CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`
`
`
`APPLICATION NUMBER:
`
`
`209472Orig1s000
`
`
`
`
`
`
`
`ADMINISTRATIVE and CORRESPONDENCE
`
`
`DOCUMENTS
`
`
`

`

`,,,~,
`
`<...:J.-.. DEPARTMENT OF HEALm AND HUMAN SERVICES
`
`PINO 126831
`
`Eagle Pharmaceuticals, Inc.
`Attention: Foma Rashkovsky
`Vice President, Regulatory Affairs
`50 Tice Boulevard, Suite 315
`Woodcliff Lake, NJ 07677
`
`Dear Mr. Rashkovsky:
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`MEETING MINUTES
`
`Please refer to your Pre-Investigational New Drug Application (PIND) file for Pemetrexed
`Injection, 25 mg/mL.
`
`We also refer to the teleconference between representatives of your firm and the FDA on January
`21, 2016. The purpose of the meeting was to discuss the proposed nonclinical study to qualify
`impurity and degradation products in the ready-to-dilute (RTD) product and the appropriateness
`to submit a waiver request for in vivo bioavailability studies in the New Drug Application
`(NDA).
`
`A copy of the official minutes of the teleconference is enclosed for your information. Please
`notify us of any significant differences in understanding regarding the meeting outcomes.
`
`If you have any questions, call me at (240) 402M6611.
`
`Sincerely,
`
`{See appended electronic signature page)
`
`Leah S. Her, M.S.
`Regulatory Health Project Manager
`Division of Oncology Products 2
`Office of Hematology and Oncology Products
`Center for Drug Evaluation and Research
`
`Enclosure:
`• Meeting Minutes
`
`Reference ID: 3889966
`Reference ID: 4662511
`
`

`

`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EV ALDA TION AND RESEARCH
`
`MEMORANDUM OF MEETING MINUTES
`
`Meeting Type:
`Meeting Category:
`
`B
`Pre-IND/Pre-ND A
`
`Meeting Date and Time:
`Meeting Location:
`
`January 21, 2016 I 12:00- 1:00 PM (EST)
`Teleconference
`
`126831
`Application Number:
`Pemetrexed Injection, 25 mg/mL
`Product Name:
`The same indications as approved for listed product Alimta
`Indication:
`Sponsor/Applicant Name: Eagle Pharmaceuticals, Inc.
`
`Meeting Chair:
`Meeting Recorder:
`
`Suzanne Demko
`Leah Her
`
`FDA ATTENDEES
`Joseph Gootenberg
`Gideon Blumenthal
`Barbara Scepura
`LeahHer
`Whitney Helms
`Anwar Goheer
`Joyce Crich
`Xing Wang
`Om Anand
`Joan Zhao
`Hong Zhao
`Sriram Subramaniam
`TamyKim
`
`Deputy Director, OHOP/DOP2
`Clinical Team Lead, OHOP/DOP2
`Clinical Reviewer, OHOP/DOP2
`Regulatory Project Manager, OHOP/DOP2
`Nonclinical Supervisor, OHOP/DHOT
`Nonclinical Reviewer, OHOP/DHOT
`CMC Lead (Acting), OPQ/ONDP/DNDPI/NDPBII
`CMC Reviewer, OPQ/ONDP/DNDPI/NDPBII
`Biopharmaceutics Reviewer, OPQ/ONDP/DB
`Biophannaceutics Reviewer, OPQ/ONDP/DB
`Clinical Pharmacology Team Lead, OTS/OCP/DCPV
`Clinical Pharmacology Reviewer, OTS/OCP/DCPV
`Associate Director of Regulatory Affairs, OHOP
`
`SPONSOR ATTENDEES
`Adrian Hepner
`Steven L. Krill
`Mark Smith
`Foma Rashkovsky
`Feng-Jing Chen
`Brian Chanas
`Todd Jenson
`Sonal Patel
`
`E.V.P. of Clinical Research, Medical & Regulatory Affairs
`E.V.P. and Chief Scientific Officer
`V.P. of Preclinical Development
`V.P. of Regulatory Affairs
`V .P. of Pharmaceutical Development
`Director Preclinical Development
`Senior Director, Project Management
`Senior Director, Project Management
`
`Reference ID: 3889966
`
`Reference ID: 4662511
`
`

`

`PIND 126831
`Page2
`
`BACKGROUND
`
`On November 24, 2015, Eagle PharmaceuticaJs (Eagle) requested a Type B meeting to discuss
`their 505(b)(2) development plan for a ready-to-dilute (RTD) pemetrexed product [Pemetrexed
`Injection for Intravenous Use, 25 mg/mL (500 mg/20 mL multiple-dose vial)] referencing the
`listed product, Alimta. Specifically, Eagle seeks FDA agreement on the proposed nonclinical
`study to qualify impurity and degradation products in the RTD product and to obtain feedback on
`the appropriateness to submit a waiver request for in vivo bioavailability studies in the New
`Drug Application (NDA). The meeting request was granted on December 8, 2015 as a
`teleconference meeting.
`
`Chemistry, Manufacturing and Controls
`The proposed ready-to-dilute (RTD) pemetrexed product contains drug substance pemetrexed
`which is different from pemetrexed disodium salt, the drug substance used for
`the listed drug Alimta. The chemical name for pemetrexed is: N-[4-[2-(2-amino-4,7-dihydro-4-
`oxo-l H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid.
`with a molecular formula of C20H21N 50 6 and a molecular
`weight of 427.41. Commercially available Alimta (pemetrexed for injection) is a lyophilized
`powder which must first be reconstituted with 0.9% Sodium Chloride Injection (to yield a
`solution concentration of 25 mg/mL). According to the additional information provided by
`Eagle following the January 21, 2016, teleconference, the proposed liquid formulation contains
`pemetrexed (25 mg/mL) and the following excipients: propylene glycol (260 mg/mL);
`tromethamine (16.5-19.9 mg/mL) and hydrochloride acid for adjusting pH
`; and water
`for injection
`It is intended to be stored at
`(2-8°C).
`
`Nonclinical
`Eagle proposes to conduct a GLP-compliant 6-week repeat dose IV study ofRTD Pemetrexed
`solution in mice in order to provide toxicology data to support potential differences in the
`impurity/degradation levels for the proposed product that exceed those in the listed drug. No
`other nonclinical studies are planned. Eagle intends to rely on data from the listed drug to
`support other pharmacology/toxicology requirements for this pemetrexed solution application.
`
`Clinical
`Eagle's RTD liquid formulation pemetrexed product
`
`. Eagle expects that the safety and efficacy profiles of their ready to dilute liquid
`formulation pemetrexed product will be comparable to the listed drug, Alimta.
`
`Eagle states that the indications and usage for their pemetrexed product are the same as for the
`listed drug, Alimta:
`
`1.
`
`treatment of locally advanced or metastatic nonsquamous non-small cell lung cancer
`(NSCLC)
`
`•
`•
`
`for initial treatment in combination with cisplatin
`for maintenance treatment of patients whose disease has not progressed after four
`cycles of platinum-based first-line chemotherapy
`
`Reference ID: 3889966
`Reference ID: 4662511
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`PIND 126831
`Page 3
`
`•
`
`after prior chemotherapy as a single-agent
`
`2. treatment of mesothelioma is in combination with cisplatin
`
`DISCUSSION
`
`1.
`
`Background: See Company Position on page 6 to 7 of the Briefing Document.
`
`Does the Agency agree that a 6-week repeat dose IV mouse GLP toxicology study is
`appropriate to qualify impurity/degradation product levels that may be present in RTD
`Pemetrexed Injection?
`
`FDA Response: Yes, the proposed toxicology study appears sufficient in design to support the
`qualification of impurity/degradation product levels in RTD pemetrexed; however a final
`determination of the adequacy of the submitted data will be determined following a full review
`of the reports included in the original NDA submission. In addition, develop and validate a
`suitable analytical method to cover the range of impurity/degradant levels in the proposed
`toxicology study.
`
`Eagle Emailed Response of 1/20/16: An analytical method for the assessment of the drug
`product has been developed and validated to cover the range of impurity/degradant levels for the
`product to be used in the proposed toxicology study.
`
`Discussion During the Meeting of 1/21/16: FDA acknowledged Eagle' s response. FDA stated
`that Eagle submit related method and validation report in the NDA submission.
`
`2.
`
`Background: See Company Position on page 7 of the Briefing Document.
`
`Does the proposed IV repeat-dose study in mice obviate the need for an independent
`assessment of local tolerance?
`
`FDA Response: Yes, the design of the proposed IV study in mice is sufficient to obviate the
`need for an independent local tolerance study.
`
`Eagle Emailed Response of 1120/16: We agree with your responses to questions 2 and 3 and no
`further discussion is requested at this ti.me for questions 2 and 3.
`
`Discussion During the Meeting of 1/21116: None
`
`Reference ID: 3889966
`
`Reference ID: 4662511
`
`

`

`PIND 126831
`Page4
`
`3.
`
`Background: NA
`
`Eagle anticipates using the 505(b )(2) NDA filing pathway for RTD Pemetrexed Injection.
`Does Agency agree with this approach?
`
`FDA Response: Yes, based on the information provided in the meeting package, the 505(b )(2)
`pathway appears to be appropriate. See additional comments under 505(b)(2) REGULATORY
`PATHWAY below.
`
`Please be advised that circumstances could change that would render a 505(b )(2) application for
`this product no longer appropriate. For example, if a pharmaceutically equivalent product were
`approved before Eagle's application is submitted, such that Eagle's proposed product would be a
`"duplicate" of a listed drug and eligible for approval under section 5050) of the FD&C Act, then
`it is FDA's policy to refuse to file Eagle's application as a 505(b)(2) application (21 CFR
`314.101(d)(9)). In such a case, the appropriate submission would be an Abbreviated New Drug
`Application (ANDA) that cites the duplicate product as the refer~nce listed drug.
`
`Eagle Emailed Response of 1/20/16: We agree with your responses to questions 2 and 3 and no
`further discussion is requested at this time for questions 2 arid 3.
`
`Discussion During the Meeting of 1121116: None
`
`4.
`
`Background: See Company Position on page 8 of the Briefing Document.
`
`Does Agency agree that it will be appropriate to submit a waiver request for in vivo
`bioavailability studies in the NDA?
`
`FDA Response: Yes, Eagle may include a biowaiver request in the NDA submission; however,
`Eagle's proposed drug product contains different APis (
`instead of disodium salt) and
`excipients (propylene glycol and tromethamine instead ofmannitol and sodium hydroxide).
`Difference in APis and excipients may affect the pharmacological activity of pemetrexed.
`Therefore, to support a waiver request of the requirement for the submission of in vivo
`bioavailability (BA) and/or bioequivalence (BE) data, submit sufficient justification and
`supporting data (e.g., published literature, study data, etc.) demonstrating that the existing
`difference in the API and excipients used do not affect in a,ny way the pharmacokinetics,
`efficacy, and safety of the proposed Eagle's RTD Pemetrexed Injection product, as compared to
`the listed drug product, Alimta.
`
`In support of the biowaiver request, FDA recommends that Eagle include (but not limited to) in
`the NDA the following information/data demonstrating the comparability of Eagle's proposed
`RID Pemetrexed product to Alimta:
`
`Reference ID: 3889966
`Reference ID: 4662511
`
`(b) (4)
`
`

`

`PIND 126831
`Page 5
`
`a. Comparative general information:
`i. Qualitative and quantitative composition of the formulations before and after
`reconstitution or dilution, dosage form, administered volume, labeling, etc., for the
`proposed drug product and the listed drug in a side-by-side comparison table.
`
`Eagle Emailed Response of 1/20/16: We agree with the Agency to include the comparative
`general information as recommended by FDA in the NDA in support of the biowaiver
`request.
`
`Discussion During the Meeting of 1121/16: None
`
`b. Comparative physico-chemical studies:
`1. Analysis methods confirming chemical structure of proposed API in the RTD
`product vs. the active moiety in Alimta, after reconstitution/dilution.
`Assessment of comparative dissociation of Eagle's proposed drug product vs.
`Alimta in an aqueous environment with respect to the ions formed.
`
`11.
`
`Eagle Emailed Response of 1/20/16 for 4(b)(i, ii): The proposed API for Eagle's
`RTD product, pemetrexed (
`diacid) is identical to the active moiety in
`Alimta and its basis of strength per Alimta prescribing information by Eli LilJy and
`Company, revised in 9/2013.
`
`Reference ID: 3889966
`
`Reference ID: 4662511
`
`(b) (4)
`
`(b) (4)
`
`

`

`PIND 126831
`Page6
`
`mg/mL
`25
`260
`Adjust pH to
`Adjust pH to 1
`
`Table 1. Quantitative Composition and Function of each Component in Eagle's
`P
`ed I .
`25
`I L
`f
`n1ec •on. m2,m
`eme rex
`t
`Ingredient
`Pemetrexeda
`Propylene Glycol, USP/EP
`Tromethamine, USP/EP
`Hydrochloric Acid, NF/EP
`Water for Injection, USP
`
`Function
`Active
`
`l
`
`I
`I
`
`pH Adjustment
`pH Adjustment
`
`I
`Discussion During the Meeting of 1/21/16 for 4(b)(i. ii): FDA acknowledged that
`Eagle will not perform the analysis as requested in 4(b)(i). FDA stated that Eagle
`provide justification in the NDA submission.
`
`With regards to Eagle's response for 4(b)(ii), Eagle agreed to demonstrate that
`different excipients in the proposed product would not affect the solubility of
`proposed product as compared to the listed product, Alimta. FDA stated that Eagle
`provide the data and justification for not pursuing additional studies in the NDA
`submission.
`
`iii.
`
`Similarity with Ali.rota in terms of physico-chemical characteristics relevant for the
`safety of drug product: appearance, visible particles, pH, and osmolality for the used
`proposed drug product and listed drug product. The measurements should be done in
`triplicate for each lot tested of the proposed product relative to the reconstituted/
`di luted Alimta product.
`
`Reference ID: 3889966
`Reference ID: 4662511
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`PIND 126831
`Page7
`
`Eagle Emailed Response of 1/20/16 for 4(b)(iii): We agree to include the
`comparative physico-chemical information recommended by FDA in the NDA in
`support of the biowaiver request.
`
`Discussion During the Meeting of 1/21/16 for 4(b)(iii): None
`
`1.
`
`ii.
`
`c. Comparative nonclinical studies:
`In vitro study to assess the affinity of Eagle's RTD Pemetrexed and Alimta to
`OA T3 renal receptors and to demonstrate similar elimination profile.
`In vitro study to assess the transport of Eagle' s RID Pemetrexed and Alimta by
`PCFT and RFC receptors and to demonstrate that both proposed and listed drug
`products follow the same pharmacological pathways.
`In vitro study to assess the binding of Pemetrexed to human plasma proteins, serum
`albumin and al-acid glycoprotein. The similarity in protein binding for both
`proposed and listed drug products should be demonstrated.
`
`111.
`
`Eagle Emailed Response of 1/20/16 for 4(c): As outlined in our response to 4b (above), at
`the point of patient exposure, Pemetrexed in the Eagle RTD formulation is identical to that in
`Alimta, as both drug products are a 'true solution'
`therefore the results of any comparative in vitro assay would be the
`same between the Eagle and Alimta 'pemetrexed' drug substances. In terms of potential
`excipient mediated effects on the transporter/receptor mechanisms noted; all excipients in the
`Eagle RTD formulation are below the FDA Inactive Ingredient Database (IID) limits (for
`intravenous administration), and are considered standard excipients consistent with the
`design of a dosage form for intravenous infusion. It is therefore our position that in vitro
`characterization of the Eagle RID product vis-a-vis Alimta (in the nonclinical studies listed
`in response to 4c-i, iii, and iii) would provide no information further to the understanding of
`the Eagle RTD product as the comparable nature of any data is self-evident.
`
`Discussion During the Meeting of 1/21/16 for 4(c): Eagle agreed to submit their proposal to
`address FD A comment 4( c) within 2 weeks of this meeting.
`
`d. Comparatfve in vivo PK study in an animal model:
`i.
`To further demonstrate that Eagle's proposed RTD Pemetrexed product and Alimta
`have similar pharmacokinetic profile, regardless of the differences in the active and
`inactive ingredients, provide in-vivo bioavailability/ bioequivalence data from a
`nonclinical phannacokinetic study conducted in an animal model (i.e., Beagle dogs)
`following IV administration of the proposed and listed Pemetrexed products. This
`infonnation will help to further understand the in vivo behavior of Eagle's proposed
`R TD Pemetrexed product in comparison with the listed drug product, Alimta, and
`demonstrate similarity.
`
`Eagle Emailed Response of 1/20/16 for 4(d): As outlined in our response to 4b (above), at
`the point of patient exposure, Pemetrexed in the Eagle RTD formulation is identical to that in
`Alimta as both drug products are a 'true solution'
`
`Reference ID: 3889966
`
`Reference ID: 4662511
`
`(b) (4)
`
`(b) (4)
`
`

`

`PIND 126831
`Page 8
`
`It is therefore self-evident that the pharmacokinetic profile of the
`Eagle RTD product following intravenous infusion will be the same as Alimta
`This statement is predicated on all excipients in the Eagle RTD formulation being
`below the FDA Inactive Ingredient Database (IID) limits (for intravenous administration). It
`is therefore our position that none of the formulation excipients (in either the Eagle R TD
`formulation, or in the reconstituted Alimta formulation) have an impact on the
`pharmacokinetic profile of Pemetrexed.
`
`Discussion During the Meeting of 1/21/16 for 4(d): Eagle agreed to submit their proposal
`to address FDA comment 4(d) within 2 weeks of this meeting.
`
`Be aware that based on the outcome of the review of the biowaiver supporting information, an
`additional clinical study(ies) may be necessary for approval.
`
`Eagle Emailed Response 0(21412016 (or 4c and 4d: During the teleconference it was discussed
`that the recommended in vitro studies (item 4c) are customarily conducted with active
`pharmaceutical ingredient solubilized in a medium compatible with the mammalian cell culture
`system being employed. It was agreed that as Eagle will be providing data in the submission
`demonstrating the comparability of the active pharmaceutical ingredient between the Eagle-RTD
`product and Alimta, that further characterization of pemetrexed diacid in these in vitro studies is
`not required.
`
`Furthermore, the pharmacokinetic profile of the Eagle-RTD product is expected to be
`comparable to the PK profile of Alimta, as both drug products are 'true solutions'
`
`order to demonstrate the pharmacokinetic bioequivalence of the Eagle RTD product as
`compared to Alimta, Eagle proposes to conduct a comparative pharmacokinetic study in
`(beagle) dogs.
`
`In
`
`Does the Agency agree that the demonstration of solubility tnjinal admixture, and
`pharmacokinetic equivalence in dogs, is sufficient to support a biowaiver request?
`
`FDA Response: FDA acknowledges the discussion of the in-vitro tests under Question 4c above
`during the teleconference on 21412016; however, it is FDA 's current thinking that at a minimum,
`similarity in protein binding for both proposed and listed drug products should be demonstrated.
`This protein binding study should be conducted with the reconstituted listed drug and the
`proposed RTD product. In addition to the "determination of solubility in the final admixture",
`provide the other comparative physicochemical data as previously discussed.
`
`Upon further evaluation of the proposed pharmacokinetic equivalence study in dogs as well as
`the proposed study in mice comparing Pemetrexed Injection with the listed drug (which will
`include toxicokinetic data), FDA has determined that an additional comparative PK study in
`dogs is not warranted.
`
`Reference ID: 3889966
`Reference ID: 4662511
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`PIND 126831
`Page9
`
`ADDITIONAL COMMENTS
`
`5.
`
`Submit an Initial Pediatric Study Plan (iPSP) within 60 days of this meeting or no less
`than 210 days prior to the submission of an NDA application. Please see additional
`comments under PREA REQUIREMENTS below.
`
`Eagle Emailed Response of 1/20/16: Eagle did not request additional discussion.
`
`Discussion During the Meeting of 1/21/16: None
`
`PREA REQUIREMENTS
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
`active ingredients (which includes new salts and new fixed combinations), new indications, new
`dosage forms, new dosing regimens, or new routes of administration are required to contain an
`assessment of the safety and effectiveness of the product for the claimed indication(s) in
`pediatric patients unless this requirement is waived, deferred, or inapplicable.
`
`Please be advised that under the Food and Drug Administration Safety and Innovation Act
`(FD ASIA), you must submit an Initial Pediatric Study Plan (iPSP) within 60 days of this meeting
`or no less than 210 days prior to the submission of an NDA application. The PSP must contain
`an outline of the pediatric study or studies that you plan to conduct (including, to the extent
`practicable study objectives and design, age groups, relevant endpoints, and statistical approach);
`any request for a deferral, partial waiver, or waiver, if applicable, along with any supporting
`documentation, and any previously negotiated pediatric plans with other regulatory authorities.
`The PSP should be submitted in PDF and Word format. Failure to include an agreed iPSP with a
`marketing application could result in a refuse to file action.
`
`For additional guidance on the timing, content, and submission of the PSP, including a PSP
`Template, please refer to the draft guidance for industry, Pediatric Study Plans: Content of and
`Process for Submitting Initial Pediatric Study Plans and Amended Pediatric Study Plans at:
`http://www.fda.gov I downloads/Drugs/GuidanceComplianceRegulatorylnformation/Guidances/U
`CM360507.pdf. In addition, you may contact the Division of Pediatric and Maternal Health at
`301-796-2200 or email pdit@fda.hhs.gov. For further guidance on pediatric product
`development, please refer to:
`http://www.fda.gov/Drugs/DevelopmentApprova1Process/DevelopmentResources/ucm049867.ht
`m.
`
`Reference ID: 3889966
`
`Reference ID: 4662511
`
`

`

`PIND 126831
`Page 10
`
`PRESCRIBING INFORMATION
`
`In your application, you must submit proposed prescribing information (Pl) that conforms to the
`content and format regulations found at 21 CFR 201.56(a) and Cd) and 201.57 including the
`Pregnancy and Lactation Labeling Rule (PLLR) (for applications submitted on or after June 30,
`2015). As you develop your proposed PI, we encourage you to review the labeling review
`resources on the P LR Requirements (or Prescribing In(ormation and Pregnancy and Lactation
`Labeling Final Rule websites, which include:
`
`• The Final Rule (Physician Labeling Rule) on the content and format of the PI for human
`drug and biological products
`• The Final Rule (Pregnancy and Lactation Labeling Rule) on the content and format of
`information related to pregnancy, lactation, and females and males of reproductive
`potential
`• Regulations and related guidance documents
`• A sample tool illustrating the format for Highlights and Contents, and
`• The Selected Requirements for Prescribing Information (SRPI) - a checklist of
`important format items from labeling regulations and guidances.
`• FDA's established phannacologic class (EPC) text phrases for inclusion in the
`Highlights Indications and Usage heading.
`
`The application should include a review and summary of the available published literature
`regarding drug use in pregnant and lactating women, a review and summary of reports from your
`pharmacovigilance database, and an interim or final report of an ongoing or closed pregnancy
`registry (if applicable), which should be located in Module 1. Refer to the draft guidance for
`industry - Pregnancy, Lactation, and Reproductive Potential: Labeling/or Human Prescription
`Drug and Biological Products - Content and Format
`(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatorylnformation/Guidances/
`UCM425398.pdf).
`
`Prior to submission of your proposed Pl, use the SRPI checklist to ensure conformance with the
`format items in regulations and guidances.
`
`DATA STANDARDS FOR STUDIES
`
`Under section 745A(a) of the FD&C Act, electronic submissions "shall be submitted in such
`electronic format as specified by [FDA)." FDA has determined that study data contained in
`electronic submissions (i.e., NDAs, BLAs, ANDAs and INDs) must be in a format that the
`Agency can process, review, and archive. Currently, the Agency can process, review, and
`archive electronic submissions of clinical and nonclinical study data that use the standards
`specified in the Data Standards Catalog (Catalog) (See
`http://www.fda.gov/forindustry/datastandards/studydatastandards/default.htm).
`
`Reference ID: 3889966
`Reference ID: 4662511
`
`

`

`PIND 126831
`Pagel l
`
`On December 17, 2014, FDA issued final guidance, Providing Electronic Submissions in
`Electronic Format--- Standardized Study Data
`(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatorylnformation/Guidances/
`UCM292334.pdf). This guidance describes the submission types, the standardized study data
`requirements, and when standardized study data will be required. Further, it describes the
`availability of implementation support in the form of a technical specifications document, Study
`Data Technical Conformance Guide (Conformance Guide) (See
`http://www.fda.gov I downloads/F orlndustry/DataStandards/StudyDataStandards/UCM3 84 7 44.pd
`!), as well as email access to the eData Team (cder-edata@fda.hhs.gov) for specific questions
`related to study data standards. Standardized study data will be required in marketing
`application submissions for clinical and nonclinical studies that start on or after December 17,
`2016. Standardized study data will be required in commercial IND application submissions for
`clinical and nonclinical studies that start on or after December 17, 2017. CDER has produced a
`Study Data Standards Resources web page that provides specifications for sponsors regarding
`implementation and submission of clinical and nonclinical study data in a standardized format.
`This web page will be updated regularly to reflect CDER's growing experience in order to meet
`the needs of its reviewers.
`
`Although the submission of study data in conformance to the standards listed in the FDA Data
`Standards Catalog will not be required in studies that start before December 17, 2016, CDER
`.strongly encourages IND sponsors to use the FDA supported data standards for the submission of
`IND applications and marketing applications. The implementation of data standards should
`occur as early as possible in the product development lifecycle, so that data standards are
`accounted for in the design, conduct, and analysis of clinical and nonclinical studies. For
`clinical and nonclinical studies, IND sponsors should include a plan (e.g., in the IND) describing
`the submission of standardized study data to FDA. This study data standardization plan (see the
`Conformance Guide) will assist FDA in identifying potential data standardization issues early in
`the development program.
`
`Additional information can be found at
`http://www.fda.gov/Drugs/DevelopmentApprovalProcess/F ormsSubmissionReq uirements/Electr
`onicSubmissions/ucm248635.htm
`
`For general toxicology, supporting nonclinical toxicokinetic, and carcinogenicity studies,
`CDER encourages sponsors to use Standards for the Exchange of Nonclinical Data (SEND) and
`submit sample or test data sets before implementation becomes required. CDER will provide
`feedback to sponsors on the suitability of these test data sets. Information about submitting a test
`submission can be found here:
`http://www.fda.gov/Drugs/DevelopmentApprovalProcess/F ormsSubmissionRequirements/Electr
`onicSubmissions/ucm174459.htm
`
`LABORATORY TEST UNITS FOR CLINICAL TRIALS
`
`CDER strongly encourages IND sponsors to identify the laboratory test units that will be
`reported in clinical trials that support applications for investigational new drugs and product
`
`Reference ID: 3889966
`
`Reference ID: 4662511
`
`

`

`PIND 126831
`Page 12
`
`registration. Although Systeme lnternational (SI) units may be the standard reporting
`mechanism globally, dual reporting of a reasonable subset of laboratory tests in U.S.
`conventional units and SI units might be necessary to minimize conversion needs during review.
`Identification of units to be used for laboratory tests in clinical trials and solicitation of input
`from the review divisions should occur as early as possible in the development process. For
`more information, please see the FDA website entitled, Study Data Standards Resources and the
`CDER/CBER Position on Use of SI Units for Lab Tests website found at
`http://www.fda.gov/F orindustry/DataStandards/StudyDataStandards/ucm3 725 53 .htm.
`
`MANUFACTURING FACILITIES
`
`To facilitate our inspectional process, we request that you clearly identify in a single location,
`either on the Form FDA 356h, or an attachment to the form, all manufacturing facilities
`associated with your application. Include the full corporate name of the facility and address
`where the manufacturing function is performed, with the FEI number, and specific
`manufacturing responsibilities for each facility.
`
`Also provide the name and title of an onsite contact person, including their phone number, fax
`number, and email address. Provide a brief description of the manufacturing operation
`conducted at each facility, including the type of testing and DMF number (lf applicable). Each
`facility should be ready for GMP inspection at the time of submission.
`
`Consider using a table similar to the one below as an attachment to Form FDA 356h. Indicate
`under Establishment Information on page 1 of Form FDA 356h that the information is provided
`in the attachment titled, "Product name, NDA/BLA 012345, Establishment Information for Form
`356h."
`
`. . : ·.
`
`Site Name ··
`
`Site Address ·.
`
`Federal ·
`· Establishment
`·· indicator
`··-(FEl)or ··
`Registration
`··
`· Number
`CF
`
`Dnig .. ·
`Master ·.
`File
`··.Number
`(if
`applicable)
`
`Manufacturing Step( s)
`. or Type of Testing
`· · · .. [Establishment. ·
`·.function.]
`
`1.
`2.
`
`Reference ID: 3889966
`Reference ID: 4662511
`
`

`

`PIND 126831
`Page 13
`
`Corresponding names and titles of onsite contact:
`
`Site Name·
`
`Site Address
`
`Onsite Contact
`· (Person, Title)
`
`Phone and
`Fax
`ntimber
`
`Email address · ·
`
`I ··•
`
`1.
`2.
`
`505(b)(2) REGULATORY PATHWAY
`
`The Division recommends that sponsors considering the submission of an application through
`the 505(b)(2) pathway consult the Agency's regulations at 21 CFR 314.54, and the draft
`guidance for industry Applications Covered by Section 505(b)(2) (October 1999), available at
`http://www.fda.gov/Drugs/GuidanceComplianceRegulatorylnformation/Guidances/default.htm.
`In addition, FDA has explained the background and applicability of section 505(b )(2) in its
`October 14, 2003, response to a number of citizen petitions that had challenged the Agency's
`interpretation of this statutory provision (see Docket FDA-2003-P-0274-0015, available at
`http://www.regulations.gov ).
`
`If you intend to submit a 505(b)(2) application that relies for approval, in part, on FDA's finding
`of safety and/or effectiveness for one or more listed drugs, you must establish that such reliance
`is scientifically appropriate, and must submit data necessary to support any aspects of the
`proposed drug product that represent modifications to the listed drug(s). You should establish a
`"bridge" (e.g., via comparative bioavailability data) between your proposed drug product and
`each listed drug upon which you propose to rely to demonstrate that such reliance is
`scientifically justified.
`
`If you intend to rely, in part, on literature or other studies for which you have no right of
`reference but that are necessary for approval, you also must establish that reliance on the studies
`described in the literature or on the other studies is scientifically appropriate. You should
`include a copy of such published literature in the 505(b )(2) application and identify any listed
`drug(s) described in the published literature (e.g., trade name(s)).
`
`If you intend to rely, in part, on the Agency's finding of safety and/or effectiveness for a listed
`drug(s) or published literature describing a listed drug(s) (which is considered to be reliance on
`FDA's finding of safety and/or effectiveness for the listed drug(s)), you should identify the listed
`drug(s) in accordance with the Agency's regulations at 21 CFR 314.54. It should be noted that
`21 CFR 314.54 requires identification of the "listed drug for which FDA has made a finding of
`safety and effectiveness," and thus an applicant may only rely upon a listed drug that was
`approved in an NDA under section 505(c) of the FD&C Act. The regulatory requirements for a
`505(b)(2) application (including, but not limited to, an appropriate patent certification or
`statement) apply to each listed drug upon which a sponsor relies.
`
`Reference ID: 3889966
`
`Reference