reduction in potency may be offset by relative increased formation. The levels of "
`‘
`metabolites exceed parent by 250 times in rat and monkey. Excretion in monkeys is
`~50% fecal and urinary whereas in humans 95% is urinary. Fecal excretion predominates
`in'rat (~60%).
`
`A number of toxicities have been identified that are of clinical concern because they
`occur in animals at relatively low exposure multiples. These include: hypocalcemia,
`cardiovascular toxicity (QTc prolongation, myocardial degeneration/necrosis, lefi
`ventricular arterial hyperplasia rat/juvenile dog, CPK increase and muscle degeneration ‘
`monkey), GI toxicity, endocrine changes (decreased testosterone, testicular atrophy, T3
`decrease, T4 increase, decreased Vit. D monkey), liver (minimal enzyme induction,
`decreased serum protein, vacuolation/necrosis rat, monkey) and renal toxicity
`(BUN/creatinine increase mineralization rat). A number of these nonclinical findings
`were observed in the clinic including: nausea, vomiting, hypocalcemia, convulsions,
`' decreased testosterone and QTc prolongation.
`
`In acute and chronic toxicity studies in rats, dogs and monkeys signs of hypocalcemia:
`hypoactivity, neuromuscular and respiratory effects, tremors, excessive salivation and
`convulsions were observed. In a 2 week rat study convulsions were observed at 500
`mg/kg/day (23X human AUC @ 180 mg/day) in conjunction with hypocalcemia.
`Convulsions and CNS toxicity were observed in an acute study with a putative
`metabolite/degradation product m at 100 mg/day (exposure relative to the
`clinical dose is unknown). Serum calcium was not measured which further suggested
`that the toxicity observed may be a function of the metabolites formed and hypocalcemia.
`It is unclear whether the metabolites have a differential capacity to alter calcium
`homeostasis. Also related to the hypocalcemic effect is the OTC prolongation (maximum
`. 80 msec) observed in the 3 land 12 month monkey studies at exposures <2X the human
`therapeutic. Interestingly the EKG effects appear to attenuate after 12 months of
`4
`treatment compared to 6 months although the hypocalcemia (10—40%) does not. QT
`prolongation Was not observed in a one month dog study despite a maximal serum
`, calcium reduction of 20% at doses similar to those tested in the monkey. The QTc
`prolongation and convulsions may reflect at least a partial contribution of hypocalcemia
`.or may be mediated by a direct effect of cinacalcet and/or its metabolites on CaR in these
`tissues. Hence the clinical relevance of hypocalcemia and the contribution of metabolites
`to this mechanism should be explored further.
`
`A clinical consult from Cardio-Renal Drugs (HFD-l 10) recommends a thorough
`evaluation of QT effects including a_dosing regimen that challenges tolerability, allows
`for production of metabolites and suggest the timing of the EKG to Cmax (parent +
`metabolites), external control of plasma calcium is relevant in order to delineate this
`confounder. Based on the in vitro data indicating significant inhibition (95% at 500
`ng/ml) of Kim ion channels by cinacalcet and the relationship these channels have in
`cardiac preconditioning in ischemic stress; Dr. Kuijpers’ pharmacology/toxicology
`review recommends a clinical investigation of stress EKG'testing. Since secondary HPT
`patients may have an increased incidence of cardiovascular disease this would seem
`prudent.
`
`

`

`Serum testosterone levels were decreased in the chronic monkey study at exposures S 2
`times the human therapeutic dose'concomitant with a decrease in testicular weight only at
`' 100 mg/kg/day. Testicular tubular atrophy/degeneration was observed in the one and 6
`month rat studies at 3 and 8 times human therapeutic AUC and in a one month dog study
`at human therapeutic exposures. Fertility studies in male rats did not indicate a
`significant reduction in fertility index. A complete battery of reprotoxicity studies in
`rats and rabbits was performed. Dosing was limited by maternal toxicity. Cinacalcet is
`secreted into milk at appreciable levels and crosses the placenta in rabbit where fetal
`levels’are ~1/10 maternal plasma levels. No fertility effects were observed in male or .
`female rats at exposures 3 times human therapeutic. Higher doses resulted in observable
`maternal toxicity. In segment H studies maternal toxicity was observed at all doses
`although the only fetal effect was decreased body weight. Exposures in this study were
`less than human therapeutic. Similar studies in rabbit do not result in any fetal adverse
`effects (exposures less than human therapeutic) despite maternal toxicity. Segment 1H
`studies in pregnant rats show no adverse fetal/pup effects at human therapeutic exposures
`in the absence of maternal toxicity. Exposures twice human therapeutic exposure was
`accompanied by maternal mortality, parturition difficulties, litter loss and reductions in
`maternal and pup body weight. The maternal toxicity seen here is likely related to
`hypocalcemia based on the increased need for calcium during parturition. Based on the
`fetal body weight effects in the absence of maternal toxicity pregnancy category C was
`indicated as proposed by the sponsor.
`
`The genotoxicity standard battery was negative. The rat and mouse 2-year dietary
`carcinogenicity studies were reviewed by ECAC, however the Committee found that
`there were no relevant tumor findings related to drug treatment.
`
`Recommendation: A full complement of nonclinical pharmacology and toxicology
`studies have been performed in this application which have identified findings of clinical
`relevance. Additional nonclinical studies are not needed for further hazard identification
`at this time however additional clinical evaluation may be needed at the discretion of the
`clinical team (see HFD-l 10 consult). Pharmacology/ Toxicology recommends approval
`(AP) pending labeling comments (see memo of 2/10/04).
`
`.433 7
`0;;09/332:W47
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`
`/8/
`
`Karen Davis—Bruno
`
`2/17/04 10:11:41 AM
`PHARMACOLOGIST
`AP
`
`

`

`Office of Drug Evaluation ODE II
`
`, Food and Drug Administration
`Center for Drug Evaluation and Research
`
`, FACSIMILE TRANSMITTAL SHEET
`
`DATE: February 13, 2004
`
`To: Pamela Danagher
`
`From: Randy Hedin
`
`Company: Amgen Inc.
`
`'
`
`Division of Metabolic and Endocrine Drug
`Products
`
`Fax number: 805-480-1330
`
`Fax number: 301—443-9282
`
`Phone number: 805-447-0214
`
`.
`
`Phone number: (301) 827-6392
`
`Subject: Cardio Renal Consult
`
`~
`
`. Total no. of pages including cover:
`
`2
`
`Comments:
`
`
`
`Document to be mailed:
`
`[JYES
`
`' El NO ‘
`
`'
`
`. THIS DOCUMENT IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM IT IS ADDRESSED
`AND MAY CONTAIN INFORMATION THAT IS PRIVILEGED, CONFIDENTIAL, AND PROTECTED
`FROM DISCLOSURE UNDER APPLICABLE LAW.
`
`If you are not the addressee, or a person authorized to deliver this document to the addressee,
`you are hereby notified that any review, disclosure, dissemination, copying, or other action based
`on the content of this communication is not authorized.
`If you have received this document in
`error, please notify us immediately by telephone at (301) 827-6430. Thank you.
`
`

`

`From:
`Sent:
`To:
`Subject:
`
`I Hedin, Durand M
`Friday, February 13, 2004 4:11 PM
`'Danagher, Pamela'
`NDA 21-688, Revised Draft Label
`
`Dear Ms. Danagher:
`
`Please refer to your September 5, 2003 new drug application (N‘DA).submitted under
`section 505(b) of the Federal Food, Drug, and cosmetic Act for Sensipar (cinacalcet
`HCl) Tablets.
`
`We are reviewing the labeling of your submission, and have attached a word document
`with revised draft labeling. Please be advised that these are initial comments by the
`Division. Additional, comments and recommendations will be requested by the Division,
`and the Office.
`
`If you have any questions, call me at (301) 827-6392.
`
`Sincerely,
`
`Randy Hedin
`
`as
`N21688
`lge Insert 2 13 2
`
`

`

`
`
`— H? page(s) 0f
`1
`reVised draft labeling
`- has been redacted
`from this portion Of
`T
`1 ,thereview ’
`
`1
`
`

`

`This'Is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`/8/
`
`Randy Hedin
`2/13/04 04:32:03 PM
`CSO
`'
`
`|
`
`

`

`‘
`
`
`
`
`
`page(s> of. .
`I
`. revised draft labeling
`has been redacted
`from this pertion 0f
`thereview.
`
`

`

`This is a repreSentation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Karen Davis-Bruno
`
`2/10/04 01:23:47 PM
`PHARMACOLOGIST
`
`P/T label comments
`
`

`

`From:
`Sent:
`To:
`Subject:
`
`Hedin, Durand M
`Monday, February 09, 2004, 3:31 PM
`'Danagher, Pamela'
`RE: NDA 21-688
`
`‘ Dear Ms. Danagher:
`
`Please refer to your September 5, 2003 new drug application (NDA) submitted under
`section 505(b) of the Federal Food, Drug, and Cosmetic Act for Sensipar (cinacalcet
`HCl) Tablets.
`
`We are reviewing the clinical section of your submission and have the following
`comments and information requests. We request a prompt written response in order to
`continue our evaluation of your NDA.
`'
`
`Pooled Data from Studies 172 I83. and 188
`
`0 For the Cinacalcet group, please provide a histogram of the doses of drug that
`patients were receiving at the ends of the Titration and Efficacy-Assessment
`phases.
`
`0 What were the mean and median doses for patient who achieved a iPTH < 250
`pg/ml?
`
`0 What was the association between risk for hypocalcemia (< 8.4 mg/dl) and dose
`of Cinacalcet?
`
`0
`
`If available, please provide follow up information on the SGPT levels ofpatients
`16302 and 13910.
`'
`
`'
`
`Studies 236 and 239
`
`o For 236, please provide the mean and median doses for the patients in the
`Cinacalcet group who achieved a iPTH < 65 pg/ml.
`
`. 0 For 239, please provide the mean and median doses for the patients in the
`Cinacalcet group who achieved a iPTH reduction of 2 30% from baseline.
`
`Study 120
`
`0 Please provide the percentage of patients in each group who developed a serum
`calcium level of < 8.4 mg/dl on at least one occasion during the trial.
`
`0 Please provide the percentage of patients in each group who developed a serum
`calcium level < 7.4 mg/dl on at least one occasion during the trial.
`
`0 Please provide a histogram of the changes from baseline to Week 52 in iPTH and
`
`

`

`calcium levels forithe two groups.
`
`0 Please provide the mean and median doses of Cinacalcet at Week 52 of the study.
`
`'
`
`0 We are concerned that you may have “enriched” the population of patients
`enrolled into Study 120 by including 22 patients who previously participated in
`Study 980125. Please explain.
`
`, If you have any questions, call me at (301) 827-6392.
`
`Sincerely,
`
`Randy Hedin
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`/S/
`
`Randy Hedin
`2/9/04 03:52:15 PM
`CSO
`
`

`

`From: Hedin, Durand M
`Sent: Wednesday, February 04,2004 2: 18 PM
`To: 'Danagher, Pamela’
`‘
`Subject: RE: NDA 21688
`Dear Ms. Danagher:
`
`Please refer to your September 5,2003 new drug application (NDA) submitted under '
`section 505(b) of the Federal Food, Drug, and Cosmetic Act for Sensipar (Cinacalcet
`' HCl) Tablets.
`'
`'
`
`We are reviewing the clinical section ofyour submission and have the following
`cements and information requests. We request a prompt written response in order to
`continue our evaluation of your NDA.
`
`Please provide the PTH assays that were used in each of the phase 2 and 3 clinical studies
`included in the Cinacalcet NDA submission. This information should include:
`
`Name of the‘study
`Dates the assay(s) was used
`
`Trade name of the assay
`
`Methodological description of the assay
`
`x————-—- ‘ performed the PTH assays, we believe it is important that
`Because
`——.'~verify in writing the above information.
`
`If you have any questions, call me at (301) 827-6392.
`
`Sincerely,
`
`Randy Hedin
`
`

`

`This is a representation of an electronic record that was signed electronicallyand
`this page is the manifestation of the electronicsignature,
`
`/S/
`
`. Randy Hedin
`2/4/04 02:40:15 PM
`CSO
`
`

`

`From: Hedin, DurandM
`
`Sent: Thursday, January 22, 2004 4:29 PM
`To: '.pame1ad@amgencom‘
`Cc: 'jfellows@amgen.com'
`Subject: NDA 21-688
`Dear Ms. Danagher:
`
`Please refer to your September 5,2003 new drug application (NDA) submitted under
`section 505(b) of the Federal Food, Drug, and Cosmetic Act for Sensipar (cinacalcet
`HCl) Tablets
`
`We are reviewing the clinical section of your submission and have the following
`comments and information requests. We request a prompt written response in order to
`continue our evaluation of your NDA.
`
`If you have any questions, call me at (301) 827-6392.
`
`Sincerely,
`
`Randy Hedin
`
`For the following questions, please provide answers or reference the appropriate
`section(s) of the NDA where the answers can be found.
`
`From the’ Entire Clinical Development Database (phase 1- 3):
`
`1. Please»provide all WHOART primary adverse event terms that could reasonably
`be associated with increased acid secretion in the stomach or duodenum.
`
`2. Based on the WHOART terms in question 1, please provide the number of
`patients and treatment assignment who experienced symptoms that could
`reasonably be associated with increased acid secretion in the stomach or
`' duodenum.
`
`Using the pooled data from studies 172, 183, and 188:
`
`3. Based on the WHOART terms in question 1, please provide the number of
`patients in the cinacalcet and placebo groups who experienced symptoms that
`could reasonably be associated with increased acid secretion in the stomach or
`duodenum.
`
`4. Please provide the number of patients in the cinacalcet and placebo groups that
`received, on at least one occasion, a medication to treat an increased stomach
`acidity, GERD, gastritis, etc.
`
`

`

`,
`For studies 990126, 990740 and 20010141:
`5. Please provide end of study values and analysis for the bone turnover parameters:
`mineralization lag time, osteoid thickness and osteoid surface
`
`For study 20000l 88:
`
`6. For the data provided in Tables 8 and 11 of the Internal Report on the Assessment
`of Hormone Levels, please provide appropriate statistical analyses of the
`comparison between the placebo and cinacalcet groups for the mean changes in
`' total and free testosterone from baseline to Weeks 16 and 26.
`
`7. For the data provided in Tables 10 and 13 of the Internal Report on the
`Assessment of Hormone Levels, please provide appropriate statistical analyses of
`the comparison of the proportion of subjects in the placebo and cinacalcet groups
`with normal baseline and below normal range levels of total and free testosterone
`at Weeks 16 and 26.
`
`APPEARS nus w
`ON 0010mm AY
`
`

`

`This'Is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Randy Hedin
`1/22/04 04:49:51 PM
`CSO
`
`

`

`From:
`Sent:
`To:
`Cc:
`Subject:
`Dear Ms. Danagher:
`
`:
`
`Hedin, Durand M ’
`Wednesday, January 14, 2004 1:47 PM
`'Danagher‘, Pamela'
`'jfellows@amgen.com'
`NDA 21-688
`
`Please refer to your September 5, 2003 new drug application (NDA) submitted under
`section 505(b) of the Federal Food, Drug, and Cosmetic Act for Sensipar (cinacalcet
`HCI) Tablets;
`’
`-
`
`We are reviewing the clinical section of your submission and have the following
`comments and information requests. We request a prompt written response in order to
`continue our evaluation of your NDA.
`
`If you have any questions, call me at (301) 827-6392.
`
`Sincerely,
`
`Randy Hedin
`
`Using the pooled data from studies 172, 183, and 188:
`
`1. Please provide the number of patients in the cinacalcet and placebo groups that
`received, on at least one occasion, a medication to treat an episode of nausea or
`vomiting.
`'
`'
`
`2. Please provide the reference range for normal serum calcium used by the ~2—
`laboratory.
`'
`'
`
`3. Please provide the number and % of patients in each treatment group who had at least
`one serum calcium level < 8.4 mg/dl; the number and % of patients who were
`instructed to increase their calcium intake; the number and % of patients who had
`their dose of vitamin D increased; and the number and % of patients who had their
`study drug withheld. Please present data in total and stratified, based on treatment,
`treatment period and strata.
`
`4. Please provide the baseline heart rates in the placebo and cinacalcet groups along
`with the mean changes from baseline to Week 26.
`
`5. Please provide the mean percent change from baseline to Week 26 for all of the
`parameters listed in section 2.7.4.3.1.1 of the Clinical Summary, Summary of Clinical
`Safety.
`
`6. Please provide the number and % of patients in the placebo and cinacalcet groups
`
`

`

`who developed SGPT values that were > 1x ULN, > 2 x ULN, and > 3 x ULN. Please
`also provide the absolute value for the largest increase in SGOT in the placebo and
`cinacalcet groups. In addition to providing the overall results of these analyses, please
`present data stratified, by treatment group, treatment period (titration, efficacy
`assessment) and all of the pre—defined subgroup strata.
`
`Was body weight systematically measured during the trials? If so, please provide the
`mean percent change from baseline to Week 26 for the placebo and cinacalcet groups.
`
`Please provide the modified WHO lab ranges used and precise definitions of the
`derived levels used to define the various grades for abnormal laboratory values used
`in the shifl tables.
`:
`
`Please providethe number of all protocol deviations and eligibility deviations, stratify
`by study, treatment group,,treatment period (titration, efficacy assessment), andall
`pre-defmed subgroup strata.
`
`Using 2'ooled data from studies 236 and 239:
`
`‘
`
`10. Please provide the number and % of patients in each treatment group who had at least
`one serum calcium level < 8.4 mg/dl; the number and % of patients who were
`instructed to increase their calcium intake; the number and % of patients who had
`their dose of vitamin D increased; and the number and % of patients who had their
`study drug withheld.
`
`11.
`
`Please provide the mean baseline serum calcium, levels for the cinacalcet and placebo
`groups and the mean percent change from baseline to Week 16 (with min and max
`values).
`
`From the Entire Clinical Development Database (phase 1- 3):
`
`12. Please provide the number of patients who experienced a seizure during participation
`in any of the phase 1 — 3 clinical Studies. Please also indicate which clinical study and
`treatment group (cinacalcet or placebo) the patients were assigned to.
`
`13. Are there WHOART primary adverse event terms‘in addition to convulsions,
`convulsions local, and status epilepticus that could indicate seizure activity?
`
`14. Please provide the number of patients who experienced esophagitis, gastritis, or upper
`GI bleed during participation in any of the phase 1 — 3 clinical studies. Please also
`indicate which clinical study and treatment group (cinacalcet or placebo) the patients
`Were assigned to.
`
`Clinical Study 240:
`
`

`

`15. What determined whether a patient entered study 240?
`
`APPEARS nus WAY
`0N ORIGINAL *
`
`

`

`This is a representation. of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`/S/
`
`Randy Hedin
`1/14/04 03 40 40 PM
`cso
`
`

`

`MEMORANDUM OF TELECON
`
`DATE; January 7, 2005
`
`APPLICATION NUMBER: NDA 21—688, Sensipar (cinicalcet HClj Tablets
`
`BETWEEN:
`
`Name:
`Phone:
`
`)
`
`Pamela Danagher, Manager, Regulatory Affairs
`805-447-0214
`
`Representing: Amgen Inc.
`
`AND
`
`Narne:
`
`Randy Hedin, Senior Regulatory Management Officer
`Division of Metabolic and EndOcrine Drug Products, HFD-510
`
`SUBJECT: Request QT and PK Information
`
`I called Ms. Danagher and requested the following infOrmatiOn:
`
`-
`
`0
`
`Submit a very brief summary of the multiple-dose PK data including Tmax and dei,
`serum calcium.
`
`Submit all QT data for phases 1-3 and include a description of patient populations and
`indicate the time ECGs were obtained relative to the most recent dose of drug.
`
`Ms. Danagher stated that Amgen would try to get this information to us in a week, but, they try
`to turn-around all information requests in two weeks
`'
`
`Randy Hedin
`
`Senior Regulatory Management Officer
`
`

`

`This'Is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`/S/
`
`Randy Hedin
`1/7/04 04:06:12 PM
`CSO
`
`

`

`l
`
`. § é DEPARTMENTorHEALTII&HUMANSERVICES
`
`m",
`
`I‘WW3
`
`PublicHealthService
`
`Food and Drug Administration
`Rockville, MD 20857
`
`NDA 21-688
`
`INFORMATION REQUEST LETTER
`
`Amgen Inc.
`Attention: Pamela Danagher
`Manager, Regulatory Affairs
`One Amgen Center Drive
`Thousand Oaks, CA 91320-1799
`
`Dear Ms. Danagher:
`
`Please refer to your September 5, 2003 new drug application (NDA) submitted under section
`505(b) of the Federal Food, Drug, and Cosmetic Act for Sensipar (cinacalcet HCl) Tablets.
`
`We also refer to your submission dated December 3, 2003.
`
`We are reviewing the Chemistry, Manufacturing and Controls section of your submission and
`have the following comments and information requests. We request a prompt written response
`in order to continue our evaluation of your NDA.
`
`Drug Substance:
`
`1.
`
`2.
`
`3.
`
`If you plan to recycle any of the solvents involved in the drug substance manufacturing,
`provide the protocol for the procedure.
`
`Provide typical storage temperatures, and duration, for the storage of the intermediates
`used in the synthesis of the drug substance, cinacalcet HCl.
`
`Inform us if “pooling” multiple lots of an intermediate may occur. If so, what is your
`protocol for “pooling?”
`'
`
`' 4.‘ The values of LOD' and LOQ reported in the analytical procedure for impurities‘(p. 74 of
`the Method Validation Package, Volume 1 of 3) are not consistent with those values
`reported in the validation report (p. 100 of the Method Validation Package, Volume 1 of
`. 3 and p. 24 of NDA CMC section 3.2.8.4). Provide clarification for this disorepancy.
`
`5. Your acceptance criteria should include a specific identity test (e.g. by IR) for the
`packaging component which directly contacts the drug substance. Therefore, provide an
`ID test for your .
`
`.
`
`6. Your primary stability studies for the drug substance are performed at 25°C. Therefore,
`the proposedlstorage statement in the NDA should be revised.
`
`

`

`NDA 21-688
`
`’ Page 2
`
`7.
`
`Concerning your proposal for the primary reference standard (PRS) specification limits
`(Table 1, page 8, Response to CMC questions, NDA 21-688 Amendment 3), the
`acceptance criteria of future PRS lots should be at least the same as those for the first
`PRS lot. In order to adequately characterize each future PRS, your protocol for this
`
`purpose should also include a
`for the new standard.
`
`Drug Product:
`
`In Section 3.2.P.2;2.1 (Formulation Development), [-
`
`
`
`“I’m
`
`HWJ
`
`If you have any questions, call Randy Hedin, Senior Regulatory Management Officer, at (301)
`827-6392.
`»
`'
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Kati Johnson
`
`~
`
`Chief, Project Management Staff
`Division of Metabolic and Endocrine Drug Products
`' Office of Drug Evaluation 11
`Center for Drug Evaluation and Research
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Randy Hedin
`.
`12/23/03 03:28:17 PM
`Signing for Kati Johnson
`
`

`

`qr,
`
`.
`
`.
`
`=*
`,3:
`
`
`
`‘4 DEPARTMENTOFHEALTH&HUMANSERVICES PublicHealthService
`
`h/IW’“
`
`Food and Drug Administration
`Rockville MD 2085?
`
`711% e011,
`
`"m."m
`
`NBA 21-688
`
`’ Amgen Inc.
`Attention: Pamela Danagher
`Manager, Regulatory Affairs
`One Amgen Center Drive
`Thousand Oaks, CA 91320-1799
`
`Dear Ms. Danagher:
`
`Please refer to your September 5, 2003 new drug application (NDA), submitted under section 505(b)
`of the Federal Food, Drug, and Cosmetic Act for Sensipar (cinacalcet HCl) Tablets.
`
`' We have completed our filing review and have determined that your application is sufficiently
`complete to permit a substantive review. Therefore, this application has been filed under section
`505(b) of the Act on November 7, 2003 in accordance with 21 CFR 314.101(a). Our filing review is
`only a preliminary review and deficiencies may be identified during substantive review of your
`application.
`'
`
`In our filing review, we have identified the following potential review issues:
`
`Drug Substance:
`
`1.; I,
`
`
`
`-2. Please provide an executed batch record for a representative commercial lot of the drug
`substance.
`
`

`

`NDA 21-688
`' Page 2
`
`3. DeScribe any remedial actions you take, priOr to the final step, in the manufacture of the drug
`substance, when any in-process acceptance criteria are not met.
`
`Drug Product:
`
`1.
`
`In section 32 ..P3, you state that 1W
`substance prior to use in manufacturing the drug product. Is this ~ the same as that
`
`performed by.
`for their release of the drug substance? If not, describe
`the differences
`
`2. Please indicate whether or not any reprocessing, in the manufacture of your drug product, may
`be carried out. If there18 any reprocessing during manufacture, describe the procedures that
`may be carried out.
`
`3. Your acceptance criteria should include specific identity tests (e.g. by IR) for those packaging
`components that may contact the drug product. Consequently, provide specific identity tests
`
`for your \— bottles, the appropriate surface of your
`—~« filler, and relevant seals on your child-resistant—closure.
`
`, 4. Your release and stability data for the batches ofmanufactured drug product show total
`
`"
`impurities atmuch lower levels than your’proposed acceptance criteria of
`' Accordingly,
`your specification for total impurities in the drug product should have a lower limit.
`.
`
`5. Provide your justification for not including a test for amorphous cinacalcet HCl in your drug
`product specification.
`
`We are providing the above cements to give you preliminary notice "of potential review issues. Our
`filing review is only a preliminary evaluation of the application and is not indicative of deficiencies
`that may be identified during our review. Issues may be added, deleted, expanded upon, or modified
`- as we review the application.
`
`

`

`NDA 21-688
`
`Page 3
`
`Please respond only to the above requests for additional information. While we anticipate that any
`response submitted in a tiinely manner will be reviewed during this review cycle, such review
`decisions will be made on a case-by-case basis at the time of receipt of the submission.
`
`If you have'any questions, call Randy Hedin, R.Ph., Senior Regulatory Management Officer, at (301)
`827-6392.
`‘
`=
`'
`.
`'
`
`Sincerely,
`
`{See appended electronic signature page}
`
`David G. Orloff, MD.
`Director
`
`.
`
`Division of Metabolic and Endocrine Drug Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
`

`

`This'Is a representation of an electronic record that was signed electronically and ’
`this page is the manifestation of the electronic signature.
`
`David Orloff
`
`11/18/03 09:44:15 AM
`
`

`

`NBA/EFFICACY SUPPLEMENT ACTION PACKAGE CHECKLIST
`
`.
`
`\
`
`
`3 Mia/{21-688
`)
`Eflicac SuilementTpe SE—
`
`505 2
`«anemone: x 505 1
`Application ClaSSifications
`'
`
`——
`——
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`Special programs (indicate all that apply)
`
`
`
`
`_
`
`( X) None
`Subpait H
`()21, CFR 314.510 (accelerated
`' approval)
`() 21 CFR 314.520
`
`(restricted distribution)
`
`() Fast Track
`
`() Rolling Review
`
`
`
`
`() Small business
`
`() Public health
`
`
`() Baxrier-to—Innovation
`
`
`Other
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`
`
`
`User Fee
`0 User Fee waiver
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`
`
`
`
`
`0 User Fee exception
`
`'
`
`'3' Application Integrity Policy (AIP)
`.
`.
`.
`Applicant is on the AIP
`
`‘
`
`1
`
`() Orphan designation
`() No-fee 505(b)(2)
`Other‘
`
`'
`
`() Yes
`
`(X ) No
`
`
`
`4
`
`(X ) No
`() Yes
`This application is on the AIP
`0
`Exception for review (Center Director’s memo) _
`0
`ocaearancerorapprovan —
`.
`.
`O
`
`
`(X) Verified
`-
`'
`0.9 Debannent certification: verified that qualifying language (e.g., willingly, knowingly) was
`
`
`
`
`
`not used in certification & certifications from forei y: a - licants are cosi. ed b US a ent.
`
`0
`Information: Verify that form FDA-3542a was submitted.
`
`0
`Patent certification [505(b)(2) applications]: Verify type of certification
`submitted.
`‘
`
`
`
`
`
`(X) Verified
`’
`21 CFR 3 14.50(i)(1)(i)(A)
`()1 ()11
`() 1H () IV
`
`
`
`21 em 314.50(i)(1)
`ii
`iii
`
`
`
`For paragraph IV certification, verify that the applicant notified the patent
`holder(s) of their certification that the patent(s) is inValid, unenforceable, or will
`not be infringed (certification of notification and documentation of receipt of
`
`
` notice .
`'9 Excluswity (approvals only) as. ._...dx.A—._.._._.__..‘
`0
`Exclusivity summary
`March 8, 2004
`o
`Is there an existing orphan drug exclusivity protection for the active moiety for
`() Yes, Application #
`the o-roosed indication s ? Re er to 21 CFR 316.3 . 13 or the de mition o
`( X ) No
`‘
`
`() Verified
`
`
`
`
`
`Version: 9/25/03
`
`

`

`NDA 21-688
`
`/ ‘
`__ Page 2
`W
` samenessfor an orphan drug (i.e., active moiety). This definition is NOT the
`'2' Administrative Reviews (Project Manager, ADRA) (indicate date ofeach review)
`gswggcigoggao’ 2003
`I?
`
`
`same as that used or NDA chemical classi teation!
`
`,
`
`,
`
`'
`
`i
`
`(X)AP NDA21-688
`(X) AE NDA 21-688/8-001
`NDA 21 -688/S-002
`
`(X) Material requested in AP letter
`Reviewed for Sub ' art H
`.
`
`,0
`
`Proposed action
`
`_
`
`0’ Previous actions (specify type and date for each action taken)
`.
`.
`Status of advertising (approvals only)
`0
`
`Public communications
`
`Press Office notified of action (approval only)
`
`-
`
`'
`
`‘
`
`,
`
`0
`
`Indicate what types (if any) of information dissemination are anticipated
`
`'9 Labeling (package insert, patient package insert (if applicable), MedGuide (if applicable»
`0 Division’s proposed labeling (only if generated afier latest applicant submission
`
`
`of labeling)
`_
`__
`_
`_
`__
`.,
`___
`0 Most recent applicant-proposed labeling
`
`=
`
`'
`'v
`k
`
`g
`
`>
`
`.
`
`
`I;
`
`0 Original applicant-propOSed labeling
`0
`Labeling reviews (including DDMAC, DMETS, DSRCS) and minutes of
`labelin
`s indicate dates 0! reviews and meetin 3
`o ‘ Other relevant labeling (e.g., most recent 3 in class, class labeling)
`E
`'3' Labels (immediate container & carton labels)
`,
`fi
`‘
`a
`0 Division proposed (only ifgenerated afier latest applicant submission) _ ’i
`.
`,
`September 5, 2003
`‘
`-_ Applicant proposed
`Feb
`.
`26, 2004
`,
`Chemistry, February 26, 2004
`RCV'CWS
`'
`March 3,2004 '
`91' Post-marketing commitments '
`0 Agency request for post—marketing commttments
`,,,,,, “4.,
`0
`Documentation of discusswns and/or agreements relating to post-marketing
`March 3 2004 m, «T, r, W _ w “,4,“ _ MM,” M
`commitments
`'
`’
`——
`
`( ) Not applicable
`
`(X) Yes
`( ) None
`(X) Press Release
`(X ) Talk Paper
`( ) Dear Health Care Professional
`Letter
`
`I
`
`March 5, 2004
`
`.
`
`'
`September 5, 2003
`DMETS, November 8, 2003
`March 5, 2004
`
`,
`
`5‘
`
`
`
`— “
`
`fire-NDA meeting<iraeagzae_~__
`
`_._____-
`
`February 11, 2004
`
`.
`
`.
`
`F
`
`o v
`
`Advisory Committee Meeting
`
`Date of Meeting
`48-hour alert
`
`0
`
`Version: 9/25/03
`
`

`

`WM)?
`
`PublicHealthService
`
`Food and Drug Administration
`Rockville, MD 20857
`
`3’
`
`,5 g DEPARTMENTOFHEALTH&HUMANSERVICES
`
`NDA 21-688
`
`Amgen Inc.
`Attn: Pamela Danagher
`'
`Manager, Regulatory Affairs
`One Amgen Center Drive, Mail Stop l7—2-A
`Thousand Oaks, CA 91320-1799
`
`Dear Ms. Danagher:
`
`We have received your new drug application (NDA) submitted under section 505(b) of the
`Federal Food, Drug, and Cosmetic Act for the following:
`'
`
`Name of Drug Product:
`
`_
`
`Sensiparw (cinacalcet HCI) Tablets
`
`Review Priority Classification:
`
`Priority (P)
`
`Date of Application:
`
`September 5, 2003
`
`Date of Receipt:
`
`September 8, 2003
`
`Our Reference Number:
`
`' i. A NDA 21‘-688
`
`Unless we notify you within 60 days of the receipt date that the application is not sufficiently
`complete to permit a substantive review, we will file the application on November 7, 2003 in
`accordance with 21 CFR 314.101(a). If the application is filed, the user fee goal date will be
`March 8, 2004.
`
`' Please cite the NDA number listed above at the top ofthe first page Of any communications
`w~ ~ ~ .. . «v: concerning this application: Address all communications concerning this NDA as followsz' "‘
`
`“
`,
`
`"‘ ‘
`‘
`>7 ___._-,..v
`
`,-3 -.
`
`U.S. PostaI Service/Courier/Overnight Mail:
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Metabolic & Endocrine Drug Products, HFD-S 10
`Attention: Fishers Document Room, 8B45
`5600 Fishers Lane
`Rockville, Maryland 20857
`
`

`

`NDA 21-688
`
`Page 2
`
`If you have any questions, call me at (301) 827-6429.
`
`I
`
`Sincerely,
`
`{S’éfiendedelectronicsignaturepage}
`
`Randy Hedin, R.Ph.
`Senior Regulatory Management Officer
`Division of Metabolic & Endocrine Drug Products
`Office of Drug Evaluation 11
`Center for Drug Evaluation and Research
`
`.5.» ..,...
`
`-w. .
`
`“r‘
`
`

`

`
`
`This Is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the