`
`AW
`
`mu9"
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`Page 1 of 12
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`Biogen Exhibit 2166
`
`Mylan v. Biogen
`IPR 2018-01403
`
`Biogen Exhibit 2166
`Mylan v. Biogen
`IPR 2018-01403
`
`Page 1 of 12
`
`

`

`NDA 21-120
`
`lmmunex Corporation
`Attention: Mark Gauthier
`
`Sr. Mgr., Regulatory Affairs
`51 University Street
`Seattle, WA 98101
`
`Dear Mr. Gauthier:
`
`Please refer to your new drug application (NDA) dated June 2, 1999, received June 4,
`1999, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for
`Novantrone (mitoxantrone hydrochloride) injection.
`
`We acknowledge receipt of your submissions dated:
`
`May 22, 2000
`August 10, 2000
`
`May 24, 2000
`August 21, 2000
`
`July 12, 2000
`August 29, 2000
`
`July 25, 2000
`September 5, 2000
`
`Your submission of April 13, 2000 constituted a complete response to our March 1,
`2000 action letter.
`
`This new drug application provides for the use of Novantrone (mitoxantrone
`hydrochloride) Injection for reducing neurologic disability and/or the frequency of clinical
`relapses in patients with secondary (chronic) progressive, progressive relapsing, or
`worsening relapsing-remitting multiple sclerosis (i.e., patients whose neurologic status
`is significantly abnormal between relapses). NOVANTRONE is not indicated in the
`treatment of patients with primary progressive multiple sclerosis.
`
`We have completed the review of this application, as amended, and have concluded
`that adequate information has been presented to demonstrate that the drug product is
`safe and effedive for use as recommended in the agreed upon enclosed labeling text.
`Accordingly. the application is: approved effective on the date of this letter.
`
`The final printed labeling (FPL) must be identical to the enclosed labeling (text for the
`package insert, text for the patient package insert). Marketing the product with FPL that
`is not identical to the approve-d labeling text may render the product misbranded and an
`unapproved new drug.
`
`Please submit 20 paper copies of the FPL as soon as it is available, in no case more
`than 30 days after it is printed. Please individually mount ten of the copies on
`
`heavyweight paper or similar material. Alternatively, you may submit the FPL
`
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`

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`NDA 21 -1 20
`
`Page 2
`electronically according to the guidance for industry titled Providing Regulatory
`Submissions in Electronic Format - NDAs (January 1999). For administrative purposes,
`this submission should be designated "FPL for approved NDA 21-120." Approval of
`this submission by FDA is not required before the labeling is used.
`
`Be advised that, as of April 1, 1999, all applications for new active ingredients, new
`dosage forms, new indications, new routes of administration, and new dosing regimens
`are required to contain an assessment of the safety and effectiveness of the product in
`pediatric patients unless this requirement is waived or deferred (63 FR 66632)(21 CFR
`314.55 (or 60127)).
`
`Reference is made to your correspondence dated September 29, 1999, requesting a
`waiver for pediatric studies.
`
`We have reviewed the information you have submitted and agree that a waiver is
`justified for Novantrone for secondary progressive and progressive relapsing multiple
`sclerosis for the pediatric population. Accordingly, a waiver for pediatric studies for
`these two populations is granted under 21 CFR 314.55 at this time.
`
`However, the agency has not made a determination if a health benefit would be gained
`by studying Novantrone in pediatric patients with worsening relapsing-remitting multiple
`sclerosis. FDA is deferring submission of the pediatric assessments of safety and
`effectiveness that may be required under these regulations. Please submit a rationale
`for waiving pediatric studies in this population by January 12, 2001. FDA will reply
`whether pediatric studies are-required under the rule. If FDA determines at that time
`that pediatric studies are necessary, FDA will also set a specified time at which you
`must submit the required assessments.
`
`We remind you that you must comply with the requirements set forth under 21 CFR
`314.80 and 314.81 for an approved NDA. To comply with these regulations, all 3-day
`and 15-day alert reports, periodic adverse drug experience reports, field alerts, annual
`reports, supplements, and other submissions should be addressed to the original NDA
`19-297 for this drug product, not to this NDA; This includes the quarterly periodic
`adverse drug experience reports required by this new NDA.
`In the future, any
`submission specific to multiple sclerosis should be fonrvarded to this division only as a
`courtesy desk copy. No submissions should be made to this NDA except for the 20
`copies of the final printed labeling as requested above.
`
`In addition, please submit three copies of the introductory promotional materials that
`you propose to use for this product. All proposed materials should be submitted in draft
`or mock-up form, not final print. Please submit one copy to this Division and two copies
`of both the promotional materials and the package insert directly to:
`Division of Drug Marketing, Advertising, and Communications, HFD—42
`\
`Food and Drug Administration
`
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`

`

`NDA 21-120
`
`Page 3
`
`5600 Fishers Lane
`
`Rockville, Maryland 20857
`
`Please submit one market package of the drug product when it is available.
`
`We remind you that you must comply with the requirements for an approved NDA set
`forth under 21 CFR 314.80 and 314.81.
`
`PHASE 4 COMMITMENTS:
`
`Biopharmaceutics
`
`1. PK requests were conveyed to you in the November 4, 1998 End of Phase II
`meeting, the April 12, 1999 Pre-NDA meeting, and in comments from the original
`review of NDA 19-297 (March 5, 1986) as well as in comments from asupplemental
`review of NDA 19-297 (November 13, 1996) prior to the submission of this NDA and
`during the review of the approved Novantrone NDA.
`In addition, these deficiencies
`were communicated to you in the Approvable letter of March 1, 2000. Specifically,
`the deficiencies are:
`
`A. The application is lacking a validated analytical method for the determination
`of mitoxantrone concentration in biological fluids and tissues.
`B. Adequate information about the metabolic fate and pathway of mitoxantrone
`has not been provided.
`C. There is inadequate evaluation of the kinetics of mitoxantrone, including a
`determination of the- terminal half—life, as well as a lack of an analysis of the
`kinetics by gender, age, and race.
`D. Drug — drug interactions have not been provided.
`
`No information about the kinetics of mitoxantrone is available for patients with
`multiple Jsclerosis.
`
`The due date for completion of these commitments is December 31, 2001.
`
`Safeg
`
`Please provide the results of the “Prospective, Open-Label Safety Monitoring Study
`of Novantrone in a Selected Cohort of Multiple Sclerosis Patients" in the time frame
`previously agreed upon.
`Please provide a detailed plan of your proposed “Assessment of Novantrone Dosing
`and Monitoring in MS in a Range of Practice Settings" and its results as they
`become available.
`
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`

`NDA 21-120
`
`Page 4
`
`. Please provide the results of your Marketing Research Assessment of your
`proposed Education Plan (Appendix C of your April 1, 2000 submission).
`
`If you have any questions, call Teresa Wheelous, R.Ph., Regulatory Management
`Officer, at (301) 594-2850.
`
`Sincerely,
`
`Russell Katz, MD.
`Director
`
`Enclosure
`
`Division of Neuropharmacological Drug Products
`Office of Drug Evaluation l
`Center for Drug Evaluation and Research
`
`_
`
`‘
`
`APPEARS THIS WAY
`0N ORIGIN
`
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`m?!
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`

`NDA 21-120
`
`"AR -" am
`
`lmmunex Corporation
`Attention: Mark W. Gauthier
`Senior Regulatory Affairs Manager .
`51 University Street
`Seattle, WA 98101
`
`APPE
`DNAglstlltliil'l'Vs WAY "
`A'-
`
`—
`
`Dear Mr. Gauthier:
`
`Please refer to your new drug application (NDA) dated June 2,1999 received
`June 4, 1999, submitted under section 505(b) the Federal Food, Drug, and
`Cosmetic Act for Novantrone (mitoxantrone hydrochloride) Injection 20 mg, 25
`mg 30 mg (2 mg/ml).
`
`_ We acknowledge receipt of your submissions dated:
`
`August 13, 1999
`September 29. 1999
`October 15, 1999
`
`September 10, 1999
`October 1, 1999
`October 26, 1999
`
`September 27, 1999
`October 14, 1999
`November 5, 1999
`
`in addition, we refer to a meeting of the Peripheral and Central Nervous Systems
`Advisory Committee meeting of January 28, 2000. in which this application was
`discussed. At that meeting, as you know, the Committee concluded that
`substantial evidence of effectiveness and sufficient evidence of safety had been
`submitted to support approval of the application.
`
`We have completed the review of this application, as amended, and it is
`approvable. Before the application may be approved. however. it will be
`necessary for you to address the following:
`
`ClInIcal
`
`‘-
`
`1 As you know, the Advisory Committee concluded that Novantrone had
`demonstrated an effect on decreasing the relapse rate in both Studies 901
`' and 902. However. given that relapses were diagnosed by unblinded
`observers in both studies, the Committee was able to conclude that the drug
`had an effect on relapses only because of your assertion that the relapses
`were, in general, rated as “severe", and therefore their diagnosis was not
`likely to have been affected by blind breaking.
`In order for us to conclude
`definitively that the treatment does have an effect on relapses, you must
`submit evidence that, in fact, these relapses were severe.
`In particular, it
`
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`

`

`NDA 21-120
`
`-
`
`Page 2
`
`would be useful to document how many of the relapses met each specific
`criteria of “severe” that were described at the Advisory Committee meeting.
`
`2 In addition, the Committee concluded that the treatment has ar effect on
`"worsening” relapsing-remitting patients based on your assertion that patients
`in Study 902 did, indeed. progress on their EDSS prior to enrollment. Please
`submit the data that support this conclusion.
`
`In addition, patients enrolled in Study 901 were said to have progressive
`disease as well (either chronic progressive or relapsing progressive). Please
`submit evidence, analogous to that requested above for Study 902. that
`documents that patients in Study 901 were, indeed, progressive.
`
`3
`
`It is critical to establish that the EDSS scores in both studies were not
`obtained during, or closely temporally related to. exacerbations. Were this to
`be the case, they would be unreliable indicators of a patient's chronic
`neurologic status. Please submit documentation that, in general, EDSS
`scores were obtained removed in time from relapses.
`
`In addition, because EDSS scores in patients in Study 902 were also rated by
`an unblinded rater. there is no valid independent replication of the effect on
`progression of neurologic status that was ostensibly shown in Study 901. For
`this reason. in order for a claim for an effect on neurologic status (as
`measured by EDSS) to be considered. we must be assured that the effect
`seen in Study 901 was a robust finding. Toward this end, it is important that _
`you document that the effect seen on EDSS in Study 901 was persistent and
`not transient; i.e., the effect. once achieved. persisted for a reasonable
`duration (e.g.. 3-6 months). We would be happy to explore with you ways to
`examine this question.
`
`fiippharmaceutics
`
`As we have discussed with you on several occasions. the metabolism of
`Novantrone is not well characterized. For this reason, and given the introduction
`of this treatme t into the MS population. a population significantly different than”
`the ones for w om Novantrone is currently indicated, it is critical that you obtain
`additional information about Novantrone's metabolism prior to its approvaHor the—
`MS population. This information may be obtained from in vitro assays; our staff
`of the Office of Cl.‘nical Pharmacology and Biopharrnaceutics will be happy to
`discuss with you the specific studies needed.
`
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`

`

`NDA 21-120
`
`Labefing
`
`'
`
`Page 3
`
`In some places we have drafted
`We have included draft labeling with this lettr‘.
`specific language which differs from that you proposed; we ask that you adopt
`this language verbatim.
`In other places. we have inserted notes to you thatwill-
`require you to draft additional language. ItIs important to note‘that this labeling
`should be considered provisional at this time; in addition to changes that you may
`propose. it may need to undergo extensive revision depending upon the results
`of our analyses of the data we have requested above.
`
`In addition, we believe that labeling should include information to be given to the
`patient. Please draft such a document in.the form of a Medication Guide (see 21
`CFR 208.20 for the content and form of a Medication Guide). The document
`should focus on the specific symptoms patients should be aware of that are
`related to the major toxicities seen with Novantrone (e.g., cardiotoxicity.
`hematologic) and should also emphasize the fact that cardiac monitoring must
`be performed after a cumulative dose of 100 mg/mz, and that ordinarily a dose of
`140 mg/m2 should not be exceeded. Whether this information will ultimately be
`contained in such a guide, or in a patient package insert. remains to be
`determined.
`In addition, it will be necessary to have further discussions to agree
`on a mechanism that will insure that patients receive this information. given that
`the treatment is not dispensed directly to the patient to be self-administered.
`
`Registg
`
`As you know, we believe that the safe use of Novantrone in MS patients requires
`that they be evaluated for cardiac toxicity at and beyond a cumulative dose of
`100 mg/mz. We continue to believe that the most reliable way to assure that all
`patients are appropriately monitored is for all patients to be enrolled in a registry.
`so that their cumulative dose can be centrally recorded. Such a system has the
`advantage of being capable of not only assuring that the treating physician is
`aware of the time at which monitoring becomes mandatory. but also can. ideally.
`detect when a patient has reached the maximum dose. thereby preventing
`inappropriate overdosage. We will be happy to discuss this issue with you.
`4.
`In addition to the information needed to be submitted and reviewed prior to
`approval, we ask you to agree to address the following deficiencies as a Phase 4
`commitment:
`
`APPEARS ““5 WAY
`0N ORIGINAL
`
`Page 9 0f 12
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`

`NDA 21-120
`
`.
`
`'
`
`'
`
`Page 4
`
`PHASE 4 COMMITMENTS:
`
`Biopharmaceutics
`
`‘
`
`l
`
`PK requests were conveyed to you in the November 4, 1998 End of Phase
`II meeting, the April 12, 1999 Pre-NDA meeting, and in.comments from
`the original review of NDA 19-297 (March 5, 1986) as well as in comments
`from a supplemental review of NDA 19-297 (November 13, 1996) prior to
`the submission of this NDA and during the review of the approved
`Novantrone NDA. Several of these deficiencies are still outstanding.
`specifically, the deficiencies are:
`A
`The application is lacking a validated analytical method for the
`determination of mitoxantrone concentration in biological fluids and
`tissues.
`
`B
`
`C
`
`D
`
`Adequate information about the metabolic fate and pathway of
`mitoxantrone has not been provided.
`There is inadequate evaluation of the kinetics of mitoxantrone,
`including a determination of the terminal half-life, as well as a lack
`of an analysis of the kinetics by gender, age, and race.
`Drug — drug interactions have not been provided.
`
`II
`
`No information about the kinetics of mitoxantrone is available for patients
`with multiple sclerosis.
`
`In future submissions please provide adequate summaries of the individual PK
`' reports and literature to facilitate Agency review.
`
`If additional information relating to the safety or effectiveness of this drug
`becomes available. revision of the labeling may be required.
`
`Under 21 CFR 314.50(d)(5)(vi)(b), we request that you update your NDA by
`submitting all safety information you now have regarding your new drug. Please
`provide updated information as listed below. The update should cover all studies
`and uses of tlle drug including: (1 ) those involving indications not being sought in
`the present submission, (2) other dosage forms, and (3) other dose levels, etc.
`
`1.‘ Retabulation of all safety data including results of trials that were still
`ongoing at the time of NDA submission. The tabulation can take the
`” same form as in your initial submission. Tables comparing adverse
`reactions at the time the NDA was submitted versus now will facilitate
`revrew.
`
`2. Retabulation of dropouts with new dropouts identified. Discuss, if
`appropriate.
`3. Details of any significant changes or findings.
`
`Page 10 0f 12
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`

`NDA 21-120
`
`-
`
`'
`
`Page 5
`
`4. Summary of worldwide experience on the safety of this drug.
`5. Case report forms for each patient who died during a clinical study or
`who did not complete a study because of an adverse event.
`6. English translations of any approved foreign labeling not previously
`submitted.
`
`"‘
`
`7.
`
`lnfonnation suggesting a substantial difference in the rate of
`occurrence of common. but less serious, adverse events.
`
`In addition, please submit three copies of the introductory promotional materials
`that you propose to use for this product. All proposed materials should be
`submitted in draft or mock-up form, not final print. Please send one copy to this
`division and two copies of both the promotional materials and the package insert
`directly to:
`
`Division of Drug Marketing. Advertising. and Communications. HFD-40
`Food and Drug Administration
`5600 Fishers Lane
`
`Rockville, Maryland 20852
`
`Within 10 days after the date of this letter. you are required to amend the
`application, notify us of your intent to file an amendment, or follow one of your
`other options under 21 CFR 314.110. In the absence of such action, FDA may
`proceed to withdraw the application. Any amendment should respond to all the
`deficiencies listed. We will not process a partial reply as a major amendment nor
`will the review clock be reactivated until all deficiencies have been addressed.
`
`The drug product may not be legally marketed until you have been notified in
`writing that the application is approved.
`
`If you have any questions, contact Ms. Teresa Wheelous. R.Ph., Regulatory
`Project Manager. at (301) 594-2850.
`
`‘6
`
`_
`'
`APPEARS THIS WAY
`0N ORIGINAL
`
`Sincerely Yours,
`
`” ys/
`
`Mm
`
`Russell Katz. M.D.
`Director
`»
`Division of Neurophannacologioal
`Drug Products
`Office of Evaluation l
`
`Center for Drug Evaluation and
`Research
`'
`
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`" Number of Pages
`Redacted £9;
`
`0
`0:00:00..
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`Draft Labeling
`(not releasable)
`
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