CENTER FOR DRUG EVALUATION AND RESEARCH
`
`_ APPLICA TI0N NUMBER:
`
`50-805 __
`
`ADMINISTRATIVE and CORRESPONDENCE V
`DOCUMENTS
`
`

`

`OraceaTM (doxycycline r Mpsules) 40mg.
`Orignial NDA 50—805
`.
`
`CollaGenex Pharmaceuticals, Inc.
`Patent Information
`
`PATENTINFORMATION UNDER 21 CFR 314.53“!
`
`US Patent:
`
`5,789,395
`
`Effective Filing Date
`Effective Issue Date:
`
`August 30, 1996
`August 4, 1998
`
`Expiration Date:
`
`August 30, 2016
`
`Type of Patent:
`
`Method of Use
`
`Patent Owner:
`
`The Research Foundation of State University of New York
`
`DECLARATION
`
`In accordance with 21 CFR 314.53© the undersigned declares that Patent No. 5,789,395
`covers the formulation, composition, and/or method of use of OraceaTM. This product is
`the subject of this application for which approval is being sought.
`
`
`
`'
`
`.-
`‘
`- 111mg N. Fei
`Attorney for Patent Owner
`Hoffmann & Baron
`6900 Jericho Turnpike
`Syoffet, NY 11791
`
`Respectfully submitted,
`
` Christop er Powala
`Vice President, Drug Development
`And Regulatory Affairs
`CollaGenex Pharmaceuticals, Inc.
`41 University Drive
`Newtown, PA 18940
`
`

`

`OraceaTM (doxycycline ———-f—-—-'_‘
`Original NDA 50—805
`
`capsules) 40mg.
`
`CollaGenex Pharmaceuticals, Inc.
`Patent lnfonnation
`
`PATENT INFORMATION
`
`Patents Issued:
`
`NDA 50—805 contains three (3) method of use patents for which the Sponsor certifies.
`These patents are:
`
`Patent No. 5,789,395: Method of using tetracycline compounds for inhibition of
`endogenous nitric oxide production.
`
`Patent No. 5,919,775: Method of inhibiting inducible nitric oxide synthase with
`tetracyclines.
`
`Patent No. 6,015,804: Method of using tetracycline compounds to enhance interleukin-
`10 production.
`
`A copy of the licensing agreement between CollaGenex Pharmaceuticals, Inc. and the
`Research Foundation of the State University of New York is attached. This document
`provides CollaGenex Pharmaceuticals with rights to the above referenced patents. This
`Agreement immediately follows this summary.
`'
`
`Patents Pending:
`
`During the review period of NDA 50—805 , the Sponsor anticipates that the following
`patents will be issued by the US. Patent and Trademark Office that will cover further the
`formulation and methods of use for- OraceaTM. The Sponsor will submit these patents as a
`minor amendment to this NDA within 30 days of the date of issuance as required by 21
`CFR 314.53(d)(1). Those patents expected to issue during the NDA review period are:
`
`Application Serial No. 10/117,709: Method of treating acne wherein the said acne is
`acne rosacea.
`
`Application Serial No. 10/414,808: Method of simultaneously treating ocular rosacea
`and acne rosacea.
`
`Application Serial No. 10/272,499: Use of tetracyclines and tetracycline derivatives to
`treat acne and telangiectasia.
`
`Application Serial No. 10/474,240: Controlled delivery of tetracyclines and tetracycline
`derivatives.
`
`Application Serial No. 10/819,620: Once daily formulations of doxycycline.
`
`

`

`OraceaTM (doxycycline
`Original NDA 50—805
`
`'Mcapsules) 40 mg
`
`CollaGenex Pharmaceuticals, Inc.
`1.3.2 Patent Certification
`
`1.3.2 Patent Certification
`
`The Sponsor certifies Patent Numbers 5,789,395; 5,919,775, and 6,015,804. Copies of the
`certifications follow.
`
`

`

`(Complete for all filed original applications and efficacy supplements)
`
`PEDIATRIC PAGE
`
`I NDA/BLA #:
`
`50 - 805
`
`Supplement Type (e.g. SE5):
`
`Supplement Number:
`
`HEB—540
`
`Trade and generic names/dosage form: ”1*?!“
`
`
`Applicant: CollaGcnex Pharmaceuticals Inc.
`
`Therapeutic Class: g
`
`Indication(s) previously approved:
`
`Each approved indication must have pediatric studies: Completed, Deferred, and/or Waived.
`
`Number of indications for this application(s): 1
`
`Indication #1: For the topical treatment of psoriasis vulgaris in adults aged 18 years and above
`
`Is there a full waiver for this indication (check one)?
`
`X Yes: Please proceed to Section A.
`
`Partial Waiver
`No: Please check all that apply:
`NOTE: More than one may apply
`Please proceed to Section B, Section C, and/or Section D and complete as necessary.
`
`Deferred _Completed
`
`: Fuiy Waived Studies
`:
`ection
`
`Reason(s) for full waiver:
`
`3 Products in this class for this indication have been studied/labeled for pediatric population
`D Disease/condition does not exist in children
`
`.,_ .
`
`@300 few children with disease to study
`[1 There are safety concerns
`
`[3 (Ether:
`
`Ifstudies are,fully waived, then pediatric information is complete for this indication. If there is another indication, please see
`Attachment A. Otherwise, this Pediatric Page is complete and should be entered into DFS.
`
`Sectio VB. Pariflaly Waived Studies
`
`Age/weight range being partially waived:
`
`Min
`
`Max
`
`kg
`kg
`
`yr. _
`mo. 0
`
`mo. 0
`yr.
`
`
`Tanner Stage
`Tanner Stage
`
`Reason(s) for partial waiver:
`
`3 Products in this class for this indication have been studied/labeled for pediatric population
`D Disease/condition does not exist in children
`Too few children with disease to study
`There are safety concerns
`Ci Adult studies ready for approval
`fl Formulation needed
`U Other: Sponsor specified exact population to study.
`
`

`

`Ifstudies are deferred, proceed to Section C. Ifstudies are completed, proceed to Section D. Otherwise, this Pediatric Page is
`complete and should be entered into DFS.
`
`“Section C: Deferred Studies
`
`Age/weight range being deferred:
`
`Min
`Max
`
`kg
`kg
`
`mo.
`mo.
`
`yr.
`yr.
`
`Tanner Stage
`Tanner Stage
`
`Reas0n(s) for deferral:
`
`D Products in this class for this indication have been studied/labeled for pediatric population
`Ci Disease/condition does not exist in children
`
`1:? Too few children with disease to study
`There are safety concerns
`Adult studies ready for approval
`a Formulation needed
`Other:
`
`Date studies are due (mm/dd/yy):
`
`Ifstudies are completed, proceed to Section D. Otherwise, this Pediatric Page is complete and should be entered into DFS.
`
` Secnio D. Completed Studies
`
`Age/weight range of completed studies:
`
`Min
`Max_
`
`kg
`kg
`
`mo. 0
`mo. 0
`
`yr. 18 Tanner Stage
`yr. 90 Tanner Stage
`
`Comments: 18 years and above
`
`Ifthere are additional indications, please proceed to Attachment A. Otherwise, this Pediatric Page is complete and should be entered
`into DFS.
`
`This page was completed by:
`
`{See appended electronic signature page}
`
`Shalini Jain, PA—C
`Reguiatory Project Manager
`
`cc: NBA
`HFD-960/Grace Carmouze
`
`(revised 12-22-03)
`
`FOR QUESTIONS ON COMPLETING THIS FORM CONTACT THE DIVISION OF PEDIATRIC DRUG
`DEVELOPMENT, HFD-960, 301-594-7337.
`
`

`

`COLLAGENEX
`
`
`pharmaceuticals
`
`September 8, 2005
`
`Jonathan K. Wilkin, M.D., Director
`Division of Dermatological & Dental Drug Products
`Food and Drug-Administration
`5901-8 Ammendale Road
`
`Beltsville, MD 20705-1266
`
`RE: NDA 50-805
`Capsules) 40mg
`OraceaTM (doxyeycliner —-—-——-—-*——""""
`Minor Amendment: Addendum to Debarment Statement
`
`Dear Dr. Wilkin:
`
`Please refer to NDA 50-805 for OraceaTM (doxycycline W
`capsules) 40mg which is proposed for use as a treatment .7 1"7
`inflammatory lesions
`in patients with rosacea.
`
`Additional reference is made to the debarment statement contained in Module 1, Volume
`1.1, Section 1.3.3. CollaGenex is providing herewith an addendum to the debarment
`statement:
`‘
`
`Debarment Statement: Addendum:
`
`In accord with the Food, Drug and Cosmetic Act, section 306(k)(1) CollaGenex
`Pharmaceuticals, Inc. further certifies, by signature below, that it did not and will not use
`in any capacity, the services of any person debarred under section 306 of the Food, Drug
`and Cosmetic Act in connection with the above-referenced new drug application.
`
`Certified and attested to this 8:}: Day of September, 2005, by:
`
`
`
`Vice President, Drug Development
`& Regulatory Affairs
`
`Desk Copy:
`
`Shalini Jain, PA-C, HFD-540
`
`CollaGenex Pharmaceuticals, Inc, M Universily Drive, Suite 200, Newlown, PA 18940 USA
`'
`215-579-7388 voice 2155798577 lax
`
`

`

` .COLLAGENEX
`
`pharmaceuticals
`
`June 30, 2005
`
`Jonathan K. Wilkin, M.D., Director-
`Division of Dermatological & Dental
`Drug Products (HFD-540)
`Food and Drug Administration
`9201 Corporate Drive
`Rockville, MD 20857
`
`RE: NDA 50-805
`OraceaTM (doxycycline __'__"____________..
`
`capsules) 40mg
`
`Dear Dr. Wilkin:
`
`The United States Federal Food, Drug and Cosmetic Act contains a requirement that
`Sponsors of new drugs report to the U.S. Food and Drug Administration (FDA) whether
`they utilize the services of any person or firm in connection with the development or
`submission of an abbreviated new drug application or antibiotic application that has itself
`been debarred by FDA or whose employees involved with the application have been
`debarred by FDA or convicted of certain acts. CollaGeneX Pharmaceuticals, Inc. is
`providing the following information:
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`CollaGeneX is not currently, nor has it ever been debarred by FDA;
`
`CollaGenex is not currently, nor has it ever been involved in a debarment
`proceeding with FDA;
`
`CollaGeneX has not, within the past 5 years, nor has it ever, been convicted of
`a felony under U.S. Federal law for conduct relating to the development or
`approval, including the process for development or approval, of any
`abbreViated antibiotic drug applications (ANDA) or abbreviated antibiotic
`drug applications (AADA) or convicted of a conspiracy or accessory to do the
`same;
`
`CollaGenex has not, within the past 5 years, nor has it ever, been convicted of
`a misdemeanor under U.S. federal law or a felony under state law for conduct
`relating to development or accessory to do the same;
`
`No employee of CollaGeneX who workedon NDA 50—805 or data to support
`any pre-market approval application is currently, or ever been, debarred by
`FDA;
`
`ColioGenex Pharmaceuticals, inc, All University Diive, Suite 200, Newtown, PA l8940 USA
`2657977388 ware 305517918577 lax
`
`

`

`Jonathan K. Wilkin, M.D
`NDA 50-805
`
`Debarment Statement
`
`_.
`
`‘
`
`June 30, 2005
`
`6.
`
`7.
`
`No employee of CollaGenex who worked on an application or data to support
`NDA 50-805 is currently, or was ever involved in a debarment proceeding
`with FDA.
`
`No employee of CollaGenex who worked the application or data to support
`NDA 50—805 has in the past five years, or ever been convicted of any of the
`following acts:
`
`(I)
`
`(11)
`
`(111)
`
`a felony relating to the development Or approval, including the process
`for development or approval, of any drug product or to any act relating
`to the regulation of any drug product under the U.S. federal Food,
`Drug and Cosmetic Act, or a conspiracy to commit or an accessory in
`such a felony;
`'
`
`a misdemeanor under U.S. federal law or a felony under U.S. state law
`relating to or approval of any drug product or to any act relating to the
`regulation of drug products under the Food, Drug and Cosmetic Act,
`or a conspiracy. or accessory to committhé’fofgo’inflgwor a felony under
`U.S. federal law relating to the same.
`'
`
`A felony under either federal or state law (U.S.) which involved:
`bribery, payment of illegal gratuities, fraud, perjury, false statement,
`racketeering, blackmail, extortion, falsification or destruction of
`records, or interference with, obstruction of an investigation into, or
`prosecution of, any criminal offense or a cOnspiracy or accessory to do
`the same.
`
`Certified and attested to this 30 Day of Tune
`
`, 2005, by:
`
`
`
`Christopher Powala
`Vice President, Drug Development
`& Regulatory Affairs
`
`

`

`Jonathan K. Wilkin, MD
`NDA 5 0- 8 05
`
`Debarment Statement
`
`June 30, 2005'
`
`1/
`
`CollaGenex Pharmaceuticals, Inc. hereby certifies, to the best of its knowledge, that at no
`time did it utilize the services of any person, clinical investigator, or firm that has been
`debarred under the Federal Food, Drug and Cosmetic Act, in connection with this new
`drug application (NDA 50—805).
`
`The following contract research organizations were employed by CollaGenex during the
`development of OraceaTM and are accompanied by a letter of certification reporting their
`position of good standing:
`
`1. H
`
`,
`
`provided the following services: clinical monitoring, safety
`._-—_——-
`surveillance and AE reporting, statistical development, report writing, quality
`assurance and GCP auditing. A letter of certification13 provided1n
`Attachment 1.
`
`2. WM
`
`_,,——————-——-——-— ' provided clinical laboratory services used to
`generate lab data in the pharmacokinetic and clinical trials provided in NDA
`50-805. A letter of certification is provided in Attachment 2.
`
`
`
`-—-—— will be the supplier of
`__...—— provided the drug substance.
`doxycycline monohydrate to be used in the manufacture of the commercial
`batches. A letter of certification is provided in Attachment 3.
`
`4.
`
`Cardinal Health, 1100Enterprise Drive, Winchester, KY 40391, 5
`“Wcm“mm-£3111all-tumm
`
`Cardinal Winchester manufactures and release bulk drug product. Cardinal
`CC w
`.
`,
`A letter of certification from each facility is provided in Attachmeht 4.
`
`3\
`
` ,WRWWme—‘EV—mmx‘ao‘z’wsfl-mxamww"
`
`H 1 provides packaging services for the final d1ug product A letter of
`certification15 provided1n Attachment 5.
`'
`
`

`

`Jonathan K. Wilkin, MD
`NDA 5 0-805
`Debarment Statement
`
`'
`
`June 30, 2005
`
`6.
`
`
`
`prepared the environmental assessment/exclusion for the
`«——-—-
`drug product A letter of certificationIS providedin Attachment 6.
`
`
`
`,
`
`assisted in the writing and assembly of the new drug application.
`.-———-"’
`A letter of certification is provided in Attachment 7.
`
`

`

`Debarment Certification
`
`This Certification Statement is provided for New Drug Application (NDA) 50—805, and is
`provided in compliance with the Generic Drug Enforcement Act of 1992.
`
`;—-——.--— hereby certifies that we did not use in any capacity the services of any
`person debarred under section (a) or (b) of Section 306 of the federal Food, Drug and
`Cosmetic Actin connection with this application.
`
`3 ELM 2063”“
`Date
`
`

`

`CollaGenex Pharmaceuticals, lnc.
`
`7
`
`NBA Oracea (COL 101)
`
`Debarment Certification
`
`This Certification Statement
`Oracea (COL 101).
`
`is provided for the New Drug Application (NDA) of
`
`V
`
`_M . hereby certifies that services of any person
`debarred under subsection (a) or (b) of Section 306 of the Federal Food, Drug and
`Cosmetic Act [21 U.S.C. Section 335 a(a)(b)] were not and will not be used in any
`’ capacity in connection with activities performed.
`
`__
`
`/z ”74 g ”a;
`
`‘.
`
`Date
`
`

`

`DEBARMENT STATMENT
`
`We hereby declare that no —-—‘
`
`employee appears on the FDA Debarment List, furthermore
`
`.-—-, '
`
`>
`
`'did not and will not use in capacity the services of any person debarred under subsections (a)
`
`or (b) [section 306 (a) or (b)] of the Generic Drug Enforcement Act of 1992.
`
`

`

`
`CardinalHealth
`
`Cardinal Health
`i100 Enterprise Drive
`Winchester, KY 40391
`859.745.2200 tel
`859.745.6636 fax
`
`wvrwcazdinatcomipts
`
`DEBARMEN'T CERTJFICATION AND CONVlCTEON STATEMENT
`
`March '2, 2005
`
`Philip Freidenreich, PhD
`Director "of Q A & Compliance
`ColiaG'enex Pharmaceuticals, Inc.
`
`41 University Drive, Suite 200
`Newtown. PA 18940
`
`Attn: Philip Freidenreich
`
`to certify that Cardinal Health {formerly known as international Processing
`is
`This
`Corporation) has not used, and will not use in any capacity, the services of any person or firm
`debarred under sections 306(a) or (b) of the Generic Drug Enforcement Act of 1992 in
`connection with this application.
`
`To the best of our knowledge there have been no convictions, for which a person could be
`debarred under sections 306(a) or (b) of the Act, within the previous 5 years of the applicant.
`
`Sincerely.
`
`
`
`
`G. Keith Arvin
`
`Director, Quality Assurance
`Cardinal Health
`
`
`
`.‘ijacK ‘
`Cheryl L.
`‘
`Notary
`State-at—Large
`My commission Expires: November 21. 2006
`
`

`

`May 13, 2005
`
`Philip Freidenreich
`CollaGenex Pharmaceuticals, Inc.
`
`41 University Drive
`Suite 200
`
`Newtown, PA 18940
`
`Dear Phil,
`
`.—
`This letter is in response to your request for information relative to FDA debarment.
`'._’
`Joes not employ individuals that have been debarred by the FDA under Sections 306 (a) or
`(b) of the Generic Enforcement Act of 1992.
`
`Prior to employment, potential employees are required to complete a certification that states they
`have not been debarred under Sections 306 (a) or (b) of the Generic Enforcement Act of 1992.
`
`Therefore, no one who has been debarred by the FDA under Sections 306 (a) or (b) of the Generic
`Enforcement Act of 1992 will be associated with any client project within 7 -—-—-"'—"—“
`
`If you need any additional information, please do not hesitate to contact me.
`
`Sincerely,
`
`

`

`CoilaGenex
`
`4i Universi’ry Drive
`Sui’re 200
`
`.
`
`Newiown, PA 18940
`
`Subjeci: FDA Debarmen’r Lis’r
`
`March 2, 2005
`
`Dear Philip Freidenreich, PhD, DirecTor—Quaii’ry Assurance &Compliance,
`
`.
`There are no employees of
`Thai appear on The FDA Debarmen’r Lisr.
`
`Bes’r Regards,
`
`
`
`

`

`March 2, 2005
`
`Mr. Phillip Freidenreich
`Director of Quality Assurance and Compliance
`Collagenex Pharmaceuticals, Inc
`41 University Drive, Suite 200
`Newtown, PA 18940
`
`Dear Mr. Freidenreich '
`
`RE: Debarment Certification
`
`
`
`does not employ any individual that is debarred.
`This is to certify that
`This certification is pursuant to sections 306(a) and (b) of the Federal Food, Drug, and
`Cosmetic Act (21 U.S.C. 335(a) and (b) as published in the Federal Register.
`
`If there are any questions, or additional information required, please contact'me at
`(“/—
`
`Regards,
`
`
`
`

`

`June 23, 2005
`
`Dr. Phil Freidenreich
`
`CollaGenex Pharmaceuticals, Inc.
`
`41 University Dr.
`Suite 200
`
`Newtown, PA 18940
`
`Dear. Dr. Freidenreich:
`
`The United States Federal Food, Drug, and Cosmetic Act contains a requirement that
`sponsors of new drugs report to the US. Food and Drug Administration (FDA) whether
`they use the services of any company in connection with the development or submission
`of a new drug application that has itself been debarred by FDA or Whose employees
`involved with the application have been debarred by FDA or convicted of certain acts.
`To assist you in complying with this requirement, —-.-—_-—-———"‘
`is providing the
`following information:
`
`1. M” is not currently, nor has it ever been, debarred by
`FDA.
`
`W is not currently, nor has it ever been, involved in a
`debarment proceeding with the FDA.
`
`W has not within the last five years, nor has it ever,
`been convicted of a felony under US. federal law for conduct relating to
`the development or approval, including the process for development or
`approval, of any new drug applications (NDA) or abbreviated new drug
`applications (ANDA), or convicted of a conspiracy or accessory to do the
`same.
`'
`
`has not within the last five years, nor has it ever,
`___'_,——a
`been convicted of a misdemeanor under US. federal
`law or a felony
`under state law for conduct relating to development or approval, or the
`process of the development or approval, of any NDA or ANDA or
`convicted of a conspiracy or accessory to do the same.
`
`
`
`who worked on the application or
`No employee of
`data to support any application for Collagenex Pharmaceutical, Inc.
`is _
`currently, or ever been, debarred by FDA.
`
`

`

`6.
`
`7.
`
`No employee of --'-—-——=-——- who worked on an application or
`data to support an application for Collagenex Pharmaceutical, Inc.
`is
`' currently, or ever been, involved1n a debarment proceeding with FDA.
`
`No employee of f,— who worked on an application or
`data to support an application for Collagenex Pharmaceutical, Inc. hasin
`the past five years, or ever, been convicted of any of the following acts:
`
`a felony relating to the development or approval, including the
`(1)
`process for development or approval, of any drug product or to any act
`relating to the regulation of any drug product under the US. Federal
`Food, Drug, and Cosmetic Act (FDCA), or a conspiracy to commit or' an
`accessory in such a felony;
`
`a misdemeanor under US. federal law or a felony under US. state
`(2)
`law relating to the development or approval, of any drug product or to any
`act
`relating to the regulation of drug products under FDCA, or a
`conspiracy or accessory to commit the foregoing or a felony under US.
`federal law relating to the same;
`
`a felony under either federal or state law (U.S.) which involved:
`(3)
`bribery, payment of illegal gratuities,
`fraud, perjury, false statement,
`racketeering, blackmail, extortion, falsification or destruction of records,
`or interference with, obstruction of an investigation into, or prosecution
`of, any criminal offense or a conspiracy or accessory to do the same.
`
`Certified and attested to this
`
`
`23rd
`day of June ,2005 , by:
`
`

`

`June 15, 2005
`
`Christopher Powala
`Vice President
`
`Drug Development & Regulatory Affairs
`CollaGenex Pharmaceuticals, Inc.
`41 University Drive, Suite 200
`Newtown, PA 18940
`
`Dear Mr. Powala:
`
`On behalf of W . I hereby certify that the company itself,
`no employee of the company, and no subcontractor for the company has ever been
`debarred or involved in a debarment proceeding with the FDA.
`
`Sincerely,
`
`

`

`’
`
`
`
`INDEPENDENT
`INVESTIGATIONAL
`REVIEW BOARD INC.
`_.r Advocate for Clinical Research Participants
`
`DATE:
`
`May 25, 2005
`
`TO:
`
`FROM:
`
`Phil Freidenreich, Director
`CollaGenex Pharmaceuticals, Inc.
`
`.
`Kim Lerner, Chairman
`Independent lnvestigational ReVIew Board, Inc.
`
`SUBJECT:
`
`Confirmation of Principal Investigator Status
`
`PROTOCOL:
`
`COL-101-ROSE-302
`
`This memorandum is intended to provide verification that no Board Member or
`Administrative Staff of the Independent lnvestigational Review Board,
`Inc. has
`ever been listed on the FDA Debarment List.
`In addition,
`this verification,
`confirms that the IIRB reviewed and approved the following sites related to the
`above noted study.
`"
`
`Principal Investigator
`Robert Martin, MD
`Leonard Swinyer, MD
`Michael Gold, MD
`Peter Cooperrider, MD
`Mitchel P. Goldman, MD
`Richard White, MD
`Helen Torok, MD
`Mark Jackson, MD
`Leslie Capin, MD
`James Turner, MD
`Harry Sharata, MD
`Robert Skrokov, MD
`Jame Q. Del Rosso, DO
`Jo Lynne Herzog, M ’
`Frank Dunlap, MD
`
`Approval Date
`6/10/04
`6/10/04
`6/10/04
`6/10/04
`6/10/04
`6/10/04
`6/10/04
`6/10/04
`6/10/04
`6/10/04
`6/10/04
`7/13/04
`8/17/04
`8/17/04
`8/17/04
`
`7
`
`If additional clarification is required, please let me know.
`
`Thank you.
`
`phone 954—32 7-0778 ofax 954-327—5778 9 6.738 IvI/csl sunrise Blvd, Suite 102 = Plantation, FL 33313 0 inj0@iirl1.com (email) 0 www.iirb.c0m
`
`

`

`
`
`-
`
`.
`
`17 May 2005
`
`Philip Freidenreich, PhD
`Senior Director, Quality Assurance and Compliance
`CollaGenex Pharmaceuticals, Inc.
`41 University Drive, Suite 200
`Newtown, PA 18940
`
`Re: Disbarment certification
`
`Dear Philip:
`
`does not employ any individual
`_
`To the best of our knowledge,
`who is debarred, pursuant to sections 306(a) and (b) of the Federal Food, Drug, and Cosmetic Act
`(21 U.S.C. 3335(a) and (b). Every employee must confirm during New Hire Orientation that they
`have not been debarred from the FDA.
`
`If you have further questions, please contact us at one of the telephone numbers listed below.
`
`Regards,
`
`/
`
`/ /
`
`Copy:
`
`-
`T/ W
`
`

`

`.COLLAGENEX
`
`pharmaceuticals
`
`May 25, 2006
`
`Stanka Kukich, M.D., Director
`
`Division of Dermatology & Dental
`
`Drug Products
`
`Food and Drug Administration
`5901-8 Ammendale Road
`
`Beitsviile, MD 20705-1266
`
`RE:
`
`NDA 50-905
`General Correspondence: Phase 4 Commitment
`
`Dear Dr. Kukich:
`
`in reference to our teleconference on this date, the Sponsor is providing a
`
`response to the Division's request for a Phase 4 commitment. The Division's
`
`request is reiterated and is followed by the Sponsor’s response.
`
`FDA Reguest:
`
`A post-approval Medication Error Monitoring Program for the proprietary
`name, Oraceam' This program should consist of:
`
`9(961‘
`
`15-Day Reporting of all Medication Errors;
`Root Cause Analysis; and
`Trigger requiring a proprietary name change.
`
`Sponsor’s Response:
`
`ColiaGenex Pharmaceuticals agrees to a Medication Error Monitoring Program
`for the proprietary name, OraceaTM, consisting of the above three components.
`Specifically, the sponsor will report as if it were a "15 day report" any actual
`
`medication error, regardless of patient outcome. The sponsor will conduct a root
`
`cause analysis of any actual medication error and submit the analysis as a
`
`“idiots—Lip“ to the 15 day report.
`
`ColloGenex Pimrrnucel,:icois, Inc, 4] Universily Drive. Suite 200, Newlown, PA iBQZIO USA
`2|.5-57Q—7388 voice 215-579-8577 fax
`
`

`

`Stanka Kukich, MD, Director
`
`NBA 50-805
`
`May 25, 2006
`
`General Correspondence: Response to Request for Phase 4 Commitment
`
`CollaGenex will promptly meet with the Division (a meeting request will be
`
`submitted asking for a Type A or earlier meeting within two business days of
`
`receipt of the approval letter) to discuss the circumstances that would trigger a
`name change. CollaGenex will propose its Phase IV commitment for the
`circumstances in whiCh a name change will be triggered within two weeks of the
`
`meeting.
`
`if there are any questions regarding this document, please contact the
`
`undersigned at 215-579-7388 (telephone) or 215-402-8577 (fax).
`
`Sincerely,
`
`
`Christopher Powala
`
`Vice President, Drug Development
`
`& Regulatory Affairs,
`
`

`

`.CODlsLIiBALLCEE X
`
`
`
`MAY 2, 5 2005
`
`BKDR ‘l
`
`-
`CDER White 0
`NEWFJGRRL'PON
`NW£
`
`ill
`
`Stanka Kukich, M.D., Director
`Division of Dermatology and Dental
`Drug Products
`Food and Drug Administration
`5901-B Ammendale Road
`'
`-1266
`Beltsv1lle, MD 20705
`RE:
`NDA 50-805
`
`General Correspondence: Product and Dosage Form Name
`
`Dear Dr. Kukich:
`
`In preparation for our call on May 24, I thought it would be useful to explain our thinking about
`how the Oracea dosage form might be described in the label.
`'
`
`As we have discussed, our doxycycline product tentatively named Oracea, is composed of 75%
`
`immediate release doxycycline beads and 25% ——-—-- r:MM‘Vflmwwnw7‘2.mw“mm.“9...”...— A nan
`Wm...»— WM».U.V.~..”.4...va c
`mum-1”.“ .-
`_M.___.
`“N
`
`,Oracea does
`W” Because a portion of the product15 9,...“
`not fit FDA’S definitions of an immediate release product. The SUPACMR: Modified Release
`Solid Oral Dosage Forms guidance, for example defines an immediate release product as one
`that “allows the drug to dissolve in the gastrointestinal contents, with no intention of delaying or
`prolonging the dissolution or absorption of the drug.” ORA’s Laboratory Manual provides that
`immediate release capsules release the active ingredient “within a; small period of time, typically
`less than 30—minutes.” Oracea fits neither definition. In these circumstances, we believe that it
`
`would be misleading to state that Oracea is an immediate release product. If the drug description
`is silent as to the release characteristics, users will assume incorrectly that it is an immediate
`release product, inasmuch as it is FDA’s usual practice to say nothing in the drug description
`when a productis immediate release For this reason, silence also seems an inappropriate
`solution.
`
`The best existing category tor Oracea appears to be the “delayed release” category into which
`
`products are generally placed. The term “Capsule.
`.2 w——-—'————-——’
`" is
`I generally described asW lave been
`applied enclosed within a soluble container. (CDER Data Standards Manual attached). ThisIS
`technically a correct description of Oracea
`
`ColfaGew.
`
`?
`
`i
`
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`
`.
`
`1
`
`-
`
`.
`
`,4”)? ii
`
`

`

`Stanka Kukich, M.D., Director
`NDA 50-805
`
`May 23, 2006
`
`General Correspondence: Product and Dosage Form Name
`
`Ifthe delayed release terminology is not acceptable, we propose that a new term be identified to
`cover products that are partially immediate release and partially delayed release. In thinking
`about possibilities, we believe that ‘i _ (We would be the most descriptive, but have also
`
`considered “ x or “
`
`As we have discussed, this question is not just a technical labeling issue, but also a safety issue.
`Oracea was formulated to include aidelayed release feature solely to ensure that it would not
`reach levels in the bloodstreamthat produces an antibiotic effect. At higher dosages,
`doxycycline is an antibiotic used to- fight a variety of infections, including anthrax. Chronic use
`of doxycycline at antibiotic levels could contribute to antibiotic resistance. Physicians and
`pharmacists need to be informed of the delayed release feature and itspurpose so that they do not
`assume that any non—bioequivalent immediate release dosage form can be used to treat rosacea.
`
`For this reason, we believe'it important that the ‘
`‘
`'
`feature be included in the name
`of the product and dosage form so it will be readily available to and seen by prescribers,
`dispensers, and patients alike.
`
`We appreciate your consideration of this issue and look forward to discussing this further
`tomorrow.
`
`Sincerely,
`2 ,
`
`t
`
`>
`
`.3
`
`Christopher Powala
`Vice President, Drug Development
`& Regulatory Affairs
`
`

`

`COLLAGENEX
`.pharmaceuticals
`
`May22,2006
`
`Stanka Kukich, M.D., Director
`Division of Dermatology & Dental
`Drug Products
`Food and drug Administration
`5901—B Ammendale Road
`
`Beltsville, MD 20705—1266
`
`RE: NDA 50-805
`
`Response to Request for Phase 4 Commitments
`
`Dear Dr. Kukich:
`
`Submitted herewith is the Sponsor’sresponse to the Division’s request for Phase 4
`commitments. Each of the Division’s requests is reiterated and is followed by the
`Sponsor’s response.
`
`FDA Reguest #1:
`
`Submission of carcinogenicity study protocol and dose finding data: June 2007
`Carcinogenicity study start date: August 2007 SubmissiOn of final carcinogenicity
`study report: February 2010.
`
`Sponsor’s Response:
`
`The Sponsor agrees to this Phase 4 commitment.
`
`FDA Request #2:
`
`Conduct a properly designed human sperm motility and morphology study to
`evaluate the effects of long-term use of TRADENAME (doxycycline) 40mg on
`human sperm in male patients with rosacea. Study report submission within 2
`years from date of approval.
`
`Sponsor’s Response:
`
`The Sponsor agrees to this Phase 4 commitment.
`
`FDA Reg. uest #3:
`
`A study to examine longer term safety in at least 300 rosacea patients treated with
`TRADENAME (doxycycline) 40mg for at least 1 year. Study report submission
`within 2 years from date of approval.
`
`ColluGenex Phormrmeulicols, Inc... M University Drive, Surle 200, Newrown, PA 18940 USA
`215-579-7388 voice 215-570-8577 lox
`
`

`

`Stanka Kukich, MD.
`NBA 50-805
`
`Response to FDA Requested Phase 4 Commitments
`
`May 22, 2006
`
`Sponsor’s Response:
`
`Long-term exposure data has been collected in double—blinded, placebo-controlled studies
`on the 40mg doxycycline controlled release product as well as with a similar drug
`product with slightly higher plasma concentrations based on AUC' 0-24,
`This long-term safety data was provided to FDA in NDA 50-805. Though these data
`were collected in patients with adult periodontitis, this population, like those with
`rosacea, is relatively healthy and is of the same age range (3 30 years of age). The list
`below identifies the long-term data that currently resides with the Division:
`
`
`
`
`—m-_—
`
`
`
`
`107
`9 months
`NDA 50-783
`
`
`
`
`DOXYMR—301
`‘1
`
`
`
`
`
`
`9-18 months
`Exosures
`
`
`Stud No.
`
`Total Patient
`
`
`
`to do.
`
`c cline onl
`
`
`
`Exosure
`
`
`
`Reference
`
`
`
`133
`
`9months
`
`NDA50—805
`
`Based on the 9-18 month exposure of 455 patients to doxycycline at the proposed dose,
`the Sponsor believes that it has satisfied the ICH recommendation for long-term safety. In
`addition, the outcome from these long—term, double-blinded, placebo-controlled trials
`demonstrated an adverse event profile similar to placebo and the current proposed
`product label more than represents the warnings, precautions and adverse event profile of
`the drug product.
`
`Lastly, the Sponsor provided in the NDA, all post-marketing surveillance data captured
`from its marketed product, Periostat, which has similar, albeit slightly higher, drug
`exposure based on AUC. These spontaneOUSly reported, data were captured from a
`population prescribed more than 4 million prescriptions for long-term use. These data,
`like the data from the long-term, double-blinded, placebo-controlled clinical trials show
`that the product is safe for long term use as indicated. The Sponsor feels that long—term
`safety has been adequately demonstrated and more than meets the ICH recommendations.
`Therefore the Sponsor can not agree to this Phase 4 commitment.
`
`If there are any questions regarding this document, please contact the undersigned at 215- .
`579-7388 (telephone) or 215—402-1044 (fax).
`
`Sincerely,
`
`dag/Mac
`
`Christopher Powala
`Vice President, Drug Development
`& Regulatory Affairs
`
`

`

`.COLLAGENEX
`pharmaceuticals,
`May 22, 2006 RECEHVED'
`3?»
`:
`.
`..
`Li D UPUCATE
`MAY 2 3 2006
`
`~
`
`:-;
`
`Stanka Kukich, M.D., Director
`Division of Dermatology & Dental
`Drug Products
`Food and drug Administration
`5901-B Ammendale Road
`
`CDER Cm
`
`
`3" =1_
`‘-
`
`.
`
`Beltsville, MD 20705-1266
`
`RE:
`
`NDA 50-805
`Response to Request for Phase 4 Commitments
`
`Dear Dr. Kukich:
`
`NEW CORRESPONDENCE '
`I“
`.1
`A
`fl/i r" /LV/
`
`'
`
`i
`
`'
`
`Submitted herewith is the Sponsor’s response to the Division’s request for Phase 4
`commitments. Each of the Division’s requests is reiterated and is followed by the
`Sponsor’s response.
`
`FDA Reguest #1:
`
`Submission of carcinogenicity study protocol and dose finding