RDR
`
`E AL ATI NA DRE EA
`
`APPLIQQAIIQN NUMBER: NDA 20845
`
`ADMIEE! RATIYE DQQIJMENTS
`
`

`

`RI-IPM Overview of NBA 20-845
`
`INOmax (nitric oxide) Inhaled '
`Update November. 14, 1999
`
`Type: 1P
`May 26, 1999
`Receipt Date:
`User Fee Goal Date: November 26, I999
`Approvable Letter Issued: November 19, 1999
`
`Background
`Ohmeda originally submitted this application on June 16, 1997 for the use of nitric oxide in the treatment
`of hypoxic respiratory failure of the newborn. Orphan Drug designation was granted for this use on
`June 13. 1993. The application was withdrawn on September 17. 1997 before an action was taken.
`There have been two Advisory Committee meetings, one before the application was submitted
`(August 28, 1995) and the other after the application was withdrawn (April 9. 1998).
`[NO Therapeutics. Inc. acquired the NDA and resubmitted the application on May 26. 1999
`
`Medical Reviews
`
`There were two medical reviews of the NINOS and INO-OllOZ trials completed during the first review
`period:
`
`In his review dated November 24, 1997, Dr. Throckmorton, Medical Officer. I-lFD-l 10. recommended
`that the application not" be approved stating that there was not sufficient data suggesting a clear beneficial
`effect of I-NO on hard endpoints. This was coupled with the potential adverse events associated with 1-
`NO administration and the inadequacy of the safety database for certain key adverse events.
`
`In her review dated August 25. 1197, Dr. Pina, Medical Officer, I-IFD-570. stated that there were many
`outstanding issues that prevent us from recommending these trials as supportive of the safety and efficacy
`of NO for the treatment of hypoxia respiratory failure. See her review.
`
`There was one medical review of the CINRGI trial during the second review period:
`
`In his review dated October 29. 1999, Dr. Throcltmorton concluded that beyond the statistically
`significant findings of improvement in oxygenation and decreased ECMO, no effect of LNG on durable
`clinical efficacy (duration of hospitalization, neurologic status at discharge) was demonstrated. There
`was a trend towards less evidence of pulmonary injury at the time of discharge that is complicated by the
`baseline imbalance in pulmonary status. Using incomplete follow-up data through one year, no adverse or a
`beneficial effects of LNG on mortality of neurologic/pulmonary status were identified, again relative to
`the control group. He recommended approval with careful labeling to reflect limits of the data.
`
`Medical Team Leader Memo
`.
`In his draft review, Dr. Stockbridge provided two options: 1) Not approve the application 'because of
`inadequacies in the design and implementation of the major studies and the lack of demonstrated long-
`tenn benefit. Doing so, however, would not likely create and environment wherein a better placebo»
`controlled study would be forthcoming. 2) Approve the use of nitric oxide with a label suitably
`circumspect with regard to the potential benefits and risks. Per Dr. Stockbridge, a safety update was not
`needed because all studies were completed before the application was submitted.
`
`. Statistical Review
`
`In his review dated November 4, 1999, Dr. Cui came to essentially the same conclusions as the medical
`reviewer.
`
`,
`-
`Pharmacology
`In his review dated October 9, 1997. Dr. Oza was unable to completely assure safety because NO toxicity
`mechanisms are not known and the data did not prove beyond a reasonable doubt that NO can be
`administered at a safe dose that does not for methemoglobin. If the clinical data suggested distinct
`
`
`
`

`

`
`
`benefits, he favored the use of a very low dose. The dose should never exceed 10 ppm. There is support
`from the animal data on the efficacy for the low dose although risk cannot be excluded.
`
`Biopharmaceutical Review
`In. her review dated November 10. 1999, Dr. Nguyen states that the application does not completely fulfill
`the requirement of the Office of Clinical Pharmacology and BioPharmaceutics since the pharmacokinetic
`information in the target population was not submitted. The labeling should clearly state that the uptake.
`distribution and elimination were determined primarily in healthy adults.
`
`Clinical Inspection
`In his clinical inspection summary dated September 22, 1999. Dr. U stated that the data collected from the
`three sites can be used in support of the NDA claim.
`
`'
`-
`Chemistry Review
`In his review dated November 5. 1999, Dr. Advani stated that the NDA may be approved from a
`chemistry viewpoint. The action letter shoulél state that the expiry date is- 30 months for a drug product
`stored at 25° C. Container labels need to be provided.
`
`Trade Name:
`
`The trade name, INOmax, was found acceptable by the Labeling and Nomenclature Committee on
`November 3, 1997.
`1
`
`-
`Establishment Inspection:
`The establishment inspection was recommended acceptable on October 22, 1999.
`
`Methods Validation:
`
`The firm has submitted the validation package. It will be sent to our district laboratories for evaluation.
`
`Environmental Assessment:
`
`Nitric Oxide was found to have no significant impact on the environment on July 26, 1997.
`
`DDMAC
`.
`The firm submitted promotional material. received December 9, 1999. DDMAC is reviewing it.
`
`Cardiac and Renal Drugs Advisory Committee
`There was no Advisory Committee held specifically for this application.
`
`CSO Summary
`
`Final printed labeling was received December 9, 1999 that incorporated all labeling recommendations in
`the NDA Action Letter Routing Record and the marked-up labeling that accompanied the approvable
`letter. To my knowledge, there are no issues that would prevent action on this application.
`
`An approval letter will be drafted for Dr. Temple’s signature.
`
`cc: Orig. NDA
`RFD-110
`HFD-lllMcDonald
`
`sl
`nald, RHPM
`
`and. Mc
`
`
`
`

`

`
`
`.
`
`“
`
`u
`
`RHPM Overview of NDA 20-845
`INOmax (nitric oxide) Inhaled
`November 4. 1999
`
`Type: 1P
`May 26, 1999
`Receipt Date:
`User Fee Goal Date: November 26, 1999
`
`Background
`This application was originally submitted by Ohmeda on June 16, 1997 for the use of nitric oxide in the
`treatment of hypoxic respiratory failure of the newborn. Orphan Drug designation was granted for this
`use on June 13. I993. The application was withdrawn on September 17, 1997 before an action was taken.
`There have been two Advisory Committee meetings, one before the application was submitted
`(August 28. 1995) and the other after the application was withdrawn (April 9, 1998).
`INC Therapeutics. Inc. acquired the NDA and resubmitted the application on May 26. 1999
`
`Medical Reviews
`
`There were two medical reviews of the NINOS and IND-01102 trials completed during the first review
`period:
`“
`
`In his review dated November 24. 1997, Dr. Throckmorton. Medical Officer. I-IFD-l 10, recommended
`that the application'not be approved stating that there was not sufficient data suggesting a clear beneficial
`effect of INC on hard endpoints. This was coupled with the potential adverse events associated with 1-
`NO administration and the inadequacy of the safety database for certain key adverse events.
`
`'
`
`In her review dated August 25, 1197. Dr. Pina. Medical Officer, HFD-570. stated that there were many
`outstanding issues that prevent us from recommending these trials as supportive of the safety and efficacy
`of NO for the treatment of hypoxic respiratory failure. .__S_ee her review.
`
`There was one medical review of the ClNRGI trial during the second review period:
`
`In his review dated October 29, 1999. Dr. Throckmorton concluded that beyond the statistically
`significant findings of improvement in oxygenation and decreased ECMO. no effect of LNG on durable
`clinical efficacy (duration of hospitalization. neurologic status at discharge) was demonstrated. There
`was a trend towards less evidence of pulmonary injury at the time of discharge, that is complicated by the
`baseline imbalance in pulmonary status. Using imcomplete follow-up data through one year, no adverse
`or beneficial effects of I-NO on mortality of neurologic/pulmonary status were identified. again r ative to
`
`the control group.
`
`Medical Team Leader Memo.
`
`HeM 031k “0%
`. [M5 CED M a ‘—
`
`_
`Deputy Division Director Memo
`In his draft review, Dr. Stockbridge provided two options: 1) Not approve the application because of
`inadequacies in the design and implementation of the major studies and the lack of demonstrated long-
`term benefit. Doing so. however, wOuld not likely create and environment wherein a better placebo-
`'
`controlled study would be forthcoming. 2) Approve the use of nitric oxide with a label suitably
`circumspect with regard to the potential benefits and risks. Hr Dr WhitnfiL ’
`r10 5 a—Qfi update;
`' was “£ch because (LII Of +l‘lc slum
`weir. Comping-L bak- ye, Uu,
`fan-tam mate-n - ELL,
`_
`Statistical Review
`In his review dated November 4, 1999. Dr. Cui came to essentially the same conclusions as the medical
`.
`llllll‘l"
`reviewer.
`
`-
`
`

`

`I Pharmacology
`In his review dated October 9. 1997. Dr. 02a was unable to completely assure safety because NO toxicity
`mechanisms are not known and the data did not prove beyond a reasonable doubt that NO can be
`administered at a safe dose that does not for methemoglobin. If the clinical data suggested distinct
`benefits, he favored the use of a very low dose. The dose should never exceed 10 ppm.
`there is support
`from the animal data on the efficacy for the low dose although risk cannot be excluded.
`
`-
`Biopharmaceutical Review
`In her draft review. Dr. Nguyen states that the application does not completely fulfill the requirement of
`the Office of Clinical Pharmacology and Biopharmaceutics since the pharmacokinetic information in the
`target population was not submitted. The labeling should clearly state that the uptake. distribution and
`elimination were determined primarily in healthy adults.
`--
`
`.
`Clinical InSpection
`In his clinical inspection summary dated September 22, 1999. Dr. U stated that the data collected from the
`three sites can be used in support of the NDA claim.
`
`‘17.1y'4’r'"?’.‘.‘7t'!"‘
`
`I.
`
`.a
`
`Chemistry Review =
`In his review dated November 5, 1999, Dr. Advani stated that the NDA may be approved from a
`chemistry viewpoint. ' The action letter should state that the expiry date is 30 months for a drug product
`stored at 25" C. Container labels need to be provided.
`
`Trade Name:
`
`The trade name, INOmax. was found acceptable by the Labelng and Nomenclature Committee on
`November 3, 1997.
`
`_
`Establishment Inspection:
`The establishment inspection was recommended acceptable on October 22, 1999.
`
`‘ Methods Validation:
`The firm has submitted the validation package. It will be sent to our district laboratories for evaluation.
`
`Environmental Assessment:
`Nitric Oxide was found to have no significant impact on the environment on July 26, 1997.
`
`Cardiac and Renal Drugs Advisory Committee
`There was no Advisory Committee held specifically for this application.
`
`.
`CSO Summary
`An approvable letter will be drafted for Dr. Temple.
`
`The marked-up labeling in this package contains changes from all disciplines except Biopharm. I have
`requested container labeling from the firm.
`
`To my knowledge, there are no issues that would prevent action on the goal date, November 26. 1999-.
`
`' cc: Orig. NDA
`HFD-l 10
`
`is!
`'Zelda McDonald, RHPM
`
`
`
`

`

`,
`
`Date of Submission:
`Date of Review:
`Applicant Name:
`Product Name:
`
`Evaluation:
`
`RHPM Review ofFinal Printed Labeling
`NDA 20-845
`
`December 8. 1999
`December 13. 1999
`[No Therapeutics
`lNOmax (nitric oxide) 100 and 800 ppm for Inhalation
`
`This submission provides’for final pn'nted labeling in accordance with our approvable letter dated
`November 19. 1999.
`'
`-
`.
`
`Recommendation:
`
`15 identical in content to the marked-up labeling -
`that accompaniedthe approvable letter (November 19,1999) and the fax containing pharm/tox labeling
`additions dated November 22, 1999.
`An approval letter should‘issue for this application.
`
`_
`
`cc: orig. NDA
`RFD-110
`
`HFD-l lO/McDonald
`HF'D-l lO/Blount
`HF-2
`
`I
`
`Isl
`Edda McDonald. RHPM
`
`‘-—'-
`
`
`
`
`
`

`

`'.
`
`__
`
`‘
`
`zlitimtut
`
`RECORDOFTELEPHONE OONVERSATlON
`
`.
`
`SEP 1 l
`
`'99?
`
`Date:
`Requested:
`NDA#
`Product:
`Sponsor:
`Contact:
`Phoneii:
`
`September 9. 1997
`September 8. 1997
`2 O - 8 4 5 -
`Nitric Oxide
`Ohmeda PPD
`Ms. Priya Jambhekar
`908-604-7722
`
`Telecon Chair:
`Telecon Recorder:
`External Participant Lead:
`
`_
`
`Raymond Lipicky. M.D.
`Zelda McDon'aid
`Priya Jambhekar
`
`~.
`
`-.
`.
`
`’
`FDA Participants:
`Director, Div. Cardio-Renal Drug Products, HFD-1‘lO
`Raymond Lipicky, MD. '
`Douglas Throckmorton. MD. Medical Officer, RFD-110
`Zelda McDon‘ald
`RHPM, HFD-11O
`
`Ohmeda Participants:
`John Towse, PhD.
`Priya Jambhekar
`
`'
`
`Senior Director of Clinical and Regulatory Development
`Director. Regulatory Affairs, Ohmeda PPD
`
`Background:
`Ohmeda submitted an NBA on June 16. 1997 for theuse of inhaled nitric oxide in the treatment
`of persistent pulmonary hypertension in the neonate (PPHN). Ohmeda is scheduled to present
`inhaled nitric oxide at the Cardiac and Renal Advisory Committee (CRAC) meeting scheduled for
`October 23, 1997. Ohmeda requested this teleconference to discuss new safety information that
`has become available from a European trial.
`-
`
`Telecon:
`Ohmeda stated that in the past couple of days. new safety data have surfaced from a European
`study of use of nitric oxide in 258 Adult Respiratory Distress Syndrome (ARDS) patients. At
`present, Ohmeda did not have the details but expected to by next week and requested a meeting
`with the.Division and Dr. Temple (next week) to discuss these new data in light of the nitric
`oxide development program and the upcoming advisory committee meeting.
`'Ohmeda was
`concerned because the new study showed a higher number of deaths in the nitric oxide group
`versus the placebo group. Since Ohmeda had received an indication from the Division that there
`was a safety concern with the PPHN application. they wished to present the data to the Division
`and discuss the impact the new data may have on the advisory committee.
`
`-
`
`'
`
`The Division believed that the new data were not pertinent since Ohmeda's current NDA
`application was for use in neonates not adults. The Division advised Ohmeda to spend
`their efforts on putting their presentation for the advisory committee meeting into good
`shape instead of worrying about data from a trial they do not know much about. The
`Division did not believe it was necessary for Ohmeda to meet with the Division to make a -
`formal presentation of a trial that is not well documented, that is not in a population of
`
`
`
`

`

`H
`
`interest and that does not have the pathophysioiogy of patients of interest. Whether to
`meet would be Ohmeda's call, however. The Division believed Ohmeda would be better off
`spending their time doing a meta analysis of deaths in the PPHN controlled trials to show
`that the safety issues were not significant. Mortality data from other studies in PPHN
`and neonates would also help address the issue of the increased number of deaths. Ohmeda
`should be knowledgeable about the safety information in ARDS, but noted that ARDS is not
`what the advisory committee will be dealing with.
`
`Ohmeda believed that the data from the new ARDS study put a different inflection on their
`program and stated that the President of their Division wondered whether Ohmeda should
`withdraw the NDA.
`
`-
`
`The Division stated that the Divisiongwould not give advice as to whether the NDA should
`be withdrawn. The Division believed the best thing to do would be to present nitric oxide
`before the advisory committee. Both Ohmeda and the Division know that the nitric oxide
`data base is weak. however. Ohmeda‘s ettorts ought to go toward making a compelling case
`that nitric oxide is a therapy for PPHN.
`
`oq
`
`._
`-.
`
`’-
`
`telecon recorder:
`Signature.
`'Concurrence. Chair:
`
`LI
`
`15,! .
`h is, '
`
`..
`
`f/fl/9'7
`_
`_2(/2_[q7
`
`V
`
`:
`
`cc: Orig. IND
`H F "
`
`flaw
`Finaled: 9/11/97
`=
`Drafted:
`9/10/97
`:
`Throckmorton
`9/10/97
`
`"u".-
`
`'
`
`
`
`

`

`NBA 10-845 l-NC’all (Nick Oxide) for halal-flout
`Original NBA
`Item 13 - Plum Inform-flan
`
`13.0 PATENT INFORMATION (21 CFR 314.53)
`
`Pursuant to 505(b) of the FD ac Act and 21 cm 314.50, the following information is
`' provided on the patent(s) that apply to the New Drug Application (NDA) for nitric oxide gas
`for inhalation. The infonnation is limited to the drug substance, drug product (formulation and
`composition) and method of use patents.
`Information on process patents (If any) is not
`included in this section.
`-
`’
`
`13.1
`
`PATENT NUMBER AND EXPIRATION DATE
`
`-—
`
`13.1.1 Patent Number
`
`U. S. Patent 5,485,827
`13.1.2 5 Patent Expiration date
`
`January 23, 2013
`
`13.2
`
`TYPE OF PATENT
`
`The above mentioned patent is a method of use patent for prevention or treatment of reversible
`
`pulmonary vasoconStriction by the inhalation ofnitric oxide with an oxjigen containing gas.
`
`ll
`
`IO
`
`13.3 NAME OF THE PATENT OWNER
`
`The patent is owned by General Hospital Corporation of Boston, Massachusetts. Ohmeda
`PPD acquired rights to this patent from the patent owner.
`
`
`
`G:\Regtflatc\lno\Ptntinfo.Doc
`619/97; 1
`
`007-8 01
`
`
`

`

`EXCLUSIVITY SUMMARY FbR NDA #_20-845 '
`
`SUPP]. #
`
`Trade Name
`
`I-NOmax
`
`- Generic Name _nitric oxide
`
`-
`
`'-
`
`Applicant Name _INO Therapeutics, Inc.
`
`HFD # _l 10
`
`Approval Date If Known
`
`PART I IS AN EXCLUSIVITY DETERMINATION NEEDED?
`
`1. An exclusivity determination will be made for all original applications, but only for certain supplements.
`Complete PARTS II and Ill of this Exclusivity Summary only ifyou answer "yes" to one or more of the following
`question about the submission.
`
`a) Is it an original NDA?
`YES
`
`I_X_/ NO /___I
`
`b) Is it an effectiveness supplement?
`
`'
`
`YES
`
`/__/
`
`NO /_x_/
`
`if yes, what type? (551, SE2, etc.)
`
`‘
`
`‘
`
`-
`
`c)_ Did it require the review of clinical data other than to support a safety claim or change in labeling
`related to safety? (If it required review only of bioavailabiiity or bioequivalence data, answer “no.")
`
`If your answer is 'fno" because you believe the study is a bioavailability study and, therefore, not eligible
`for exclusivity, EXPLAIN why it is a bioavailability study, including your reasons for disagreeing with any
`arguments made by the applicant that the study was not simply a bioavailability study.
`
`-
`
`YES /_x__/
`
`NO I
`
`I
`
`
`
`
`
`If it is a supplement requiring the review of clinical data but it is not an effectiveness supplement, describe
`the change or claim that is supported by the clinical data:
`
`
`
`
`Form OGD-011347 Revised 10/13/98
`
`cc: Original NDA
`
`Division File
`
`HFD-93 Mary Ann Holovac
`
`
`
`

`

`d) Did the applicant request exclusivity?
`
`is
`
`If the answer to (d) is "yes," how many years of exclusivity did the applicant request?
`7 years — Orphan status granted on June 22, 1993
`
`YES /_x__r
`
`NO/
`
`I
`
`e) Has pediatric exclusivity been granted for this Active Moiety?
`
`No
`
`IF YOU HAVE ANSWERED '"NO" TO ALL OF THE ABOVE QUESTIONS, GO DIRECTLY TO THE
`SIGNATURE BLOCKS ON PAGE 8.
`
`—--—
`
`2. Has a product with the same active ingredient(s), dosage form, strength, route of administration, and dosing
`schedule. previously been approved by FDA for the same use? (Rx to OTC switches should be answered NO-please
`indicate as such)
`'
`
`-. YES!
`
`/ N0 /_X_l
`
`lfyes,N_DA#
`
`'
`
`.
`
`DrugName
`
`IF THE ANSWER TO QUESTION 2 IS "YES," GO DIRECTLY TO THE SIGNATURE BLOCKS 0N PAGE 8.
`
`3. Is this drug product or indication a DES] upgrade?
`
`IF THE ANSWER TO QUESTION 3 18 "YES," GO DIRECTLY TO THE SIGNATURE BLOCKS 0N PAGE 8
`(even if a study was required for the upgrade).
`
`PART II FIVE-YEAR EXCLUSMTY FOR NEW CHEMICAL ENTITIES
`
`YES /__I NO /_X_/
`
`(Answer either #1 or #2 as appropriate)
`
`l. Sinele active ingredient product.
`
`l-las FDA previously approved under section 505 of the Act any drug product containing the same active moiety as
`the drug. under consideration? Answer "yes" if the active moiety (including other esterified forms, salts, complexes,
`chelates or clathrates) has been previously approved, but this particular form of the active moiety, e.g.,
`this
`particular ester or salt (including salts with hydrogen or coordination bonding) or other non-covalent derivative
`(such as a complex, chelate, or clathrate) has not been approved. Answer_"no" if the compound requires metabolic .
`conversion (other than deesterification of an esterified form of the drug) to produce an already approved active
`morety.
`
`YES /_1
`
`NO /_x_/
`
`Page 2
`
`
`
`
`
`

`

`If "yes," identify the approved drug product(s) containing the active moiety, and; if known, the NDA #(s).
`
`" "NDM
`
`NDA#
`
`NDA#
`
`2. Combination product.
`
`If the product contains more than one active moiety(as defined in 'Part II, #1), has FDA previously approved an
`application under section 505 containing m 9115 of the active moieties in the drug product? If, for example, the
`combination contains one never-before-approved active moiety and one previously approved active moiety, answer
`"(An active moiety thatis marketed underan OTC monograph, but that was never approved under an NDA, is
`considered not previously approved)
`
`'
`
`YES!
`
`/ N0/_/
`
`1ff'yes," identify the approved drug product(s) containing the active moiety, and, if known, the NDA #(s).
`
`ND‘A #
`
`NDA#
`
`NDA#
`
`IF THE ANSWER TO QUESTION 1 OR 2 UNDER PART I] IS "NO, " GO DIRECTLY TO THE SIGNATURE
`BLOCKS ON PAGE 8.1F-"YES" GO TO PART III
`'-'-"
`
`PART III THREE-YEAR EXCLUSIVITY FOR NDA'S AND SUPPLEMENTS
`
`To qualify for three years of exclusivity, an'application or supplement must contain "reports of new clinical
`investigations (other than bioavailability studies) essential to the approval of the application and conducted or
`sponsored by the applicant." This section should be completed only if the answer to PART 11, Question 1 or 2 was
`"yes.“
`
`at
`
`u
`
`Page 3
`
`
`
`

`

`1. Does the application contain reports of clinical investigations? (The Agency interprets "clinical investigations"
`to mean investigations conducted on humans other than bioavailability studies.) If the application contains clinical
`investigations only by vinue of a right of reference to clinical investigations in another application, answer “yes,”
`then skip to question 3(a). If the answer to 3(a) is "yes“ for any investigation referred to in another application, do
`not complete remainder of summary for that investigation.
`
`YES/fNO/I
`
`IF "NO," GO DIRECTLY TO THE SIGNATURE BLOCKS ON PAGE 8.
`
`2. A clinical investigation is "essential to the approval" if the Agency could not have approved the application or
`supplement without relying on that investigation. Thus, the investigation is not essential to the approval if 1) no
`clinical
`investigation is necessary to support the supplement or application in light of previously approved
`applications (i.e., information other than clinical trials, such as bioavailability data, would be sufi‘icient to provide a
`basis for approval as an ANDA or 505(b)(2) application because of what is already known about a previously
`approved product), or 2) there are published reports of studies (other than those conducted or sponsored by the
`applicant) or other publicly available data that independently would have been sufficient to support approval of the
`application, without reference to the clinical investigation submitted in the application.
`
`investigation (either conducted by the
`is a clinical
`(a) In light of previously approved applications,
`applicant or available from some other source, including the published literature) necessary to support
`approval of the application or supplement?
`'
`:.
`
`YESI'
`
`/
`
`NO/
`
`/
`
`If "no," state the basis for your conclusion that a clinical trial is not necessary for approval AND GO
`DIRECTLY TO SIGNATURE BLOCK ON PAGE 8:
`
`
`
`(b) Did the applicant submit a list of published studies relevant to the safety and effectiveness of this drug
`product and a statement that the publicly available data would not independently support approval of the
`application?
`
`YES/lNO/l
`
`Page 4
`
`
`
`

`

`(1) If the answer to 2(b) is "yes," do you personally know of any reason to disagree with the
`applicant's conclusion? If not applicable, answer NO.
`
`YES!
`
`I
`
`N01f
`
`I
`
`If yes, explain:
`
`'
`
`(2) If the answer to 2(b) is"'no," are you aware of published studies not conducted or sponsored by
`the applicant or other publicly available data that could independently demonstrate the safety and
`effectiveness of this drug product?
`'
`
`YES/
`
`I
`
`NO/
`
`I
`
`If yes, explain:
`
`
`
`(c) {if the answers to (b)(l) and (b)(2) were both "no," identify the clinical investigations submitted in the
`application that are essential to the approval:
`
`Studies comparing two products with the same ingredient(s) are considered to be bioavailability studies for the
`purpose of this section.
`*-
`
`In addition to being essential, investigations must be "new" to support exclusivity. The agency interprets "new
`3.
`clinical investigation" to mean an investigation that 1) has not been relied on by the agency to demonstrate the
`effectiveness of a previously approved drug for any indication and 2) does not duplicate the res'ults of another
`investigation that was relied on by the agency to demonstrate the effectiveness of a previously approved drug
`product,
`i.e., does not redemonstrate something the agency considers to have been demonstrated in an already
`approved application.
`
`Page 5
`
`
`
`

`

`a) For each investigation identified as "essential to the approval,“ has the investigation been relied on by the
`agency to demonstrate the effectiveness of a previously approved drug product? (If the investigation was
`relied on only to support the safety of a previously approved drug, answer "no.")
`
`Investigation #1
`
`Investigation #2
`
`YES I
`
`YES!
`
`/
`
`/
`
`NO I
`
`' I
`
`NO/
`
`I
`
`If you have answered "yes" for one or more investigations, identify each such investigation and the NDA in
`which each was relied upon:
`'
`
`
`
`..-
`
`b) For each investigation identified as "essential to the approval", does the investigation duplicate the
`results of another investigation that was relied on by the agency to support the effectiveness of a previously
`approved drug product?
`
`Investigation #1“
`Au
`
`Investigation #2
`
`YES/
`
`YES!
`
`/
`
`/
`
`NO/
`
`NO!
`
`I
`
`I
`
`If you have answered "yes" for one or more investigation,
`investigation was relied on:
`
`identify the NDA in which a similar
`
`
`
`
`
`
`
`c) If the answers to 3(a) and 3(b) are no, identify each "new" investigation in the application or supplement
`that is essential to the approval (i.e., the investigations listed in #20:), less any that are not "new" :
`
`
`
`Page 6
`
`
`
`

`

`
`
`To be eligible for exclusivity, a new investigation that is essential to
`4.
`approval must also have been conducted or sponsored by the applicant.
`An
`inVestigation was
`"conducted or'sponsored by"
`the applicant
`if, before or
`during the conduct of the investigation, 1)
`the applicant was the sponsor of
`the IND named in the form FDA 1571 filed with the Agency, or 2)
`the applicant
`(or its predecessor in interest) provided substantial support for the study.
`ordinarily, substantial support will mean providing 50 percent or more of the
`cost of the study.
`
`a) For each investigation identified'1n response to question 3(a): if the investigation was carried out under
`an IND, was the applicant identified on the FDA 157] as the' sponsor?
`
`Investigation #1
`
`!
`
`-—
`
`IND#
`
`YES I
`
`I
`
`! NO/_1' Explain:
`
`!
`
`Investigation #2 -.
`
`!
`
`IND#
`
`_¢.
`
`.—
`YESI-
`/
`
`! N0/___/ Explain:
`
`(b) For each investigation not carried out under an IND or for which the applicant was not identified as the
`sponsor, did the applicant certify that it or the applicant's predecessor in interest provided substantial
`support for the study?
`
`Investigation #1
`
`!
`
`1
`
`-:;.
`
`YES /_/ Explain
`
`! N0/_/ Explain
`
`
`
`Investigation #2
`
`!
`
`I
`
`YES /_/ Explain
`
`! N0/_/ Explain
`
` 1
`
`! —...—.____.._
`
`Page 7
`
`
`
`

`

`Title: Regulatory Heatlh mm Manager
`
`
`
` Signaru e of 0 ice/
`
`Division Director
`
`.
`
`'
`
`' cc: Original NDA
`
`Division File
`
`HID-93 Mary Ann Holovac
`
`(c) Notwithstanding an answer of “yes” to (a) or (b), are there other reasons to believe that the applicant
`should not be credited with having “conducted or sponsored" the study? (Purchased studies may not be
`used as the basis for exclusivity. However, if all rights to the drug are purchased (not just studies on the
`drug), the applicant may be considered to have sponsored or conducted the studies sponsored or conducted
`by its predecessor in interest.)
`-
`
`YES/
`
`/
`
`NO!
`
`I
`
`If yes, explain:
`
`
`
`
`

`

`
`
`PEDIATRIC PAGE
`
`.
`
`{Complete tor all original applications and all efficacy supplements)
`NOTE: A new Pediatric Page must be completed at the time of each action even though one was prepared at
`time of the last action.
`
`'Wiriwi'5— Stpplementii
`HFDvUD Tradeandgenericnan'rec/dosagetomr
`
`
`
`Circieone:SE1 s52 sea eases see
`“HT-I
`'
`‘
`4-
`Adim: AP AE NA
`
`lndmtron(s)prevr0istyawmved None.-
`Pediatric information in labeling of approved indicati
`I
`_
`'n this app"
`.
`
`(s is adequate
`
`:
`
`____
`‘ ..
`inadequate_
`-
`
`born
`
`FOR SUPPLEMENTS. ANSWER THE FOLLOWING QUESTIONS IN RELATION TO THE PROPOSED INDICATION.
`IS THE DRUG NEEDED IN ANY PEDIATRIC AGE GROUPS? _Yes (Continue with questions) _No (Sign and return the
`form)
`(Check all that apply)
`IN WHAT PEDIATRIC AGE GROUPS IS THE DRUG=NEEDED7
`_Neonates (Binh-tmcnth) _lnfants (1 month-2yrs) _Children (2-12yrs) _Adolecentst12-16yrs)
`
`_1. PEDIATRIC LABELING IS ADEQUATE FOR AL]. PEDIATRIC AGE GROUPS. Appropriate information has been
`submitted in this or previous applications and has been adequately summarized in the labeling to permit satisfactory labeling for
`all pediatric age groups. Further information is not required.
`
`2 PEDIATRIC LABELING IS ADEQUATE FOR QEfilAlfl AGE GROUPS. Appropriate information has been submitted
`in this or previous applications and has been adequately summarized in the labeling to permit satisfactory labeling for certain
`pediatric age groups (e.g., infants, chlldren, and adolescents but not neonates). Further information is not required.
`
`_ 3. PEDIATRIC STUDIES ARE NEEDED. There is potential tor use in children. and further information is required to permit
`adequate labeling for this use.
`
`_ a A new dosing fonnulalion is needed, and applicant has agreed to provide the appropriate Ionnulation.
`
`_ b. A new dosing formulation is needed. however the sponsor is either; not willing to provide it or is in negotiations with
`FDA
`_
`.
`
`-
`
`‘.
`
`_ c. The applicant has committed to doing such studies as will be required.
`_ (1) Studies are ongoing,
`____
`(2) Protocols were submitted and approved.
`_ (3) Protocols were submitted and are under review.
`(4] if no protocol has been submitted, attach memo describing status of discussions.
`
`_ d It the sponsor is not willing to do pediatric studies, attach copies of FDA's written request that such studies be done
`and of the sponsors written response to that request.
`
`4. PEDIATRIC STUDIES ARE NOT NEEDED. The dmg/biologic product has little potential for use in pediatric patients.
`Attach memo explaining why pediatric studies are not needed.
`
`_5. If none of the above apply, attach an explanation. as necessary.
`
`ARE THERE ANY PEDIATRIC PHASE 4 COMMITMENTS IN THE ACTION LETTER? _ Yes
`ATTACH AN EXPLANATION FOR ANY OF THE FOREGOING ITEMS, AS NECESSARY.
`
`No
`_—
`
`‘This page was completed based on information fromMEAML— (9.9., medical review. medical officer. team
`
`Date “/1 I q?
`
`/8
`leader)
`'Signature of Preparer and Title '
`n».- Duo/ILA #30 am”
`HM File
`NDA/BLA Action Pa kage
`.
`.
`(revised mac's?)
`Ecmwnt‘
`ESTION ON COMPLETING THIS FORM, CONTACT KHYATI ROBERTS. HFD-B (ROBERTSK)
`
`HFD
`
`FO
`
`'
`
`'
`
`
`
`

`

`Sent By: 1N0 Therapeutics;
`
`908 238 0779;
`
`Nov-18-99
`
`3:50PM;
`
`Page 2/2
`
`938 238 ms
`
`NDA 20—845, NITRIC 0x10}: FOR INHALATION
`NEW DRUG APPLICATION _
`"-, --
`
`DEBARMENT/CQNVICTIQN CEEI TFTQA 1 JOE
`
`In accordance with the reguirement ol' the Federal Food, Drug. and Cosmetic Act. IN0 '
`Therapeutics. Inc. hereby certifies that it did not and-will not use, in any capacity. the
`services of any person debarred by the Food and Drug Administration (FDA).
`
`Furthermore, [NO Therapeutics, Inc. certifies that. neither the applicant nor any affiliated
`persons responsible for the development or submissiori of the application has been
`debarred by the FDA.
`
`2 {M a -
`
`Richard N. Williams. PhD.
`Vice President
`
`'
`
`IDale: NOV-
`
`1'67,-
`
`’272
`
`Worldwide Regulatory Affairs
`
`
`
`

`

`
`
`'- '- MEMORANDUM
`
`DATE:
`
`NOV 19 1999
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`FROM:
`
`Robert Temple, MD.
`Director, Office of Drug Evaluation 1, RFD-101
`
`SUBJECT:
`
`INOrnax (Nitric Oxide, ING Therapeutics, N'DA 20—845)
`
`TO:
`
`uRi’ymond J. Lipicky, MD.
`Director, Division of Cardio-Rena] Drug Products, HFD-l 10
`File NDA 20-845
`
`Both Drs'Z'Stockbridge and Throckmorton have recommended approval of inhaled NO for the treatment of
`hypoxic respiratory failure (of various causes) in neonates, with close attention