09/ 07/ 2007 17:11 FAX 3012304144
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`LTWGN
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`141001/006
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`Food and Drug Administration
`Center for Drug Evaluation and Research
`
`I. Office of Drug Evaluation II
`
`Memorandum of Facsimile Correspondence
`
`Date:
`
`September 7, 2007
`
`To:
`
`Michael Bernhard, Ph.D.
`· Senior D irector, Regulatory Affairs
`
`Company: Med.Pointe Pharmaceuticals
`
`Fax:
`
`732-564-2377
`
`Phone:
`
`732-564-2353
`
`From:
`
`Philantha Bowen, MPH, RN
`Senior Regulatory Management Officer
`Division of Pulmonary and Allergy Products
`
`Subject:
`
`IND 77363; Re: 10 Sept 07 Meeting Q & A
`
`# of Pages:
`
`TIDS 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 ...
`Ifyou·are not the addressee, you are hereby notified that any review, disclosure,
`dissemination, copying, or other action based on the content of this communication is oot
`authorized. If you received this document in error, please immediately notify us by
`telephone at (30 1) 796-2300 and return it to us at FDA, 10903 New Hampshire Ave,
`Building 22, DP AP, Silver Spring, MD 20993.
`
`Thank you.
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`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
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`PLAINTIFFS' §
`TRIAL EXHIBIT!
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`PTX0110 t
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`MEDA_APTX03071175
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`PTX011 0-00001
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`CIP2164
`Argentum Pharmaceuticals v. Cipla Ltd.
`IPR2017-00807
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`1
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`IND 77,363
`, . . ... .
`Azelastine-Fluticasone
`MedPointe Pharmaceuticals .
`
`Attached are the FDA responses to the questions (in bold italics) in your July 31, 2007,
`meeting package regarding azelastine/fluticasone. You have the option of canceling our
`meeting on September 10,2007, if these answers are clear to you. Jfyou choose to have
`the meeting, we will be prepared to clarify any questions you have regarding our
`responses. However, please note that if there are any major changes to your development
`plan (based upon our responses herein), we will not be prepared to discuss, nor reach
`agreement on, such changes at the meeting. Any modifications to the development plan
`or additional ·questions for which you would like FDA feedback should be submitted as a
`new meeting request.
`
`Please let me know as soon as possible if you would like to cancel the meeting or change
`it to a teleconference.
`
`Introductory comment
`
`According to 21 CFR300.50, two or more drugs may be combined in a single dosage form
`when each component makes a contribution to the claimed effects. Your development
`program should demonstrate the efficacy and safety of the fixed-combination drug and
`the contribution of each component to the combination. Determination of the appropriate
`comparator monotherapy treatment arms for the pivotal studies is critical to your
`development program. One option would be to develop monotherapies that are
`essentially the combination product minus one of the active ingredients. This may
`minimize the pharmaceutical differences between the combinati.on product and the
`monotherapy components. However, as you note, one potential problem is that removal
`of an active drug substance from your combination product may change the properties of
`the monotherapy. This complicates your development program and may be difficult to
`address.
`
`You propose the following monotherapy comparators, Flonase Nasal Spray and Astelin
`nasal spray. As stated previously, there are pharmaceutical differences between your
`combination product and your proposed monotherapy comparators which may
`significantly impact efficacy and safety, complicating interpretation of clinical trial
`results. If you wish to pursue using these marketed products as the monotherapies in the
`pivotal studies, you would need to adequately demonstrate the comparability of
`fluticasone delivered as Flonase and fluticasone delivered via your combination product,
`as well as, the comparability of azelastine delivered as Astelin and azelastine delivered
`via your combination product. ··Demonstration of comparability is quite a high hurdle and
`would include in vitro, pharmaeok:inetic, and pharmacodynamic data. Because of the
`pharmaceutical differences and lack of an objective pharmacodynamic endpoint for
`allergic rhinitis, demonstration of comparability is likely not feasible. Furthermore,
`blinding of such commercial comparators in pivotal studies would be problematic due to
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`HIGHLY CONFIDENTIAL-
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`differences in the delivery systems. Incorporating appropriate du.nlmy products for
`blinding would introduce additi~nal issues regarding spray volumes. Thus, we do not see
`a path forward for using Flonase and Astelin as the comparator monotherapies.
`
`In addition, according to 21CFR300.50, the combination should be safe and effective for
`.a significant patient population requiring such concurrent therapy as defmed in the
`labeling for the drug. Therefore, you need to identify a patient population that requires
`such a combination product. Your clinical development program should evaluate the
`proposed combination product in the proposed patient population that requires concurrent
`therapy with both azelastine and fluticasone propionate. Identification of such a patient
`population may be a challenge for your development program.
`
`Question 1:
`
`We plan to demonstrate the clinical efficacy and safety of our proposed combination
`drug product through two pivotal comparative, placebo-controlled cUnical trials
`and to demonstrate clinical safety in an additiona112-montb trial, as proposed in
`our IND. The proposed safety study should provide adequate data to determine the
`safety of the proposed formulation, delivery device, and dosing schedule.
`Considered along with the proposed toxicology program (lND 77-363 initial
`submission), does the Division agree that safety issues are adequately addressed.
`
`Division response: The proposed safety program (two pivotal placebo-controlled trials
`and a 12 month clinical safety trial) appears reasonable, assuming selection of
`appropriate monotherapy comparators in the pivotal studies as discussed in the
`introductory coinment. However, additional safety data may be required depending on
`the adverse event profile and systemic exposure observed for the proposed combination
`drug product.
`
`Question 2:
`
`Does tbe Division agree that Flonase is an appropriate control for tbe proposed 12-
`month clinical safety trial?
`
`Division response: No, we do not agree. While inclusion of an active comparator such
`as Flonase or Astelin is your choice, the proposed 12-month safety trial should include a
`placebo treatment group.
`
`Question 3:
`
`We are proposing a drug/drug combination product that, based on our proof of
`concept study (MP428), may have significant clinical advantages over the
`commercially available monotherapies. Our proposed clinical program includes a
`vehicle placebo control, thus providing comparison to the potential effects of the
`excipients without drug actives. · Combining a soluble and an insoluble API in a
`single nasal spray formulation presents unique issues, rendering this an atypical
`· .. · ~ --~~-.. -- -~
`....
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`PTX011 0-00003
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`situation that requires careful consideration. Does the Division agree that this
`proposed combination product is atypical and as such may require an alternative
`approach that will also satisfy the combination product rule?
`
`Division response: We agree that your combination product poses some unique issues
`that may be difficult to address. However, this does not change our interpretation of
`what is necessary to satisfy the combination product ruJe.
`
`We note that you propose your combination product will have significant advantages
`over commercially available monotberapies. If you intend to pursue a superiority claim,
`· we recommend you discuss the feasibility of such a claim with the Agency.
`
`Also, we note a potential disadvantage of the proposed combination over the
`con1mercially available monotherapies. For example, a fixed-dose combination does not
`allow the downward dose titration or as needed administration of fluticasone propionate,
`which are options with the commercially available monotherapy.
`
`Question 4:
`
`Formulating monotherapy comparators with identical formulations to the proposed
`combination product but without one or the other of tbe APis may result in changes
`to the formulation that render the monotherapies unsuitable for the proposed use.
`For example, removing fluticasone may change the viscosity and/or spray pattern,
`droplet size, or plume geometry of the Division proposed azelastine monotherapy
`comparator when compared to tbe combination formulation. Similarly, removing
`azelastine may cause changes. Thus, the monotherapies proposed by the Division
`may demonstrate differences between these monotherapies and tbe proposed
`combination product and thus not be consistent with the Division's intent when
`proposing these monotherapies. Does the Division agree?
`
`Division response: As stated in the introductory comment, we acknowledge the
`potential for your monotherapy product to be affected by removal of one of the APis.
`This could complicate your development program and may be difficult to address.
`
`Question 5:
`
`The proposed combination product cannot use the same nasal spray device as each
`approved monotherapy because Astelin and Flonase use different metered spray
`pumps. Using the proposed combination product spray pump with the Division's
`recommended, specially formulated monotherapy comparators may affect the
`efficacy of the monotherapy comparators as compared to the approved
`monotherapies. Using the approved monotberapies assures the comparators will
`have the efficacy and safety physicians associate with these products.
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`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
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`4
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`PTX011 0-00004
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`4
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`a. Does tbe Division agree that tbe use of specially formulated monotberapy
`comparators witb a spray pump designed for use with the proposed
`combination product may alter the known efficacy of the monotberapies?
`
`b. Does the Division agree tbat using the monotberapies proposed by the
`Division with tbe proposed combination product spray pump may not
`meet the Division's intent in proposing the use of these specially
`formulated monotberapies?
`
`Division response: _Refer to the introductory comment and response to Question 4.
`
`Questfon 6:
`
`The use of specially formulated mono therapies for comparator controls in pivotal
`clinical trials provides comparator data that are only directly appli~ble to the
`specially formulated monotberapy comparators and may not reflect either the
`efficacy or safety of tbe approved monotberapies. Data derived from the nse of
`these specially formulated monotberapies will not provide prescribing physicians
`usable information about the approved commercial monotberapies compared to the
`proposed combination product to assist in their prescribing decisions. We believe
`the use of the approved monotberapies will provide physicians the information they
`need to assess the value of the proposed combination.
`
`c. Does tbe Division agree?
`
`d. If not, can the Division expand upon their position and how the results of
`the studies using the specially formulated comparators would be
`explained in the package insert and provide usable information for the
`physician?
`
`Division response: c) We do not agree. Refer to the introductory comment. The fixed(cid:173)
`combination drug regulations do not stipulate that clinical trials establish a comparison
`with coiiliilercially available monotherapies. d) For an example of a description of
`clinical studies to support approval of a combination product, we refer you to the
`Symbicort Inhalation Aerosol product label.
`
`...... _~,- ·~ -- - -~ -· .
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`5
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`HIGHLY CONFIDENTIAL-
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`MEDA_APTX03071179
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`PTX011 0-00005
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`5
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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/
`
`Philantha M Bowen
`9/7/2007 05:03:31 PM
`cso
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`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
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`MEDA_APTX03071180
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`PTX011 0-00006
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`6
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