CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`205029Orig1s000
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`OTHER ACTION LETTERS
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`g CDEPARTMENT OFHEALTHAND HUMAN SERVICES
`3%”-
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`NDA 205029
`
`Belcher Pharmaceuticals, LLC
`Attention: Mihir Taneja
`Vice President
`
`6911 Bryan Dairy Road
`Suite 210
`
`Largo, FL 33777
`
`Dear Mr. Taneja:
`
`Food and Drug Administration
`Silver Spring MD 20993
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`COMPLETE RESPONSE
`
`Please refer to your New Drug Application (NDA) dated November 30, 2012, received December 4,
`2012, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act, for
`epinephrine injection 1 mg/mL.
`
`We acknowledge receipt of your amendments dated January 3, 4, 8, February 6, March 4, 8, and April 8,
`2013.
`
`We have completed our review of this application, as amended, and have determined that we cannot
`approve this application in its present form. We have described our reasons for this action below and,
`where possible, our recommendations to address these issues.
`
`PRODUCT UALITY
`
`1.
`
`data from the two batches manufactured in February 2013 to support your contention.
`
`
`In response to our question about evaluation of the manufacturing process for
`epinephrine, you have stated that anal sis of two batches of E '
`hrine In'ectlon
`
` in the drug product without providing adequate justification. However, you have not provided
`Therefore, we recommend that on re-evaluate the manufacturing process establishing the-W andprovide dataincludin butnot
`te to
`gpr uctre easean sta 1 ty
`testa
`s andjusfifytheMtoensure
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`that the drug product meets the critical quality attributes for intended use
`
`ou out
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`e s elf-life.
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`We also recommend that you provide data in regard to:
`
`a. Evaluating the effect of selected in-process pH
`during manufactunn'g process and on storage
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`of the drug product
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`b. The extentof” drug product on storage by analyzing samples
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`from either comp etc or curren y ongomg sta
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`ty studies.
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`c. Chiral stability-indicating HPLC method and its validation report for evaluation.
`
`Ifthe data convincingly demonstrate that! is mainly attributed to the
`_ step, you should consider an ternatlve sterilization process such as
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`Reference ID: 3384731
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`NDA 205029
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`Page 2
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`—
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`2. Provide a description and controls for the preparation of epinephrine solution in- employed in
`compounding bulk drug product solution.
`
`3. The manufacturing process as described does not include verification of the epinephrine content at
`any stage. We recommend that you incorporate in-process testing of the bulk drug product solution
`for epinephrine content with appropriate acceptance limits during manufacturing prior to filling.
`
`4. The HPLC analytical method for the assay of epinephrine and related substances employed in
`generating batch release and stability data presented in your application does not meet the system
`suitability requirements for intended use.
`
`For example, the HPLC analytical method currently employed for the assay of epinephrine and
`related substances of drug product batches (Section 3.2.P.5.2.6) as described show that system
`suitability criteria are inadequate as: i) the standard concentration is not verified with second standard
`preparation in all three methods, and ii) in the present version, %RSD is determined based on three
`standard injections instead of a minimum of five injections as recommended per USP<621>.
`Additionally, review of method validation information for the current method shows that:
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`a. Data presented for precision correspond to anal
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`is of six r
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`solution, andtworelatedsubstances,fl and
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`instrurnent/inj ection precision (part 0 system smtability instea of method precision, i.e.
`analysis of six replicate sample preparations.
`
`licate injections of a single assay
`
`establishing
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`b. While data presented for intermediate recision correspond to three replicates for each of
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`Epinephrine,F and
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`these data were om Single injections 0
`preparation.
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`by two analysts and on two days, it was not clear if
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`cc preparations or three injections of a single sample
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`Finally, stability data presented for the drug product batches (manufactured and placed on stability at
`the same time) show consistently large variations in assay values across all three batches. These
`almost identical variations in assay values observed at each interval seen for the three batches are
`most likely due to failure to verify the standard concentration as part of system suitability for the
`method.
`
`We recommend that you appropriately revise the analytical method for assay of epinephrine and
`related substances and revalidate following the Guidance for Industry, “Analytical Procedures and
`Methods Validation: Chemistry, Manufacturing and Controls Documentation” for ensuring the
`quality of Epinephrine injection in terms of its identity, purity, strength and potency of L-Epinephrine
`at release and during its shelf-life.
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`LABELING
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`Submit draft labeling that incorporates revisions in the attached labeling. In addition, submit updated
`content of labeling [21 CFR 314.50(IXl)(i)] in structured product labeling (SPL) format as described at
`http://wwwfda.gov/Forhldustry/DataStandards/StructuredProductLabelingZdefaulthtm
`
`To facilitate review of your submission, provide a highlighted or marked-up copy that shows all changes,
`as well as a clean Microsofi Word version. The marked-up copy should include annotations that support
`any proposed changes.
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`Reference ID: 3384731
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`NDA 205029
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`Page 3
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`Please submit draft carton and container labeling revised as follows:
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`A. General Comments for Container Labels and Carton Labeling
`1. Revise the proprietary name and established name to appear in title case.
`2. Revise the order for the statement of strength so the mg/mL is the primary expression of strength
`(not the ratio 1:1000).
`3. Present the number 1000 with a comma to help differentiate it from the number 10000 (the other
`strength of epinephrine).
`4. Present the proprietary name, established name, and strength in a stacked format, similar to the
`following:
`
`Tradename
`(Epinephrine Injection, USP)
`1 mg/mL
`(1:1,000)
`
`6.
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`8.
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`5. Ensure that the established name is at least half the size of the proprietary name. Ensure the
`established name has prominence commensurate with the proprietary name taking into account all
`pertinent factors including typography, layout, contrast and other printing features per 21 CFR
`201.10(g)(2).
`Increase the prominence of the route of administration statement and relocate it directly below the
`strength statement. In addition, replace the word
` with the word “Infusion” in the statement
`that begins with “For Intravenous
` to improve clarity of the intended route of
`administration given that epinephrine is currently given by multiple routes of administration for
`other indications.
` (that follows the route of
`7. Delete the phrase
`administration statement) to reduce clutter on this small label. Accordingly, revise the statement
`to read “For Intravenous Infusion.”
`In order to ensure proper administration of epinephrine of diluting prior to intravenous infusion,
`we recommend adding the statement “Dilute Before Intravenous Infusion”. If space permits,
`prominently display this statement on the principal display panel under the strength statement.
`9. Decrease the prominence of the “Rx Only” statement and relocate the statement to the side panel
`to minimize distraction from other more important information on the principle display panel.
`10. Delete the
` located on the principal display panel as it is redundant
`as it is already found on the side panel.
`11. Delete the statement “Contains No Sulfites” found on the principle display panel to reduce clutter
`on a crowded small label.
`12. Add the statement “Single Dose Ampule” to the bottom of the principle display panel.
`13. Remove the color block from the proprietary name and strength expressions to enhance the
`contrast and improve readability of the establish name since it is currently difficult to read the
`established name.
`B. Container Label-1 mL Ampule
`1. Relocate the
`label.
`
` statement to the side panel to reduce clutter on a crowded small
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`Reference ID: 3384731
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`NDA 205029
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`Page 4
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`4.
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` statement which will provide additional space to
`2. Consider deleting the
`enlarge the area of the principle display panel.
`C. Carton Labeling-1 mL (10 Ampules)
`1. Unbold and revise the net quantity statement to read “10 Single-Dose Ampules x1 mL each”.
`Relocate this statement to the lower portion of the principle display panel to avoid competing
`with the strength statement.
`2. Relocate the “preservative free” statement from the top to the bottom of the principal display
`panel. Delete the “Contains no sulfites” statement.
`3. Delete or minimize and relocate the graphic away from the proprietary name to avoid
`misinterpretation as a letter ‘O’ in the proprietary name.
`Increase the prominence of the strength statement since the purple box is difficult to discern
`against a dark blue background.
`5. Relocate the storage condition statement to the side panel to reduce clutter on the principal
`display panel.
`If space is needed to accommodate the additional statements, consider relocating the “Each mL
`contains…” statement from below the strength statement to the side panel.
`7. Revise the storage condition statement to include the units °C or °F, respectively, and replace the
`hyphen within the temperature designations with the word “to” for improved clarity and to be
`consistent with USP standards. We recommend not using the hyphen between the numbers
`because a hyphen can be misinterpreted as a minus sign when discussing temperatures. Therefore,
`revise the storage statement to read “Store between
` to 25°C (
` to 77°F)”.
`8. Revise the statement after the word” WARNINGS” to appear in mixed case to enhance the
`readability of the statement “Do not use if discolored or precipitated.”
`9. Debold the storage statement “Store between …” to improve readability.
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`6.
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`REQUIRED PEDIATRIC ASSESSMENTS
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`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active
`ingredients, 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
`in pediatric patients unless this requirement is waived, deferred, or inapplicable.
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`We note that you have requested a full waiver of pediatric studies because studies are impossible or
`highly impractical. We do not agree that such studies are impossible or highly impractical. In addition, we
`believe there are sufficient data available in the literature to assess the safety and effectiveness of
`epinephrine for the claimed indication in pediatric patients. Therefore, your request for a waiver of
`pediatric studies is denied. Please submit information from all available sources, including literature, to
`appropriately label this product for the pediatric population.
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`SAFETY UPDATE
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`When you respond to the above deficiencies, include a safety update as described at
`21 CFR 314.50(d)(5)(vi)(b). The safety update should include data from all nonclinical and clinical
`studies/trials of the drug under consideration regardless of indication, dosage form, or dose level.
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`1. Describe in detail any significant changes or findings in the safety profile.
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`Reference ID: 3384731
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`(b) (4)
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`(b) (4)
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`NDA 205029
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`Page 5
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`(cid:120)
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`(cid:120)
`(cid:120)
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`2. When assembling the sections describing discontinuations due to adverse events, serious adverse
`events, and common adverse events, incorporate new safety data as follows:
`Present new safety data from the studies/clinical trials for the proposed indication using the
`(cid:120)
`same format as the original NDA submission.
`Present tabulations of the new safety data combined with the original NDA data.
`Include tables that compare frequencies of adverse events in the original NDA with the
`retabulated frequencies described in the bullet above.
`For indications other than the proposed indication, provide separate tables for the frequencies
`of adverse events occurring in clinical trials.
`3. Present a retabulation of the reasons for premature trial discontinuation by incorporating the drop-
`outs from the newly completed trials. Describe any new trends or patterns identified.
`4. Provide case report forms and narrative summaries for each patient who died during a clinical
`trial or who did not complete a trial because of an adverse event. In addition, provide narrative
`summaries for serious adverse events.
`5. Describe any information that suggests a substantial change in the incidence of common, but less
`serious, adverse events between the new data and the original NDA data.
`6. Provide updated exposure information for the clinical studies/trials (e.g., number of subjects,
`person time).
`7. Provide a summary of worldwide experience on the safety of this drug. Include an updated
`estimate of use for drug marketed in other countries.
`8. Provide English translations of current approved foreign labeling not previously submitted.
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`OTHER
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`Within one year after the date of this letter, you are required to resubmit or take other actions available
`under 21 CFR 314.110. If you do not take one of these actions, we may consider your lack of response a
`request to withdraw the application under 21 CFR 314.65. You may also request an extension of time in
`which to resubmit the application. A resubmission must fully address all the deficiencies listed. A partial
`response to this letter will not be processed as a resubmission and will not start a new review cycle.
`
`Under 21 CFR 314.102(d), you may request a meeting or telephone conference with us to discuss what
`steps you need to take before the application may be approved. If you wish to have such a meeting,
`submit your meeting request as described in the FDA Guidance for Industry, “Formal Meetings Between
`the FDA and Sponsors or Applicants,” May 2009 at
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM1532
`22.pdf.
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`If you have any questions, call Russell Fortney, Regulatory Project Manager at (301) 796-1068.
`
`Sincerely,
`
`{See appended electronic signature page}
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`Reference ID: 3384731
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`NDA 205029
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`Page 6
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`Norman Stockbridge, M.D., Ph.D.
`Director
`Division of Cardiovascular and Renal Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
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`ENCLOSURE: Draft Labeling
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`Reference ID: 3384731
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`23 Pages of Draft Labeling have been Withheld in Full as b4 (CCI/TS)
`immediately following this page.
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`NORMAN L STOCKBRIDGE
`10/04/2013
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`Reference ID: 3384731
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