CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`
`
`
`APPLICATION NUMBER:
`
`
`210875Orig1s000
`
`
`
`
`
`
`
`ADMINISTRATIVE and CORRESPONDENCE
`
`
`DOCUMENTS
`
`
`

`

`
`
` DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`IND 110955
`
`Sunovion Pharmaceuticals Inc.
`Attention: Sonya Roeloffzen
`Director, Global Regulatory Affairs
`88 Waterford Drive
`Marlborough, MA 01752-7010
`
`Dear Ms. Roeloffzen:
`
`Food and Drug Administration
`
`Silver Spring MD 20993
`
`MEETING MINUTES
`
`Please refer to your Investigational New Drug Application (IND) submitted under section 505(i)
`of the Federal Food, Drug, and Cosmetic Act for APL-130277.
`
`We also refer to the meeting between representatives of your firm and the FDA on February6,
`2018. The purpose of the meeting was to discuss the original new drug application (NDA).
`
`A copy of the official minutes of the meeting is enclosed for your information. Please notify us
`of any significant differences in understanding regarding the meeting outcomes.
`
`If you have any questions, call Jack Dan, Regulatory Project Manager at (240) 402-6940.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Eric Bastings, MD
`Deputy Director
`Division of Neurology Products
`Office of Drug Evaluation I
`
`Center for Drug Evaluation and Research
`
`Enclosure:
`
`Meeting Minutes
`
`Reference ID: 4231271
`Reference ID: 4613103
`
`

`

`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`MEMORANDUM OF MEETING MINUTES
`
`
`Meeting Type:
`Meeting Category:
`
`B
`Pre-NDA
`
`Meeting Date and Time:
`Meeting Location:
`
`February 6, 2018 from 3:00 pm to 4:00 pm
`White Oak, Building 22, Room 1309
`
`Application Number:
`Product Name:
`Indication:
`
`110955
`APL-130277
`Acute intermittent management of OFF episodes in patients with
`Parkinson’s disease
`Sponsor/Applicant Name: Sunovion Pharmaceuticals Inc.
`
`Meeting Chair:
`Meeting Recorder:
`
`Billy Dunn, MD
`Jack Dan, RPh
`
`FDA ATTENDEES
`Billy Dunn, MD, Director, Division of Neurology Products (DNP)
`Eric Bastings, MD, Deputy Director, DNP
`
`Nick Kozauer, MD, Associate Director, DNP
`Gerald (Dave) Podskalny, DO, MPHS Clinical Team Leader, DNP
`
`Kenneth Bergmann, MD, Clinical Reviewer, DNP
`
`LuAnn Mckinney, PhD, Nonclinical Reviewer, DNP
`
`Dan Berger, PhD, Chemistry Manufacturing Controls, Reviewer
`Atul Bhattaram, PhD, Clinical Pharmacology Reviewer, DNP
`
`
`Kun Jin, PhD, Statistical Team Leader
`
`Junshan Qiu, PhD, Statistical Reviewer
`Jack Dan, RPh, Regulatory Project Manager
`
`SPONSOR ATTENDEES
`
`Antony Loebel, MD, Executive Vice President, Chief Medical Officer, Head of Global Clinical
`Development
`Bradford Navia, MD, Senior Director, Global Clinical Development
`David Blum, MD, Head, Global Clinical Research Neurology
`Diana Hughes, MD, MSc, Head PVRM & Head Global PV
`E. Radford Decker, PhD, Senior Director DMPK
`James Rawls, PharmD, Head, Global Regulatory Affairs
`Jane Xu, PhD, Head, Global Data Science
`Kenneth Sciarappa, PhD, Senior Director, Global Data Science, Biostatistics
`
`Reference ID: 4231271
`Reference ID: 4613103
`
`

`

`IND 110955
`Page 2
`
`Kimberley Treinen, PhD, Executive Director & Head of Preclinical
`Parul Bhargava, PhD, Associate Director, Global Data Science, Biostatistics
`Paul McGlynn, PhD, Executive Director, Global Project Management
`Rachel Morrison, GRSC, Associate Director, Global Regulatory Affairs
`Renee Carroll, MS, RAC, Senior Director, Global Regulatory Affairs
`Robert Goldman, PhD, Head Global Clinical Research & Medical Affairs
`Sonya Roeloffzen Stokowski, MSc, Director, Global Regulatory Affairs
`
` Thierry Bilbault, PhD, Head, Technical Operations
`
`Yu-Yuan Chiu, PhD, Senior Director, Clinical Pharmacology
`
`1.0
`
`BACKGROUND
`
`
`Sunovion Pharmaceuticals Inc. (Sunovion) is developing APL-130277 (apomorphine
`hydrochloride) sublingual film for the acute, intermittent treatment of “OFF” episodes associated
`with Parkinson’s disease (PD)
`
`film strip of apomorphine for sublingual (sl) administration which is
`APL-130277 is a
`designed to deliver apomorphine systemically through absorption from the oral cavity mucosa,
`thus bypassing the extensive first pass metabolism associated with gastrointestinal absorption of
`the compound.
`
`APL-130277 was developed by Cynapsus Therapeutics (Cynapsus) under Investigational New
`Drug application (IND) 110,955. Sunovion acquired Cynapsus on October 21, 2016.
`
`APL-130277 obtained Fast Track designation on August 25, 2016.
`
`Sunovion will submit a 505(b)(2) NDA for APL-130277 which contains the same active
`ingredient in NDA 021264 Apokyn injection.
`
`FDA sent Preliminary Comments to Sunovion Pharmaceuticals Inc. on February 1, 2018.
`
`2. DISCUSSION
`
`Question 1: Integrated Efficacy Analysis: Sunovion proposes to submit a Summary of Clinical
`
`Efficacy (SCE) that will also meet the statutory requirement for an Integrated Summary of
`Effectiveness (ISE) for the reasons provided below. Does the Division agree with this proposal?
`
`FDA Response to Question 1:
`Yes, it is possible to submit the narrative portions of the SCE summarizing APL-130277 efficacy
`(including all subgroup analyses) within Module 2. The texts should contain functioning
`hyperlinks to the information found in the appendices, tables, figures, listings, and datasets for
`the ISE.
`
`Reference ID: 4231271
`Reference ID: 4613103
`
`(b) (4)
`
`(b) (4)
`
`

`

`IND 110955
`Page 3
`
`All appendices must have a hyperlinked table of contents (TOC) that uses logical names that
`describe its contents. If an appendix contains subsections, the TOC for the appendix should
`contain hyperlinks or bookmarks to each subsection. Create a Master TOC that lists the order
`and title of each of the appendices. The Master TOC should contain functioning hyperlinks or
`bookmarks that bring the reader to the location of each appendix listed. The SCE needs to be
`clearly labeled and navigable.
`
`Meeting Discussion:
`None.
`
`Question 2: Clinical Development: Does the Division agree that the clinical development
`package as described below is sufficient to support a substantive review of APL-130277
`(apomorphine hydrochloride) sublingual film 505(b)(2) NDA?
`
`FDA Response to Question 2:
`The clinical pharmacology and clinical trial information appear, on face, to be sufficient to
`support a review of your product. However, this will be a matter of review after your complete
`application is submitted.
`
`We remind you that in order to rely on FDA’s finding of safety and/or effectiveness for a listed
`drug, you must establish that such reliance is scientifically appropriate and establish a
`satisfactory “bridge” between your proposed product and the listed drug to be relied upon. You
`propose to rely on Apokyn (NDA 21264) and to justify such reliance through a comparison of
`your proposed product and APO-go. The acceptability of such an approach will be a matter for
`
`review and will depend on several factors, including, as we have previously noted, your ability to
`assure us of the “sameness” of the current Apokyn and APO-go products. Please refer to the
`following guidance for further information on the requirements for establishment of
`effectiveness of your product: “Guidance for Industry: Providing Clinical Evidence of
`Effectiveness for Human Drugs and Biological Products”
`https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-
`ggen/documents/document/ucm072008.pdf
`
`Meeting Discussion:
`
`The Division’s suggested including in the NDA the final results from Study 203, a comparative
`bioavailability study assessing Apokyn, Apo-go and APL-130277, because the information from
`the study may help with bridging Apokyn to APL-130277.
`
`Question 3: Integrated Summary of Safety (ISS): Sunovion proposes to summarize the
`individual study level data from Studies CTH-203 and CTH-302 separately within the ISS given
`that these are ongoing studies with only a small number of subjects enrolled at the time of NDA
`submission and their differences in study design. Does the Division agree with this proposal?
`
`Reference ID: 4231271
`Reference ID: 4613103
`
`

`

`IND 110955
`Page 4
`
` FDA Response to Question 3:
`
`Yes, we agree with your plan not to pool the available safety data from ongoing crossover design
`Study CTH-203 and proposed Study CTH-302. If your bridge to the reference drug (Apokyn)
`relies on the results of Study CTH-203 (a single dose, relative bioavailability study comparing
`the PK properties of APL-130277 with APO-go and Apokyn), you will need to include the final
`study report in the NDA.
`
`As indicated by the advice letter of May 26, 2017, your NDA submission must include safety
`information from at least 100 patients treated with dosages of APL-130277 intended for clinical
`use for 6 months or longer, with at least half treated with the highest recommended dose.
`
`Additional safety data from ongoing long-term safety studies should be submitted in the 120-day
`safety update.
`
`
`Due to the titration and flexible dosing design of your pivotal trial, CTH-300, please include a
`table of adverse events for the actual dose received by the study period (i.e., titration versus
`maintenance) for all subjects, and a separate table for subjects who had a dose reduction any time
`during the trial. Please also see our response to Question 1 regarding the need to ensure the
`navigability of the ISS in the same manner as the SCE.
`
`Meeting Discussion:
`FDA recognized that in the pivotal clinical trials, APL-130277 was administered using a flexible
`and intermittent dosing schedule, so that the requirement for having information from at least
`100 patients treated with dosages of APL-130277 intended for clinical use for 6 months or
`
`
`longer, with at least half treated with the highest recommended dose, does not directly apply.
`FDA stated that dosages described in labeling would need to be supported by the clinical trials
`(controlled and long-term) experience. The Sponsor should provide a clear and unambiguous
`presentation of the doses (mg) used, the number of doses taken each day, and for how many days
`each dose was used in the submission. The Sponsor clarified that the number of doses taken
`each day by each patient can only be inferred and calculated from the number of doses dispensed
`at each visit and the number of doses returned at the following visit. The dose and frequency of
`administration is only available from patient diaries kept for the two-day period prior to
`
`scheduled study visits.
`
`FDA suggested that diary information from the two days prior to each visit be provided to
`support the maximum daily dose and frequency of administration described in labeling (i.e., mg
`dose x number of times taken in each day).
`
`The Sponsor is encouraged to present the experience supporting the use of APL-130277 in ways
`that show the varied patterns of use among individuals but clearly indicate how adverse events
`are related to dose and method of use. This information should also be identifiable in the datasets
`for review.
`
`The Sponsor stated their intent to present the results of the thorough QT study to provide some
`reassurance for cardiac safety, especially at higher doses.
`
`Reference ID: 4231271
`Reference ID: 4613103
`
`

`

`IND 110955
`Page 5
`
`The Sponsor should make clear in both in datasets and adverse event reporting at what exposure
`
`common events, such as nausea and vomiting and orthostasis, take place. The use of
`domperidone should also be “flagged” in both the datasets and reports with the understanding
`that domperidone, a medication not approved in the US, is also not available for use in the label.
`An analysis and discussion should be provided to assess whether the concomitant anti-emetic use
`may have affected the observed side-effect profile.
`
`Question 4: Nonclinical: Sunovion has conducted a 3-month apomorphine sulfate rat toxicology
`
`study to confirm the safety of the Phase II conjugate apomorphine sulfate metabolite. Sunovion
`
`will submit an audited draft report (without SEND datasets) for the 3-month apomorphine sulfate
`rat toxicology study in the original NDA. Does the Division agree?
`
`FDA Response to Question 4:
`Nonclinical studies needed to support approval must be provided as final study reports at the
`time of NDA submission (see Written Responses, May 26, 2017).
`
`If you are not able to rely on other sources to support the safety of your proposed product (see
`the comments in our response to Question 2), you will need to provide data from a full battery of
`nonclinical studies to support an NDA (see ICH M3(R2), January 2010; ICH M3(R2), February
`2013)
`
`Meeting Discussion:
`None.
`
`Question 5: Priority Review: Does the Division have any comments regarding the proposed
`outline of the information Sunovion will provide to support a request for Priority Review of the
`APL-130277 (apomorphine hydrochloride) sublingual film NDA?
`
`FDA Response to Question 5:
`Review status is decided after the application is submitted.
`
`Meeting Discussion:
`None.
`
`Question 6: Office of Scientific Investigation (OSI) Information: Sunovion proposes to submit
`
`the necessary OSI information for Study CTH-300 given the study objectives and design and that
`it meets the requirements of a major trial used to support safety and efficacy in the application.
`Does the Division agree with this proposal?
`
`FDA Response to Question 6:
`In addition, submit the same information for open label extension study CTH-301.
`
`Meeting Discussion:
`None.
`
`Reference ID: 4231271
`Reference ID: 4613103
`
`

`

`IND 110955
`
`Page 6
`
`
`3.0 OTHER IMPORTANT INFORMATION
`
`PROSPECTIVE ASSESSMENTS OF SUICIDAL IDEATION AND BEHAVIOR IN
`CLINICAL PROTOCOLS
`
`
`Treatment-emergent suicidal ideation and behavior have been identified as a concern for a
`number of drugs and drug classes. For example, meta-analyses of clinical trial data for both
`antiepileptic drugs and antidepressants have demonstrated that these drugs increase the risk of
`suicidal ideation and behavior. Spontaneous reports have led to similar concerns with other
`drugs as well, e.g., isotretinoin and other tretinoins, beta blockers, reserpine, smoking cessation
`drugs, and drugs for weight loss. Because of these concerns, a prospective assessment for
`suicidal ideation and behavior should be included, when appropriate and feasible, in clinical
`trials involving all drugs and biological products for neurological indications. These assessments
`should generally be included in every clinical protocol, at every visit, and in every phase of
`development, with the exception of single-dose trials in healthy volunteers. These assessments
`should be conducted whether or not a particular product is known or suspected to be associated
`with treatment-emergent suicidal ideation and behavior. A Sponsor considering the omission of
`the assessment of suicidal ideation and behavior from a particular clinical protocol should
`prospectively discuss this omission with the Division of Neurology Products.
`
`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 (FDASIA), you must
`submit an Initial Pediatric Study Plan (iPSP) within 60 days of an End-of-Phase-2 (EOP2)
`
`meeting. In the absence of an EOP2 meeting, refer to the draft guidance below. The iPSP 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 iPSP 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 iPSP, including an iPSP
`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/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`
`CM360507.pdf. In addition, you may contact the Division of Pediatric and Maternal Health at
`301-796-2200 or email Pedsdrugs@fda.hhs.gov. For further guidance on pediatric product
`development, please refer to:
`http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm049867.ht
`m.
`
`Reference ID: 4231271
`Reference ID: 4613103
`
`

`

`IND 110955
`Page 7
`
`PRESCRIBING INFORMATION
`
`In your application, you must submit proposed prescribing information (PI) that conforms to the
`content and format regulations found at 21 CFR 201.56(a) and (d) 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 PLR Requirements for Prescribing Information 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 pharmacologic 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 for Human Prescription
`Drug and Biological Products – Content and Format
`
`(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
`UCM425398.pdf).
`
`Prior to submission of your proposed PI, use the SRPI checklist to ensure conformance with the
`
`format items in regulations and guidances.
`
`SUBMISSION FORMAT REQUIREMENTS
`
`
`The Electronic Common Technical Document (eCTD) is CDER and CBER’s standard format for
`electronic regulatory submissions. As of May 5, 2017, the following submission types: NDA,
`ANDA, and BLA must be submitted in eCTD format. Commercial IND and Master File
`
`submissions must be submitted in eCTD format beginning May 5, 2018. Submissions that do
`not adhere to the requirements stated in the eCTD Guidance will be subject to rejection. For
`more information please visit: http://www.fda.gov/ectd.
`
`Reference ID: 4231271
`Reference ID: 4613103
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`

`

`IND 110955
`Page 8
`
`SECURE EMAIL COMMUNICATIONS
`
`Secure email is required for all email communications from FDA when confidential information
`(e.g., trade secrets, manufacturing, or patient information) is included in the message. To receive
`email communications from FDA that include confidential information (e.g., information
`requests, labeling revisions, courtesy copies of letters), you must establish secure email. To
`
`establish secure email with FDA, send an email request to SecureEmail@fda.hhs.gov. Please
`note that secure email may not be used for formal regulatory submissions to applications (except
`for 7-day safety reports for INDs not in eCTD format).
`
`ABUSE POTENTIAL ASSESSMENT
`
`Drugs that affect the central nervous system, are chemically or pharmacologically similar to
`other drugs with known abuse potential, or produce psychoactive effects such as mood or
`cognitive changes (e.g., euphoria, hallucinations) need to be evaluated for their abuse potential
`and a proposal for scheduling will be required at the time of the NDA submission
`[21 CFR 314.50(d)(5)(vii)]. For information on the abuse potential evaluation and information
`required at the time of your NDA submission, see the Guidance for Industry, Assessment of
`Abuse Potential of Drugs, available at:
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM198650.pdf.
`
`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 (if 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.”
`
`Reference ID: 4231271
`Reference ID: 4613103
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`

`

`IND 110955
`Page 9
`
`Site Name
`
`Site Address
`
`1.
`2.
`
`Federal
`Establishment
`Indicator
`(FEI) or
`Registration
`Number
`(CFN)
`
`Drug
`Master
`File
`Number
`(if
`applicable)
`
`Manufacturing Step(s)
`or Type of Testing
`[Establishment
`function]
`
`Corresponding names and titles of onsite contact:
`
`Site Name
`
`Site Address
`
`Onsite Contact
`(Person, Title)
`
`Phone and
`Fax
`number
`
`Email address
`
`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/GuidanceComplianceRegulatoryInformation/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 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 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. by trade name(s)).
`
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`

`IND 110955
`Page 10
`
`If you intend to rely 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.
`
`
`
`If FDA has approved one or more pharmaceutically equivalent products in one or more NDA(s)
`before the date of submission of the original 505(b)(2) application, you must identify one such
`pharmaceutically equivalent product as a listed drug (or an additional listed drug) relied upon
`(see 21 CFR 314.50(i)(1)(i)(C), 314.54, and 314.125(b)(19); see also 21 CFR 314.101(d)(9)). If
`you identify a listed drug solely to comply with this regulatory requirement, you must provide an
`
`appropriate patent certification or statement for any patents that are listed in the Orange Book for
`the pharmaceutically equivalent product, but you are not required to establish a “bridge” to
`justify the scientific appropriateness of reliance on the pharmaceutically equivalent product if it
`is scientifically unnecessary to support approval.
`
`If you propose to rely on FDA’s finding of safety and/or effectiveness for a listed drug that has
`been discontinued from marketing, the acceptability of this approach will be contingent on
`FDA’s consideration of whether the drug was discontinued for reasons of safety or effectiveness.
`
`
`We encourage you to identify each section of your proposed 505(b)(2) application that is
`supported by reliance on FDA’s finding of safety and/or effectiveness for a listed drug(s) or on
`published literature (see table below). In your 505(b)(2) application, we encourage you to
`clearly identify (for each section of the application, including the labeling): (1) the information
`for the proposed drug product that is provided by reliance on FDA’s finding of safety and/or
`
`effectiveness for the listed drug or by reliance on published literature; (2) the “bridge” that
`supports the scientific appropriateness of such reliance; and (3) the specific name (e.g.,
`proprietary name) of each listed drug named in any published literature on which your marketing
`application relies for approval. If you are proposing to rely on published literature, include
`copies of the article(s) in your submission.
`
`In addition to identifying the source of supporting information in your annotated labeling, we
`encourage you to include in your marketing application a summary of the information that
`supports the application in a table similar to the one below.
`
`Reference ID: 4231271
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`

`IND 110955
`Page 11
`
`List the information essential to the approval of the proposed drug that is
`provided by reliance on the FDA’s previous finding of safety and effectiveness for
`a listed drug or by reliance on published literature
`
`Source of information
`(e.g., published literature, name of
`listed drug)
`
`Information Provided
`
`(e.g., specific sections of the 505(b)(2)
`application or labeling)
`
`
`
` 1. Example: Published literature
`2. Example: NDA XXXXXX
`“TRADENAME”
`3. Example: NDA YYYYYY
`“TRADENAME”
`
`Nonclinical toxicology
`Previous finding of effectiveness for
`indication A
`Previous finding of safety for
`Carcinogenicity, labeling section B
`
`4.
`
` 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 your application is submitted, such that your proposed product would be a
`“duplicate” of a listed drug and eligible for approval under section 505(j) of the FD&C Act, then
`it is FDA’s policy to refuse to file your 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 reference listed drug.
`
`OFFICE OF SCIENTIFIC INVESTIGATIONS (OSI) REQUESTS
`
`The Office of Scientific Investigations (OSI) requests that the following items be provided to
`facilitate development of clinical investigator and Sponsor/monitor/CRO inspection assignments,
`
`and the background packages that are sent with those assignments to the FDA field investigators
`who conduct those inspections (Item I and II). This information is requested for all major trials
`
`used to support safety and efficacy in the application (i.e., phase 2/3 pivotal trials). Please note
`that if the requested items are provided elsewhere in submission in the format described, the
`Applicant can describe location or provide a link to the requested information.
`
`
`The dataset that is requested in Item III below is for use in a clinical site selection model that is
`being piloted in CDER. Electronic submission of the site level dataset is voluntary and is
`intended to facilitate the timely selection of appropriate clinical sites for FDA inspection as part
`of the application and/or supplement review process.
`This request also provides instructions for where OSI requested items should be placed within an
`eCTD submission (Attachment 1, Technical Instructions: Submitting Bioresearch Monitoring
`(BIMO) Clinical Data in eCTD Format).
`
`Reference ID: 4231271
`Reference ID: 4613103
`
`

`

`IND 110955
`Page 12
`
` I. Request for general study related information and comprehensive clinical investigator
`
`information (if items are provided elsewhere in submission, describe location or provide
`link to requested information).
`
`1. Please include the following information in a tabular format in the original NDA for each
`of the completed pivotal clinical trials:
`a. Site number
`b. Principal investigator
`
`c. Site Location: Address (e.g., Street, City, State, Country) and contact information
`(i.e., phone, fax, email)
`d. Location of Principal Investigator: Address (e.g., Street, City, State, and Country) and
`contact information (i.e., phone, fax, email). If the Applicant is aware of changes to a
`
`clinical investigator’s site address or contact information since the time of the clinical
`investigator’s participation in the study, we request that this updated information also
`be provided.
`
`2. Please include the following information in a tabular format, by site, in the original NDA
`for each of the completed pivotal clinical trials:
`a. Number of subjects screened at each site
`b. Number of subjects randomized at each site
`c. Number of subjects treated who prematurely discontinued for each site by site
`
`3. Please include the following information in a tabular format in the NDA for each of the
`completed pivotal clinical trials:
`a. Location at which Sponsor trial documentation is maintained (e.g., , monitoring plans
`
`and reports, training records, data management plans, drug accountability records,
`
`IND safety reports, or other Sponsor records as described ICH E6, Section 8). This is
`the actual physical site(s) where documents are maintained and would be available for
`inspection
`b. Name, address and contact information of all Contract Research Organization (CROs)
`used in the conduct of the clinical trials and brief statement of trial related functions
`transferred to them. If this information has been submitted in eCTD format
`previously (e.g., as an addendum to a Form FDA 1571, you may identify the
`location(s) and/or provide link(s) to information previously provided.
`c. The location at which trial documentation and records generated by the CROs with
`respect to their roles and responsibilities in conduct of respective studies is
`maintained. As above, this is the actual physical site where documents would b