
[Federal Register Volume 84, Number 32 (Friday, February 15, 2019)]
[Notices]
[Pages 4478-4479]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-02364]



[[Page 4478]]

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

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2018-N-4414]


Established Conditions; Pilot Program

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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

SUMMARY: The Food and Drug Administration (FDA or Agency), Center for 
Drug Evaluation and Research (CDER) is announcing the opportunity for a 
limited number of applicants to participate in an Established 
Conditions Pilot Program, to propose explicit established conditions 
(ECs) as part of an original new drug application (NDA), abbreviated 
new drug application (ANDA), biologics license application (BLA), or as 
a prior approval supplement (PAS) to any of these. The concept of ECs 
was first described in the FDA draft guidance for industry entitled 
``Established Conditions: Reportable CMC Changes for Approved Drug and 
Biologic Products'', issued May 2015 and has been further discussed in 
the International Council for Harmonisation (ICH) draft guidance for 
industry entitled ``Q12 Technical and Regulatory Considerations for 
Pharmaceutical Product Lifecycle Management; International Council for 
Harmonisation'', issued May 30, 2018. FDA is implementing this pilot 
program to gain experience receiving, assessing, and engaging with 
applicants regarding proposed ECs (i.e., explicit ECs).

DATES: FDA will accept nine requests submitted before May 30, 2019 from 
applicants intending to submit NDAs, ANDAs, or BLAs, either original 
applications or prior approval supplements, with proposed ECs.

FOR FURTHER INFORMATION CONTACT: Ashley Boam, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave. Silver Spring, MD 20993, 301-796-6341, CDER-OPQ-Inquiries@fda.hhs.gov.

SUPPLEMENTARY INFORMATION: 

I. Background

    The concept of ECs was first described in the FDA draft guidance 
for industry entitled ``Established Conditions: Reportable CMC Changes 
for Approved Drug and Biologic Products'' (hereafter, ``FDA guidance'') 
issued May 2015 (80 FR 31050) and has been further discussed in the ICH 
draft guidance for industry entitled ``Q12 Technical and Regulatory 
Considerations for Pharmaceutical Product Lifecycle Management; 
International Council for Harmonisation'', (hereafter ``ICH Q12 
guidance'') issued May 30, 2018 (83 FR 25018).
    The regulations at Sec. Sec.  314.50(d)(1), 314.54(a)(1), and 
314.94(a)(9) (21 CFR 314.50(d)(1), 314.54(a)(1), and 314.94(a)(9)) 
require that any NDA or ANDA submitted to the Agency contain a 
chemistry, manufacturing, and controls (CMC) section that describes 
information such as the composition of the drug product, manufacture of 
the drug substance, and manufacture of the drug product. Similarly, 
under Sec.  601.2 (21 CFR 601.2), applicants submitting BLAs must also 
provide relevant CMC information, such as a full description of 
manufacturing methods and data establishing stability of the product 
through the dating period.
    All changes after approval of an application must be managed and 
executed in conformance with current good manufacturing practice 
(CGMP), although Sec. Sec.  314.70(a) and 601.12(a) only require a 
subset of changes to be reported to the FDA. Sections 314.70(a)(1)(i) 
and 314.97 require that, other than the exceptions or alternatives 
provided in Sec.  314.70(a)(1)(ii), an applicant notify FDA about each 
change in each condition established in an approved NDA or ANDA beyond 
the variations already provided for in the approved application. Per 
Sec.  601.12(a)(1), an applicant must inform FDA about each change in 
the product, production process, quality controls, equipment, 
facilities, responsible personnel, or labeling established in the 
approved BLA.
    After approval of an application, applicants desiring to make 
changes to this CMC information must evaluate the changes in the 
context of the regulations to determine if there is a need to report 
the change and associated supporting data and justifications to FDA. 
Although the reporting mechanism for many CMC changes has been made 
clear through publication of various guidance documents, FDA issued its 
draft guidance on ECs due to concern that there is confusion regarding 
which elements of an application are considered to be ECs. This 
confusion could have a negative impact on change management activities 
and could discourage continual improvement in product manufacturing 
processes, lead to unnecessary submission of postapproval supplements 
to FDA for changes that could be managed solely by a manufacturer's 
Pharmaceutical Quality System, or, upon inspection, lead to Form FDA 
483 observations for changes that should have been reported to FDA. 
Moreover, a better understanding of which elements of the CMC 
information constitute ECs to FDA, and where in an application these 
elements are generally expected to be described, could allow for a more 
effective postapproval submission strategy (e.g., effective use of risk 
management principles in ICH Q9 ``Quality Risk Management,'' and 
knowledge management as defined in ICH Q10 ``Pharmaceutical Quality 
System'') by the regulated industry.
    In the FDA draft guidance, ECs are defined as the description of 
the product, manufacturing process, facilities and equipment, and 
elements of the associated control strategy, as defined in an 
application, that assure process performance and quality of an approved 
product. Changes to the ECs must be reported to FDA (Sec. Sec.  314.70 
and 601.12). This definition is consistent with the ICH Q12 guidance, 
which states that ``ECs are legally binding information (or approved 
matters) considered necessary to assure product quality. Consequently, 
any change to ECs necessitates a submission to the regulatory 
authority.''
    Although each application submitted to the Agency contains ECs, as 
described in Sec. Sec.  314.70(a) and 601.12(a), FDA has not 
specifically indicated the applicable ECs for each application at the 
time of approval. In addition, the draft ICH Q12 guidance describes how 
an applicant can specifically identify and propose so-called 
``explicit'' ECs in which the EC itself or the reporting category for 
the EC, if changed, differs from existing requirements as described in 
regulations and guidance. Such explicit ECs should be supported by an 
appropriate justification that takes into consideration the applicant's 
development approach and risk to product quality. FDA recognizes that 
this process will be new for both applicants and Agency staff. 
Therefore, FDA is proposing this pilot program.

II. Objectives

    The objectives of this pilot program are to gain practical 
experience in:
     Assessing proposed ECs (i.e., explicit ECs);
     engaging with applicants during the review cycle to refine 
proposed ECs;
     ensuring assessment decisions are made without negatively 
impacting the ability to meet user fee timeframes; and
     identifying agreed-upon ECs at the time of approval.
    FDA further encourages applicants who are accepted into this pilot 
program to pursue pre-submission meetings (pre-NDA, pre-BLA, or pre-
ANDA, where

[[Page 4479]]

appropriate) through existing mechanisms. See, for example, FDA draft 
guidances entitled ``Formal Meetings Between the FDA and Sponsors or 
Applicants of PDUFA Products and Formal Meetings Between the FDA and 
Sponsors or Applicants of BsUFA Products'' (once final, these guidance 
documents will represent FDA's current thinking on these topics) to 
improve the likelihood that a list of agreed-upon ECs can be reached 
prior to application approval. Although FDA's Center for Biologics 
Evaluation and Research (CBER) is not participating in this pilot, CBER 
intends to leverage CDER's experience from the pilot as CBER assesses 
explicit ECs in future submissions.

III. Requests To Participate

    Parties who have an interest in participating in this Established 
Conditions Pilot Program and who plan to propose explicit ECs in an 
upcoming marketing application should submit a written request to the 
CDER-OPQ-Inquiries@fda.hhs.gov mailbox. The request should specify the 
request to participate in the Established Conditions Pilot Program.
    The request should also include the following items:
    1. The contact person's name, company name, and company contact 
information.
    2. The proposed application type (NDA, ANDA, BLA; original or 
supplement).
    3. The established name of the proposed product and a brief 
description (e.g., dosage form, indication).
    4. Plans for any pre-NDA, pre-BLA, or pre-ANDA meetings to take 
place prior to application submission. Requests for such meetings 
should follow previously established procedures as outlined in relevant 
guidance documents.
    5. Expected timing for submission of the application. The 
submission should be planned for receipt by FDA no later than July 1, 
2019.
    6. Acknowledgement that participation in the pilot program may be 
discontinued if the manufacturing facilities named in the application 
are not in a state of compliance with CGMP at the time of the 
application submission.
    We intend to accept nine requests that meet the criteria above and 
represent a variety of application types, as Agency resources allow. 
FDA expects to notify companies of its decision regarding acceptance 
into the pilot program in writing within 60 days of receipt of the 
request. Although incomplete and/or unclear requests will generally be 
denied, FDA may contact the applicant to request additional 
information.
    FDA intends to accept requests to participate starting on the date 
of publication of this notice.

IV. Paperwork Reduction Act of 1995

    This notice refers to previously approved collections of 
information found in FDA regulations. These collections of information 
are subject to review by the Office of Management and Budget (OMB) 
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520).
    The collections of information in 21 CFR part 314 for submitting 
NDAs and ANDAs have been approved under OMB control number 0910-0001, 
and the collections of information in 21 CFR part 601 for submitting 
BLAs has been approved under OMB control number 0910-0338.
    FDA also has OMB approval under control number 0910-0429 for 
submissions under the guidance for industry entitled ``Formal Meetings 
Between the FDA and Sponsors or Applicants,'' and under the guidance 
for industry ``Controlled Correspondence Related to Generic Drug 
Development'' (OMB control number 0910-0797).

V. References

    The following references are on display in the Dockets Management 
Staff (see ADDRESSES) and are available for viewing by interested 
persons between 9 a.m. and 4 p.m., Monday through Friday; these are 
also available electronically at https://www.regulations.gov. FDA 
verified the website addresses, as of the date this document publishes 
in the Federal Register, but websites are subject to change over time.

1. FDA draft guidance for industry entitled ``Established 
Conditions: Reportable CMC Changes for Approved Drug and Biologic 
Products'' (May 2015), available at https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm448638.pdf.
2. FDA draft guidance for industry entitled ``ICH Q12 Technical and 
Regulatory Considerations for Pharmaceutical Product Lifecycle 
Management'' (May 2018), available at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM609205.pdf.
3. FDA draft guidance for industry entitled ``Formal Meetings 
Between the FDA and Sponsors or Applicants for PDUFA Products'' 
(December 2017), available at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM590547.pdf.
4. FDA draft guidance for industry entitled ``Formal Meetings 
Between the FDA and Sponsors or Applicants of BsUFA Products'' (June 
2018), available at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM609662.pdf.
5. FDA draft guidance for industry entitled ``Controlled 
Correspondence Related to Generic Drug Development'' (November 
2017), available at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM583436.pdf.

    Dated: February 11, 2019.
Lowell J. Schiller,
Acting Associate Commissioner for Policy.
[FR Doc. 2019-02364 Filed 2-14-19; 8:45 am]
 BILLING CODE 4164-01-P


