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`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`Public Health Service
`Drug Administration
`Rockville, MD 20857
`
`Food and
`
`Our STN: BL 125104/15
`
`JUN
`
`5 2006
`
`Biogen Idee, Incorporated
`Attention: Nadine D. Cohen, Ph.D.
`Senior Vice President, Regulatory Affairs
`14 Cambridge Center
`Cambridge, MA 02142
`
`Dear Dr. Cohen:
`
`Please refer to your supplement to your biologics license application for TYSABRIi1
`(Natalizumab), to add a Boxed Warnig and update the Clincal Pharmacology, Clincal
`Adverse
`Reactions sections of the package insert with safety and efficacy data, submitted under section
`351 of the Public Health Service Act.
`
`Studies, Indication and Usage, Contraindications, Warnings, Precautions, and
`
`This supplement, considered for approval under 21 CFR 601.42 (Subpart E), at your request,
`provides for the use of TYSABRIi1 for the treatment of patients with relapsing forms of multiple
`sclerosis (MS) to delay the accumulation of physical disabilty and reduce the frequency of
`clincal exacerbations.
`
`We have completed our review of your supplement dated September 26, 2005, including all
`amendments received through June 2,2006. This supplement is approved under the provisions
`of 21 CFR 601.42 (Subpart E), effective on the date of this letter, for use as recommended in
`the components of the TOUCH™
`
`the agreed upon labeling text, required patient labeling, and
`Risk Minzation Action Plan (RiskMAP).
`
`The final printed labeling (FPL) must be identical to the enclosed labeling (text for the package
`insert submitted May 23, 2006, the Medication Guide submitted May 23, 2006, and carton and
`container labels submitted May 12, 2006). Marketing the product with FPL that is not
`identical to the approved labeling text may render the product misbranded and an unapproved
`new drug.
`
`Under 21 CFR 601.42 (Subpart E), distribution of Natalizumab (TYSABRIi1) is limted as
`described below and in the attached detailed TOUCHTM program. The primary goals of the
`TOUCHTM program are to assess the risk of progressive multifocal leukoencephalopathy (PML)
`associated with Natalizumab (TYSABRIi1), mize the risk of PML, minize death and
`disabilty due to PML, and promote informed risk-benefit decisions regarding TYSABRIi1 use.
`
`ARGENTUM EX1036
`
`Page 1
`
`

`

`Page 2 - BL 125104/15
`
`TYSABRIi1 RiskMAP:
`
`We remid you that your TYSABRIi1 RiskMAP (called TOUCHT~ is an important part of the
`include each of the following
`
`postmarketing risk management for TYSABRIi1, and must
`
`components:
`
`1. Registration in the TOUCHTM program of prescribers, infusion centers, and pharmacies
`associated with infsion centers who agree to specific responsibilties in order to
`distribute, prescribe, dispense, or inse TYSABRIi1.
`
`2. Implementation of a program and distribution of materials to educate prescribers,
`pharmacies, nurses, and patients about the risks and benefits of TYSABRIi1, including
`materials that describe the roles of the TOUCH program participants.
`
`3. Implementation of a reporting and data collection system for safety surveilance.
`
`4. Implementation of a plan to monitor, evaluate, and determe the incidence and risk
`factors for PML and other serious opportunistic inections and compliance with
`restrictions for safe use under the TOUCH™ program.
`
`The TYSABRIiI Risk Minization Action Plan, submitted on June 2, 2006 and as described in
`the attached document, adequately addresses each of these requirements. This plan includes
`ongoing assessment and periodic reporting to FDA of the operation of the program and needed
`revisions, if any. Any change to the program must be discussed with FDA prior to its
`the required components are stil present.
`We expect your continued cooperation to resolve any problems regarding the TOUCHTM
`program that may be identified following approval of this application.
`
`institution and is subject to FDA's determation that
`
`Our approval of this supplement also represents our conclusion that you have fulfiled your
`21 CFR 601.41 as stated in commtment number 1 of the
`November 23, 2004 approval letter as stated below:
`
`commtments made under
`
`1. To verify that the clinical benefit of reduction in exacerbations is sustained with
`continued Natalizumab admstration by completing the ongoing Protocols C-1801 and
`C-1802, "A Randomized, Double-blind, Placebo-Controlled, Parallel-Group,
`Multicenter Study to Determne the Safety and Effcacy of Natalizumab in Subjects with
`Relapsing-Remitting Multiple Sclerosis" and '~A Randomized, Double-Blind, Placebo-
`Controlled, Parallel-Group, Multicenter Study to Determe the Safety and Effcacy of
`Natalizumab, When Added to Avonexi1 (Interferon beta-la) in Subjects with Relapsing-
`Remitting Multiple Sclerosis" through the planed two years and to submit the results
`along with the appropriate label changes.
`
`Page 2
`
`

`

`Page 3 - BL 125104/15
`
`In addition, you have fulfiled your commtment number 2 of the November 23, 2004 approval
`below:
`
`letter as stated
`
`2. To further evaluate the safety of Natalizumab and the efficacy of Natalizumab on
`physical disabilty by completing the ongoing Protocols C-1801 and C-1802, "A
`Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study to
`Determnt the Safety and Efficacy of Natalizumab in Subjects with Relapsing-Remitting
`Multiple Sclerosis" and "A Randomized, Double-Blind, Placebo-Controlled, Parallel-
`,Determe the Safety and Effcacy of Natalizumab, When
`Added to Avonexi1 (Interferon beta-1a) in Subjects with Relapsing-Remitting Multple
`Sclerosis" through the planed two years and to submit the results along with the
`appropriate label changes.
`
`Group, Multicenter Study to
`
`All applications for new active ingredients, new dosage forms, new indications, new routes of
`admnistration, and new dosing regimens are required to contain an assessment of the safety
`and effectiveness of the product in pediatric patients unless ths requirement is waived or
`deferred. We reference the full waiver granted on August 2, 2002, for the pediatric study
`requirement for BL 125104/0 which is also applicable to this supplemental application, in
`accordance with 21 CFR 601.27(c)(2)(ii).
`
`We acknowledge your written commtment, as described in your letter of June 2, 2006, to
`conduct the postmarketing commtment outlned below:
`
`Postmarketing Study subject to reporting requirements of 21 CFR 601.70.
`
`1. To conduct a prospective, observational study in at least 5000 subjects with multiple
`sclerosis who are receiving Natalizumab, with each subject followed for at least 5
`years, by completing protocol 101-MS-402, "TYGRIS: TYSABRIi1 Global
`Observation Program in Safety." Biogen Idec wil ensure having at least 3000 patients
`increase the total subject number
`beyond 5000 if necessary to achieve this. The final protocol wil be submitted by
`June 30, 2006, the study wil be intiated by July 31, 2006, patient accrual wil be
`completed by January 31, 2009, the study wil be completed by January 31, 2014 and
`the final study report wil be submitted by September 30, 2014.
`
`with 4 years of Natalizumab treatment, and wil
`
`In addition, postmarketing commtments numbers 3 through 16 agreed to in the approval of
`STN BL 125104/0 and described in the November 23, 2004 approval letter that are not yet
`fulfiled are stil in effect.
`
`Page 3
`
`

`

`Page 4 - BL 125104/15
`
`We request that you submit clinical protocols to your IND, with a cross-reference letter to this
`biologics license application (BLA), STN BL 125104. Please use the following designators to
`label promiently all submissions, including supplements, relating to these postmarketing study
`commtments as appropriate:
`
`. Postmarketing Study Protocol
`
`. Postmarketing Study Final Report
`. Postmarketing Study Correspondence
`. Annual Report on Postmarketing Studies
`
`Fór each postmarketing study subject to the reporting requirements of 21 CFR 601.70, you
`must describe the status in an anual report on postmarketing studies for this product. The
`status report for each study should include:
`
`. inormation to identify and describe the postmarketing commtment,
`
`. the original schedule for the commtment,
`
`. the status of the commtment (i.e. pending, ongoing, delayed, termated, or
`submitted),
`. an explanation of the status including, for clinical studies, the patient accrual rate
`(i.e. number enrolled to date and the total planned enrollment), and
`. a revised schedule if the study schedule has changed and an explanation of the basis
`for the revision.
`
`As described in 21 CFR 601.70(e), we may
`
`publicly disclose information regarding these
`postmarketing studies on our Web site (http://www.fda.gov/cder/pmc/default.htm). Please
`refer to the April 2001 Draft Guidance for Industry: Reports on the Status of Postmarketing
`Modernization
`Act of 1997 (see http://www.fda.gov/cber/gdlns/post040401.htm) for further informtion.
`
`Studies - Implementation of Section 130 of the Food and Drug Admstration
`
`Under 21 CFR Part 208, we have determed that this product poses a serious and significant
`public health concern requiring the distributÍon of a Medication Guide. N atalizumab is a
`product for which patient labeling could help prevent serious adverse effects and inform the
`could affect their decisions to use, or continue to
`use, the product. Therefore, a Medication Guide is necessary for safe and effective use of this
`product and FDA hereby approves the draft Medication Guide you submitted May 23, 2006.
`Please note that:
`
`patient of serious risks relative to benefit that
`
`. this Medication Guide must be reprinted at the end of the package insert
`(21 CFR 201.57(f)(2));
`
`. you are responsible for ensuring that this Medication Guide is available for
`distribution to every patient who is dispensed a prescription for this product
`(21 CFR 208);
`
`Page 4
`
`

`

`Page 5 - BL 125104/15
`
`. the final printed Medication Guide distributed to patients must conform to all
`conditions described in 21 CFR 208.20, including a minium of 10 point text; and
`
`. you are responsible for ensuring that the label of each container or package includes
`a promient and conspicuous instruction to authorized dispensers to provide a
`Medication Guide to each patient to whom the drug is dispensed, and states how the
`Medication Guide is provided.
`
`As part of the approval under Subpart E, we acknowledge that you have submitted to the
`Agency your promotional materials (both promotional labeling and advertisements) that are to
`be used within the first 120 days after approval. In addition, as required by 21 CFR 601.45,
`you must submit all subsequent promotional materials at least 30 days before the intended time
`of intial distribution of labeling or initial publication of the advertisement with a cover letter
`requesting advisory comment. Send two copies of the promotional materials to the Food and
`Drug Admnistration, Center for Drug Evaluation and Research, Division of Drug Marketing,
`Advertising and Communication, 5901-B Amendale Road, Beltsvile, MD 20705-1266.
`Please submit final promotional materials with FDA Form 2253 to the above address at the
`time of intial dissemination of the labeling or at the time of intial publication of the
`advertisement.
`
`All promotional claims must be consistent with and not contrary to approved labeling. You
`should not make a comparative promotional claim or claim of superiority over other products
`unless you have substantial evidence to support that claim.
`
`Upon approval, you have informed us that you wil be issuing a letter communicating
`important inormation about this drug product (i.e., a "Dear Health Care Professional" letter).
`We request that you submit a copy of the letter to this BLA and a copy to the following
`address:
`
`MEDWATCH
`Food and Drug Admnistration
`WO 22, Room 4447
`10903 New Hampshire A venue
`Silver Spring, MD 20993-0002
`
`You must submit adverse experience reports under the adverse experience reporting
`requirements for licensed biological products (21 CFR 600.80). You should submit
`postmarketing adverse experience reports to the Central Document Room, Center for Drug
`Evaluation and Research, Food and Drug Admstration, 5901-B Amendale Road,
`Beltsvile, MD 20705-1266. Prominently identify all adverse experience reports as described
`in 21 CFR 600.80.
`
`Page 5
`
`

`

`Page 6 - BL 125104/15
`
`The MedWatch-to-Manufacturer Program provides manufacturers with copies of serious
`adverse event reports that are received directly by the FDA. New molecular entities and
`important new biologics qualify for inclusion for three years after approvaL. Your firm is
`eligible to receive copies of reports for this product. To participate in the program, please see
`the enrollment instructions and program description details at
`www.fda.gov/medwatch/report/mmp.htm.
`
`You must submit distribution reports under the distribution reporting requirements for licensed
`biological products (21 CFR 600.81).
`
`involves a distributed product, may affect the safety, purity, or potency of
`
`You must submit reports of biological product deviations under 21 CFR 600.14. You should
`promptly identify and investigate all manufacturing deviations, including those associated with
`processing, testing, packing, labeling, storage, holding and distribution. If the deviation
`the product, and
`meets the other criteria in the regulation, you must submit a report on Form FDA-3486 to the
`Division of Compliance Risk Management and Surveilance (HFD-330), Center for Drug
`Evaluation and Research, Food and Drug Admstration, 5600 Fishers Lane, Rockvile, MD
`deviations sent by courier or overnight mail should be addressed to
`Food and Drug Admnistration, CDER, Office of Compliance, Division of Compliance Risk
`Management and Surveilance, HFD-330, Montrose Metro 2, 11919 Rockvile Pike,
`Rockvile, MD 20852.
`
`20857. Biological product
`
`Please submit all final printed labeling at the time of use and include implementation
`information on FDA Form 356h. Please provide a PDF-format electronic copy as well as
`original paper copies (ten for circulars and five for other labels).
`
`Please refer to http://www.fda.gov/cder/biologics/default.htmfor important information
`regarding therapeutic biological products, including the addresses for submissions.
`
`Effective August 29, 2005, the new address for all submissions to this application is:
`
`Food and Drug Admstration
`Center for Drug Evaluation and Research
`Therapeutic Biological Products Document Room
`5901-B Amendale Road
`Beltsvile, MD 20705-1266
`
`Page 6
`
`

`

`Page 7 - BL 125104/15
`
`This information wil be included in your biologics license application fie.
`
`Sincerely,h ~\fl'ó(o
`
`Russell Katz, M.D.
`Director
`Division of Neurology Products
`Offce of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`Page 7
`
`