw pending
supplements, the applicant will need to submit a revised
request to include them.
www.fda.gov
66
Withdrawal of an Approved ANDA
Under 21 CFR 314.150(c) - cont. 2
3. Once a complete request is received, a withdrawal
acknowledgment letter will be issued to the
applicant. Based on the applicant’s complete
request, the withdrawal acknowledgement may
include all pending submissions.
4. FDA will publish a notice in the Federal Register
(FR) announcing the withdrawal of the approval
(usually published with several other approvals of
applications being withdrawn).
67
Withdrawal of an Approved ANDA
Under 21 CFR 314.150(c) - cont. 3
5. The FR notice will note the effective date of
withdrawal, usually 30 days after the date of
publication of the notice.
6. Until the effective date of the FR notice the
application is not officially withdrawn and the
applicant must still comply with all regulatory
requirements including those set forth for an
approved ANDA in 21 CFR 314.80 and 314.81.
68
Withdrawal of an Approved ANDA
Things to consider
• If the applicant wants to
rescind the request to
withdraw the approved
ANDA it must be done prior
to the effective date of the
withdrawal published in the
Federal Register.
• It would be helpful if the
applicant lists all pending
supplements that they wish
to withdraw in the cover
letter including the
supplement number and
submission date.
69
That’s all Folks!!
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