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`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Drug Evaluation II
`
`Memorandum of Facsimile Correspondence
`
`Date:
`
`To:
`
`May 19,2008
`
`Richard Fosko, R:Ph., .MPH
`Director, Regulatory Affairs
`
`Company:
`
`Meda PharmaceuticalS
`
`Fax:
`
`732-564-2361
`
`Phone:
`
`732-564-2358
`
`From:
`
`Philantha Bowen, MPH, RN
`Senior Regulatory Management Officer
`Division of~onary and Allergy Products
`
`Subject:
`
`IND 77363; Re: SPA Meeting Minutes
`
`# of Pages including cover: 10
`
`TffiS DOCUMENT IS INTENDED ONLY FOR THE USE OF THE PARTY TO
`WHOM IT IS ADDRESSED AND J\IAY CONTAIN INFORMATION THAT IS
`PRIVD...EGED; CONFIDENTIAL AND PROTECTED FROM DISCLOSURE
`UNDER APPLICABLE LAW.
`If you 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 not
`authorized. If you received this document in error, please immediately notify us by
`telephone at (301) 796-2300 and return it to us at FDA, 10903 New Hampshire Ave,
`Building 22, DPAP, Silver Spring, MD 20993.
`
`Thank you.
`
`RECEt'-JED
`
`MAY 1 9 2008
`REGULATORY
`AFFAIRS
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
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`PLAINTIFFS'
`TRIAL EXHIBIT
`PTX0114
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`CIP2165
`Argentum Pharmaceuticals v. Cipla Ltd.
`IPR2017-00807
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`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EV ALUATlON AND RESEARCH
`
`Meeting Type:
`Meeting Category:
`Meeting Date and Time:
`Meeting Location:
`Application Number:
`Product Name:
`
`Received Briefing ·Package
`Sponsor Name:
`Meeting Requestor:
`
`Meeting Chair:
`
`· Meeting Recorder:
`
`Meeting Attendees:
`
`Type A
`
`Special Protocol Assessment
`April29, 2008 9:00-10:00 AM
`Building 22, Conference Room 1415
`
`IND 77,363
`
`Azelastine Hydrochloride and Fluticasone
`Propionate Nasal Spray
`April 15,2008
`
`:MEDA Pharmaceuticals
`Richard Fosko, R.Ph., MPH
`
`Director, Regulatory Affairs
`Badrul A.Chowdhury, M.D., Ph.D., Director
`
`Division of Pulmonary and Allergy Products
`Philantha M. Bowen, MPH, R.N.
`Sr. Regulatory Management Officer
`
`FDA Attendees
`
`Office of Drug Evaluation II
`
`Badrul A. Chowdhury, M.D., Ph.D., Division Director, Division of
`Pulmonary and Allergy Products
`Philantha Bowen, M.P.H., RN:, Sr. Regulatory Management Officer, Division of
`Pulmonary and Allergy Products
`Sally Seymour, M.D., Clinical Team Leader, Division of Pulmonary and Allergy
`Products
`
`C. Joe Sun, Ph.D., Pbannacology!foxicology Team Leader, Division of
`Pulmonary and Allergy Products
`
`Jean Wu, M.D., Ph.D., Pharmacology!foxicology Reviewer, Division of
`Pulnionary and Allergy Products
`·
`
`Meeting Minutes
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`Page 1
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`Meeting Minutes CDER ODEWDP AP
`Application Number # IND 77,363
`
`Type A
`
`Confidential
`
`5/19/2008
`
`Office ofNew Drug Quality Assessment
`Prasad Peri, Ph.D., Pharmaceutical Assessment Lead, Division of Pre-Marketing
`Assessment 1, Branch ll
`Eugenia Nashed, Ph.D., Quality Reviewer, Division of Pre-Marketing Assessment
`I, Branch II
`
`Office of Clinical Pharmacology
`
`Wei Qiu, Ph.D., Acting Clinical Pharmacology Team Leader, Division of Clinical
`Pharmacology 2
`
`Sponsor Attendees
`
`Richard Spivey, PharmD, Ph.D., Senior Vice President, Research and
`Development
`
`Harry Sacks, M.D., Vice President, Medical and Scientific Affairs
`
`Cary Sax, Associate Director, Regulatory Affairs
`
`Warner Carr, MD, Consultant
`
`Phillip Lieberman, MD, Consultant
`
`Meeting Minutes
`
`Page2
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`Meeting Minutes CDER ODEIIJDP AJ>
`
`Type A
`
`Application Number # IND 77,363
`1.0
`BACKGROUND
`
`Confidential
`
`5/19/2008
`
`MEDA Pharmaceuticals submitted a Special Protocol Assessment (SPA) dated Deeember
`21 , 2007, for the clinical protocol MP4002 for the azelastine/fluticasone combination
`nasal spray. On January 31, 2008, the Division responded to MEDA's SPA request.
`
`MEDA Phannaceuticals submitted a Type A meeting request, dated February 29, 2008,
`to discuss the Agency's comments and responses regarding the SPA. The briefing
`package, dated April14, 2008, was reviewed by the Division. On April28, 2008, the
`Division responded to :M:EDA's questions via facsimile. The content of the fax is printed
`below.
`Any discussion that took place at the meeting is captured in section 3.0 including any
`changes in our original position. MEDA's questions are in bold italics and FDA's
`response is in italics; the discussion is in normal font.
`
`2.0
`
`QUESTIONS
`
`2.1
`
`QUESTION 1
`
`Question 1:
`
`Does the Division agree that patients with moderate/severe nasal symptoms of
`seasonal allergic rhinitis, as defined by ARIA, is an appropriate target population
`for this drug?
`
`Division Response:
`
`We do not agree. We have expressed concerns that you have not provided evidence that
`a population for this combination product exists. The ARIA Guidelines presented do not
`alleviate these concerns. The ARIA classification for allergic rhinitis classifies allergic
`rhinitis based upon intermittent and persistent symptoms and is not universally adopted
`in the United States. In particular, this type of classification is not used for approval of
`therapeutics for allergic rhinitis.
`
`The combining of different products to control symptoms of SAR is the practice of
`medicine. Single ingredient products containing azelastine or jluticasone propionate are
`approved for treatment of symptoms of seasonal allergic rhinitis. The combination
`product that you are proposing to develop is targeted to treat the same symptoms-that the
`single ingredient products are already indicated for. Demonstrating significantly greater
`symptom relief with the combination product over its individual single active ingredients
`will not be sufficient to demonstrate that both azelastine and fluticasone propionate
`contribute to the effectiveness of the combination. Demonstration of greater symptom
`relief with the combination product over its active ingredients (for the exact same
`symptoms) is likely to be due to the fact some patients may not be responding to
`
`Meeting Minutes
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`Meeting Minutes COER ODEIIIDP AP
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`Type A
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`Application Number# IND 77,363
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`Confidential
`
`5/1912008
`
`azelastine while responding to fluticasone propionate, and vice versa. Rationale based
`on pharmacodynamic reasoning, such as mechanism of action, onset of symptom relief,
`etc., are also not sufficient to justify this combination product.
`
`As stated before, combining products eliminates flexibility with dosage titration and
`potentially exposes patients to unnecessary medication; and thus unnecessary risk.
`
`2.2
`
`QUESTION 2
`
`Question 2:
`
`Does the Division agree that our proposed inclusion/exclusion criteria will study a
`population of patients with moderate/severe rhinitis?
`
`Division Response:
`
`We do not agree. We do not have specific criteria using the TNSS to define what
`.
`constitutes moderate or severe allergic rhinitis.
`
`2.3 QUESTION 3
`
`Question3:
`
`Does the Division agree that the proposed dosage of the individual components of
`the fu:ed dosage product (that are within the labeling for those marketed products)
`is appropriate for study in the MP4002 study?
`
`Division Response:
`
`We remain concerned about the lack of flexibility of dosage titration with the frxed dose
`combination (FDC). We acknowledge your explanation and ask you to make the
`reasoning in the NDA, if you are to develop this product. This will be a review issue.
`
`2.4 QUESTION 4
`
`Question 4:
`
`Does the Division agree that no new corticosteroid-specific safety issues are
`anticipated with the fu:ed dose combination product that would require MEDA to
`study a dosage that is lower than the recommended dosage in the fluticasone label?
`This question is predicated on the assumption that adequate pK studies do not show
`
`Meeting Minutes
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`Type A
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`Application Number # lND 77,363
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`Confidential
`
`5/19/2008
`
`an appreciable enhancement of absorption of Outi as one. In addition, it assumes
`that appropriate long term studies support tbe sati ty of the combination product.
`
`Division Response:
`We cannot agree. Your question is based upon assu
`time. Your FDC, as well as, the individual monother
`represent new products. The safety and efficacy of e
`established. Therefore, we cannot agree that no new
`anticipated.
`
`lions that are unknown at this
`ies, with new formulations
`h of these products have not been
`orticosteroid safety issues are
`
`2.5 QUESTION 5
`
`Question 5:
`
`If the Division still does not agree that we have ap ropriately applied the specific
`elements of the combination rule stated above, the we respectively request the
`opi.oion of the Director of tbe Office of Drug Eval ation II on the above issues. In
`addition, we would also request input from the 0 1ce of Medical Policy on the
`Division's interpretation of these elements of the c mbination rule under these
`circnmstances.
`
`We believe we have addressed your questions adequ ely and the responses can be
`discussed at the face-to-face meeting.
`
`:CMC
`
`We note that four new suspension nasal spray drug p oducts were manufactured for the
`use in this IND, i.e., aze/astine hydrochlorideljluticas ne propionate combination nasal
`spray (different formulation from the original IND su mission), two single-active(cid:173)
`comparator nasal sprays, and a placebo nasal spray. Any further development in the
`clinical program must be accompanied by_the submis ion ofthefonnal in vitro
`.
`characterization studies for these drug products, as
`scribed in our Guidance "Nasal
`Spray and Inhalation Solution, Suspension, and Dru Products". In particular, provide
`the dose perform,ance data (e.g., emitted dose, spray on tent uniformity, droplet size
`distribution, etc.) that characterizes the combination
`al spray product and the two
`monotherapy products (azelastine hydrochloride nas I spray andjluticasone propionate
`nasal spray). Provide these data in a side-by-side pn entation using graphs, in order to
`demonstrate the pharmaceutical comparability of the in vitro dose delivery for the ~ing/e
`component drugs relative to the combination produc
`
`3.0
`
`DISCUSSION
`
`Meeting Minutes
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`Type A
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`Application Number# IND 77,363
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`Confidential
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`5/1912008
`
`appropriate patient population
`'MEDA began the discussion seeking clarification on
`and a better understanding of application of the comb ation product rule. MEDA
`outlined the following points for clarification: ·
`
`• An understanding of the Division's position fwhy it is a problem that the
`proposed combination product is targeted to eat the same symptoms as the
`single product ingredients;
`• An explanation as to why the combination pr duct, if shown to demonstrate
`greater symptom relief over the single ~gred ents, is not sufficient;
`
`• Discussion and clarity of the Division's posi on that greater symptom relief with
`the combination product over the active ingr
`· ents may be a result of some
`patients responding to one single ingredient
`er the other.
`
`MEDA informed the Division that the rationale for th combination product was based
`upon input from allergists who noted they treat many ftheir SAR patients with both
`azelastine and fluticasone nasal sprays. MEDA ackno ledged the Division's comment
`that combining different products to control sympto
`of SAR is the practice of
`·
`medicine. However, MEDA explained that the comb ation product would be better than
`the individual ingredients because patients would not ave to take four sprays of
`medication at a time. With the individual component , compliance becomes an issue;
`thus leading to treatment failures and unmet patient n eds. MEDA suggested that the
`patient population would be those who have failed co
`on treatments regimens and
`those who would be inconvenienced by taking twos· gle drug products. In terms of
`safety, MEDA commented that combining the two pr ducts versus the individual
`components would not alter the safety. In fact, the pr uct will be effective and pose less
`of a risk. MEDA cited examples of other combinatio products that also treated the same
`disease, e.g. LABA and ICS for asthma. MEDA aske the Division to provide its
`expectation of efficacy for the combination product.
`
`gs to treat the same symptoms of a
`The Division responded that the combi.nlng of two
`disease is problematic. The Division noted that the c mbination of azelastille and
`fluticas~ne nasal spray is approved as Duonase in In a. The Division or MEDA's
`consultants did not know the specific background of e premise of Duonase approval in
`India. The Division mentioned that at a recent meet' g (AAAAI 2008) where one of.the
`MEDA consultants Dr. P. Lieberman spoke at an aca ernie session, a comment was made
`from the audience that suggested that the premise of
`· s combination product is that it
`treats two different types of rhinitis: allergic and non
`lergic. The Division commented
`that such a premise would seem reasonable. The Div sian noted that MEDA .proposes the
`combination product for the same indication, sympto
`of SAR. While the proposed
`combination may be a choice in the practice ofmedi ·ne, it is not necessarily rationale as
`a fixed dose combination. If we look at the cough, c ld, allergy, bronchodilator, and
`antihistamine drugs OTC monograph (21 CFR 341 ), ermitted combinations are
`described. The combinations described include com onents that treat a different aspect
`of the disease, e.g. antihistamine and decongestant or antihisiamine and antitussive. The
`
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`Application Number# IND 77,363
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`Confidential
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`S/19/2008
`
`· monograph does not allow combination of two drugs at treat the same aspect of the
`disease, e.g. antihistamine and antihistamine.
`
`The next issue is the combination rule, i.e. that each c mponent makes a contribution to
`the claimed effects. With the proposed program, ME A would use the same endpoint,
`· total nasal symptom score (TNSS), to evaluate tbe e cacy of the combination product
`and each component. This is problematic because so e patients may not respond to one
`e of the same endpoint will not
`component, but yet respond to the combination; and
`discriminate. For example, if a patient has failed aze as tine therapy, but responds to the
`combination product, then it could imply that the resp nse is toward the effects of the
`ster<;>id; however the patient would receive the combi atioo product where one
`component provides no benefit, but yet exposes them o unnecessary risk. In addition,
`the Division raised the possible safety concern regard ng the lack of flexibility for dosage
`titration for the proposed combination product.
`
`MEDA responded that patient response to the combin tion can be viewed as a synergistic
`effect. In terms of treatment failure, MEDA stated tb
`''treatment failure" could me.an
`that patients failed to get complete symptom relie[
`oreover, MEDA pointed out that
`for any combination product it may be difficult to de rmine which component is
`providing the benefit; hence, randomized studies are sed. MEDA questioned the
`Division as to why this approach could not be utiliz with the proposed product. The
`Division addressed the combination product referenc d, LABA and ICS, which have
`different endpoints to measure disease benefit. In ME A's proposed program, however,
`the endpoints are the same and the product is aimed a treating the same aspects of the
`disease with the two drugs. With such a design, the D vision reiterated that it is difficult
`to detimnine the contribution of each component.
`
`MEDA noted that there are approved combination pr ducts that have the same endpoints
`(e.g. analgesics); and questioned the application ofth combination rule in this situation.
`Tb~ Division could not comment on the application o the combination rule for those
`particular situa.tions. MEDA was informed of the rec nt regulatory action taken on a
`combination product that addressed benefit on the s
`e aspects of disease. The Division
`stated that it would be MEDA's chqice on whether to pursue the study using the same
`endpoints to measure disease benefit, but .MEDA sbo d understand the Division's
`concerns.
`
`MEDA asked whether other endpoints, such as onset faction, may address the
`Division's concerns. The Division did not think that nset of action will demonstrate the
`expected outcome. The Division responded that diffe ent methods are risky, however,
`innovation is encouraged.
`
`The Division, acknowledged MEDA's request to hav clarification of the combination
`rule, and informed MEDA of three aspects to be cons dered for combination products:
`
`• CFR 341.50 outlines the lists of monographs for combination products that are
`permitted by law. In addition, the appropria
`language for the label is provided,
`as well as, separate indications for each of th drug components. As discussed
`
`Meeting Minutes
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`Type A
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`Application Number# IND 77,363
`
`Confidential
`
`5/19/2008
`
`earlier,.this approach does not provide for co
`aspect of the disease. The rationale outlined
`is no reason tbat the same rationale would no
`
`bining prod~cts that treat the same
`CFR 341.50 is sensible, and there
`apply for prescription products.
`
`• Per CFR 300.50 each component has to mak a contribution to the claimed
`effect. As discussed earlier, the Division stat
`that it will be difficult to
`determine the contribution of each componen for MEDA;s combination product.
`
`• Per CFR 300.50, special cases are allowed if component is added to enhance.
`the safety or effectiveness of the principle ac ve component. MEDA's
`combination product does not fit this· special ase.
`
`MEDA commented that for some combination produ ts, i.e. analgesics, have the same
`endpoints and the individuals components of the prod ct, as well as the combination,
`have been superior to placebo. MEDA does not unde tand how the combination rule
`precludes development of their combination product. MEDA verbalized their
`disagreement with Division's position and commente .that the pathway for their
`proposed product for allergic rhinitis is halted.
`
`The Division informed MEDA that consultation and ollaboration had been sought with
`other offices in' the Agency, therefore the position tak n had not been in isolation. The
`pathway forward may be for MEDA to formally disp te the Division. The dispute
`process may be a way to seek the direct involvement f the Office Director. At this point,
`it will be MEDA's choice to pursue the clinical devel pment program. The Division
`commented that there appears to be no safety risk in
`DA conducting the study.
`
`The Division recommended to MEDA that if product evelopment is pursued, the CMC
`information (performance in terms of emitted dose an droplet size distribution) must be
`evaluated and addressed carefully and referred MED
`to the CMC additional comment
`provided in the Division's responses. In addition, sin e each monotherapy represents a
`new product, one API is in solution (azelastine nasal pray) and the other API is a
`suspension (fluticasone nasal spray), it was recotnme ded that MEDA address these
`differences in a side-by-side comparison format.
`
`ISSUES REQUIRING FURTHER DISCU SION
`4.0
`There were no issues requiring further discussion.
`
`ATT ACBMENTS AND HANDOUTS
`5.0
`There were no attachments or handouts for the mee · g minutes.
`
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`Linked Applications
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`Sponsor Name
`
`Drug Name
`
`IND 77363
`
`AZELASTINE/FLUTICASON E
`COMBINATION NASAL
`
`MEDA
`PHARMACEUTICALS
`MEDA
`PHARMACEUTICALS
`INC
`
`___ : ____________ ..,. _________________________________________ _
`
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`
`___ .,... __________ :______________
`
`. -----------------------
`
`Is/
`
`PHILANTHA M BOWEN
`05/19/2008
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