Transcript Slide 1

Overview of FDA's Regulatory
Framework for PET Drugs
Ravindra K. Kasliwal, Ph.D.
Office of New Drug Quality Assessment
Center for Drug Evaluation and Research
U. S. Food and Drug Administration
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PET Drug Regulatory Framework
• PET Drug Current Good Manufacturing Practice
(CGMP) Regulations
• New Drug Application (NDA)
• Abbreviated New Drug Application (ANDA)
• Investigational / Research Studies with PET
Drugs
• Drug Master Files (DMF)
• Other PET Drug Information Resources
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PET CGMP Regulations
• FDA issued final rule for CGMP for PET
drugs (21 CFR part 212) in the Federal
Register of December 10, 2009 (74 FR
65409).
• FDA also announced the availability of a
guidance entitled ‘‘PET Drugs—Current
Good Manufacturing Practice (CGMP)”.
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CGMP Rule and Guidance
Availability
• PET CGMP Rule and Guidance are
available at
– http://www.fda.gov/Drugs/DevelopmentApprov
alProcess/Manufacturing/ucm085783.htm
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PET Drugs Regulatory Framework
• The 21 CFR part 212 regulation is effective
December 12, 2011.
– The regulation will become mandatory for PET drug
production on this day.
• Starting on this date, FDA will require the
submission of a new drug application (NDA) or
abbreviated new drug application (ANDA) for
any PET drug product marketed for clinical use
in the United States.
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Applicability of PET CGMP Regulations
21 CFR 212
• Current good manufacturing practices for PET drug
products are the minimum requirements for the methods
to be used in, and the facilities and controls used for, the
production, quality control, holding, or distribution of a
safe and effective PET drug product intended for human
use.
• After Dec 12, 2011, PET drugs marketed under an
approved new drug application (NDA) or an approved
abbreviated new drug application (ANDA) must be
produced in accordance with the requirements in 21
CFR 212.
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PET Drugs-IND and RDRC
• Producers of investigational PET drugs
(IND) and research PET drugs (RDRC):
– Option to follow the requirements in part 212 or to
produce PET drugs in accordance with USP Chapter
<823> ‘‘Radiopharmaceuticals for Positron Emission
Tomography— Compounding,’’ (USP 32/NF 27)
(2009).
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Current Regulation for PET Drug
Production
• Under section 501(a)(2)(C) of the Act, a
compounded PET drug is adulterated unless it is
produced in compliance with the USP’s PET
drug compounding standards and the official
monograph for the particular PET drug.
• As per the Modernization Act (section 121(b)),
section 501(a)(2)(C) of the Act will expire after
Dec 11, 2011.
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Investigational Studies
• All human investigational / research
studies must be performed:
– Under an IND (21 CFR 312)
– As RDRC approved study (21 CFR 361)
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Proposed 21 CFR 212
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Subpart A - General Provisions
Subpart B - Personnel and Resources
Subpart C - Quality Assurance
Subpart D - Facilities and Equipment
Subpart E - Control of Components, Containers, and Closures
Subpart F - Production and Process Controls
Subpart G - Laboratory Controls
Subpart I - Packaging and Labeling
Subpart J - Distribution
Subpart K - Complaint Handling
Subpart L - Records
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Laboratory Controls
• Establish specifications for each PET drug product
– Critical quality attributes (CQA) that are indicative of product’s
safety and effectiveness
• Before final release, conduct an appropriate laboratory
determination to ensure that each batch of a PET drug
product conforms to specifications, except for sterility
– Sterility is assured by process monitoring and controls, and
confirmed by end product testing (sterility test should be started
within 30 hours of end of production)
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Laboratory Controls
• Appropriate laboratory determination could
involve
– Finished product testing of each batch
– In-process testing of an attribute that is equivalent to
the finished-product testing of that attribute
– Continuous process monitoring of one or more
attributes with statistical process controls
• QbD, PAT
– Some combination of the above approaches
• Approach should be set forth in the product’s
marketing application
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Non-Critical Quality Attributes
• Some product attributes may not be critical to the safety
or efficacy of the product, but nevertheless are important
in assessing the ongoing quality of the product and to
assure that the manufacturing process is in control
– Radionuclidic purity (sometimes)
– Certain class 3 residual solvents
• When justified, these could be tested as periodic quality
indicator tests (PQIT)
– Performed at predetermined intervals rather than on a batch-tobatch basis
– Included in product's marketing application - listed separately
from the specification
– Established and refined under firm's internal quality system
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Final Release
• Final release can only occur after the completion of
laboratory determination to ensure conformance to
specifications (except for sterility)
• A product can be shipped under manufacturer’s control
while certain tests are undergoing
– The manufacturer must have a mechanism to recall (prevent
administration to a human subject) the lot that fails testing
• Results must be available and meet the acceptance
criteria before final release is granted and the product is
administered to a human subject
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Drug Registration and Listing of
PET Drug Producers
• All PET drug producers are required to register
before December 12, 2011
• Submit drug establishment and drug listing
information through electronic submissions
• Website for information
– http://www.fda.gov/Drugs/GuidanceComplianc
eRegulatoryInformation/DrugRegistrationandL
isting/default.htm
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NDAs and ANDAs
• FDA intends to soon finalize the guidance, “PET drug
Applications – Content and Format for NDAs and
ANDAs”.
• Draft guidance website:
http://www.fda.gov/downloads/Drugs/GuidanceComplian
ceRegulatoryInformation/Guidances/UCM078738.pdf
• Provides information to assist in preparing NDAs and
ANDAs for certain PET drugs (Fludeoxyglucose F 18
injection, Sodium fluoride F 18 injection and Ammonia N
13 injection).
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Types of NDAs
• 505(b)(1) – studies submitted for seeking
approval are performed by the applicant.
• 505(b)(2) - rely for approval on references to
studies conducted by others and/or on published
literature.
• Applicants submitting 505(b)(2) NDAs for PET
drugs can rely on the FDA's review of the
literature as described in the PET Safety and
Effectiveness Notice (65 FR, 12999) and/or on
previous approvals of PET drugs for certain
indications.
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Content and Format of NDAs
•
Current preferred format for submitting an application is the Common
Technical Document (CTD)
– Paper CTD or
– electronic CTD (E-CTD) format
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The items cited in the PET NDA / ANDA guidance should be organized in a
manner which corresponds to the modules of the CTD as indicated on the
Checklist
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Guidance:
– Submitting Marketing Applications According to the ICH-CTD Format —General
Considerations
– M4Q: The CTD — Quality; M4: The CTD — Quality Questions and Answers/
Location Issues
– website:
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/ucm065006.htm
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ANDAs
• ANDA is submitted for a drug that is same as RLD
• Approved NDAs (RLDs) exist for:
– Fludeoxyglucose F 18 injection
– Sodium fluoride F 18 injection
– Ammonia N 13 injection
• Same means that the proposed drug has identical
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Active ingredient(s),
Dosage form,
Strength,
Route of administration,
Conditions of use as its RLD (with certain exceptions)
Is bioequivalent to that RLD
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ANDA RESOURCES
• Office of Generic Drugs (OGD) webpage:
http://www.fda.gov/Drugs/GuidanceComplinceRegulatory
Information/Guidances/ucm064995.htm)
• Current preferred format for submitting an application to
the OGD is the Common Technical Document (CTD)
– Paper CTD or
– electronic CTD (E-CTD) format
– The twelve items cited in the PET NDA /ANDA guidance should
be organized in a manner which corresponds to the modules of
the CTD as indicated on the Checklist
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ANDA Questions?
• Contact the Office of Generic Drugs:
Martin H. Shimer
Branch Chief, Regulatory Support Branch
FDA, Office of Generic Drugs
240 (276-8419)
[email protected]
• Submit completed application to:
Director, Office of Generic Drugs
Center for Drug Evaluation and Research
Food and Drug Administration
Metro Park North II, Rm. 150
7500 Standish Place
Rockville, MD 20855
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IND Resources
• Regulations: 21 CFR 312
• Guidance:
– Content and Format of Investigational New Drug
Applications (INDs) for Phase 1 Studies of Drugs
• http://www.fda.gov/cder/guidance/phase1.pdf
– INDs for Phase 2 and Phase 3 Studies Chemistry,
Manufacturing, and Controls Information
• http://www.fda.gov/cder/guidance/3619fnl.pdf
– IND Meetings for Human Drugs and Biologics
Chemistry, Manufacturing and controls Information
• http://www.fda.gov/cder/guidance/3683fnl.pdf
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NDA and IND Questions?
Kyong "Kaye" Kang, Pharm. D.
Chief, Project Management Staff
Division of Medical Imaging and
Hematology Products
Office of Oncology Drug Products
(301) 796-2050 (office)
(301) 796-9849 (fax)
[email protected]
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Drug Master File (DMF)
• A DMF contains information about a drug
substance, a component, or a container/closure
system that is proprietary (i.e., belongs to
someone else)
– Type II - Drug substance, drug substance
intermediate, and materials used in their preparation,
or drug product
– Type III - Packaging materials
– Type IV - Excipient, colorant, flavor, essence, or
materials used in their preparation
– Type V - FDA accepted reference information
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Drug Master File (DMF)
• The information may not be available to you, but you
may need it as part of your NDA, ANDA.
• The chemistry section of Form FDA 356h may ask you to
provide this information.
• This information is usually available from the supplier or
manufacturer of the subject of the DMF.
• Rather than providing the information directly to you, the
manufacturer may choose to hold a DMF. The DMF
holder provides the information directly to the FDA
(submits DMF to FDA).
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DMF Reference
• If a manufacturer holds a DMF that you would
like to reference, you should ask them to provide
you with a letter of authorization (LOA), which
you must include with (and reference in) your
application and list on your Form 356h.
• LOA from the DMF holder grants the FDA
authorization to refer to information in their DMF
during the review of your NDA, ANDA or IND.
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Drug Master Files (DMF) Resources
• The regulatory requirements for a DMF-21 CFR 314.420
• Guidance:
– Guideline for Drug Master Files
• http://www.fda.gov/cder/guidance/dmf.htm
• Send all comments or questions regarding DMFs to
– [email protected].
– All inquiries MUST have an entry in the "Subject" field of the email
• Current DMF submission address:
Food and Drug Administration
Center for Drug Evaluation and Research
Central Document Room
5901-B Ammendale Road
Beltsville MD 20705-1266
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Web Resources for You
• NDA
http://www.fda.gov/Drugs/DevelopmentAp
provalProcess/HowDrugsareDevelopedan
dApproved/ApprovalApplications/NewDrug
ApplicationNDA/default.htm
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Web Resources for You
• ANDA
http://www.fda.gov/Drugs/DevelopmentAp
provalProcess/HowDrugsareDevelopedan
dApproved/ApprovalApplications/Abbreviat
edNewDrugApplicationANDAGenerics/def
ault.htm
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Web Resources for You
• IND
http://www.fda.gov/Drugs/DevelopmentAp
provalProcess/HowDrugsareDevelopedan
dApproved/ApprovalApplications/Investiga
tionalNewDrugINDApplication/default.htm
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User Fees
Waiver, Reduction, Refund or Questions
Michael Jones
Food and Drug Administration
10903 New Hampshire Ave, Building 51,
Room 6216
Silver Spring, MD 20993-0002
Phone: 301-796-3602
Email: [email protected]
Fax: 301-847-8711
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Conclusion
• PET Drug Regulatory Framework
– CGMP
– NDA
– ANDA
– IND and RDRC
– DMF
– Resources for Submitting and
application to CDER / FDA
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New Drug CMC Questions?
[email protected]
• Inquiries should have an entry in the "Subject"
field of the e-mail indicating the subject of the
question
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