Unassociated Document


     

    
      

      

    

    
 

    SERVICES
      AGREEMENT

    


    


    


    


    


    


    BETWEEN

    


    


    


    


    


    


    


    

    


    


    


    


    AND

    


    


    


    


    


    Gentium

    


    


    


    


    
      

      

    

     

    
 

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    


    


    SERVICES
      AGREEMENT 

    BETWEEN
      MDS PHARMA SERVICES

    AND
      

    GENTIUM

     

    PREAMBLE

     

    This
      Services Agreement (“Agreement”) effective the 24th of October, 2005
      (hereinafter the “Effective Date”), between MDS Pharma Services s.r.l. (“MDSPS”)
      an Italian corporation, with an office at Assago
      (MI), Centro Direzionale Milanofiori, Strada 4, Palazzo A4,
      Italy
      along
      with its affiliates, and Gentium (“Sponsor”), an Italian corporation, with an
      office at Piazza
      XX Settembre, 2, 22079 Villa Guardia (CO)-Italy

     

    WITNESSETH:

     

    WHEREAS
      Sponsor is a company involved in the development and marketing of pharmaceutical
      products which require services in the area of drug development, including
      II-IV
      clinical trial services, statistics, data management, medical writing,
      regulatory, central laboratory, clinical trial supply services and any other
      agreed upon services associated with the drug development process
      and;

     

    WHEREAS
      MDSPS is a worldwide company that performs clinical research and drug
      development for companies such as Sponsor and;

     

    WHEREAS
      Sponsor and MDSPS wish to enter into this Agreement to present the terms and
      conditions under which Sponsor may hire MDSPS to provide clinical trial
      management and central laboratory services for Phase II-IV studies, hereafter
      the “Services.”

     

    NOW
      THEREFORE, the parties agree as follows: 

     

    
      	1	
              AFFILIATE:
                DEFINED

            


    

     

    For
      purposes of the Agreement, “Affiliate” shall mean any corporation, firm,
      partnership or other entity that directly or indirectly controls, is controlled
      by, or is under common control with either of the parties.

     

    
      	2	
              SCOPE
                OF AGREEMENT 

            


    

     

    
      	 	
              2.1

            	
              PURPOSE

            


    

     

    With
      the
      present Agreement and according to the terms and conditions of this Agreement
      which shall govern the Services to be provided by MDSPS to Sponsor, Sponsor
      entrusts MDSPS who accepts, with the provision of Services for the clinical
      trial Protocol VOD-DF, Eudract n° 2004-000592-33, whose title is “Prospective
      Study of the Incidence and Outcome of Veno-occlusive Disease (VOD) with the
      Prophylactic Use of Defibrotide (DF, Gentium, Italy) in Paediatric Stem Cell
      Transplantation,” hereafter “the Clinical Trial.”

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

    
      	 	
              2.2

            	
              MODIFICATION

            


    

     

    The
      parties may only modify the provisions hereof by an instrument in writing duly
      executed by the parties.

     

    If
      a
      party is requested to perform Services beyond those which are set forth in
      the
      present Agreement or if the assumptions underlying the pricing for such Services
      have changed, the party shall advise the other party of:

     

    
      	 	
              (i)

            	
              any
                adjustment in fees resulting from the
                change;

            


    

     

    
      	 	
              (ii)

            	
              any
                resulting planned changes in the
                Agreement.

            


    

     

    Any
      such
      additional Services and any adjustment in fees (hereafter, an “Amendment”) must
      be agreed upon by the parties in writing, prior to the provision of said
      Services and shall constitute an Amendment to the present
      Agreement.

     

    MDSPS
      shall have no obligation to perform any additional or modified Services unless
      and until such Amendment has been executed.

     

    Should
      Sponsor instruct MDSPS in writing to start work prior to the formal signing
      of
      such Amendment, Sponsor should (a) agree in writing on (hereafter, “the Written
      Instruction”) (i) the expected scope of activities requested by this Amendment
      and (ii) the corresponding fees and expenses and a monetary limit, and (b)
      reimburse MDSPS for all reasonable fees and expenses incurred and documented
      until the date of signature (including any non cancelable fees) based on a
      unit
      defined in the present Agreement or a monetary limit defined in the Written
      Instruction.

     

    Sponsor
      acknowledges that MDSPS will cease activities that exceed the written
      instruction in scope or monetary limit without a signed formal Amendment to
      this
      Agreement.

     

    Both
      parties agree to act in good faith and promptly when considering an Amendment
      requested by the other party.

     

    
      	 	
              2.3

            	
              PROTOCOL
                / STUDY PLAN

            


    

     

    
      	 	
              2.3.1

            	
              DEFINITION

            


    

     

    MDSPS
      will perform Services for Sponsor in accordance with the Protocol provided
      by
      Sponsor and attached to this Agreement as Appendix I. The Protocol specifies
      the
      Project design, purpose, desired information, experimental procedures, estimated
      duration of the Project, and any other relevant matters, and is made a part
      of
      this Agreement.

     

    Where
      there is no Protocol for the Services, a Study or Service Plan may be developed
      and included as an Attachment to this Agreement.

     

    
      
        
        

      

      
        3

        
          

        

      

      
        
        

      

    

     

    
      	 	
              2.3.2

            	
              PROTOCOL
                OR STUDY PLAN DEVELOPMENT BY
                MDSPS

            


    

     

    If
      requested by Sponsor, MDSPS will assist in developing the Protocol or Study
      Plan
      in a manner consistent with current applicable regulatory guidelines. MDSPS
      agrees to provide all reasonable efforts to advise Sponsor in a manner
      consistent with current regulatory guidelines. It is understood that the
      development design and adequacy of any Protocol or Study Plan or revisions
      to
      any Protocol or Study Plan shall be the sole responsibility of the Sponsor
      regardless of MDSPS’ involvement or lack thereof in suggestions or
      recommendations as a result of the Protocol writing or Study Plan development
      Services provided. Furthermore, MDSPS makes no warranty, express or implied,
      that the Protocol or Study Plan will satisfy the requirements of any Regulatory
      Authority at the time of submission.

     

    
      	3	
              DURATION

            


    

     

    This
      Agreement shall commence upon the effective date of provision of Services,
      hereafter “the Effective date,” and shall terminate without further notice upon
      total completion of the Services or after 48 months, whichever is
      sooner.

     

    MDSPS
      undertakes to comply with the time schedule of the Clinical Trial for Services
      within its entire control as determined by the Sponsor in Appendix II, on
      condition MDSPS has been provided with all necessary documents and information
      in due time.

     

    
      	4	
              RESOURCES
                AND RESPONSIBILITIES

            


    

     

    
      	 	
              4.1

            	
              RESOURCES
                AND RESPONSIBILITIES OF
                SPONSOR

            


    

     

    Sponsor
      provides or retains responsibility for all legal obligations not transferred
      to
      MDSPS. Sponsor agrees to retain any and all responsibilities that are in force
      for the applicable Clinical Research laws in the countries where the Clinical
      Trial is carried out. Sponsor agrees that MDSPS does not act as a sponsor or
      investigator in the Clinical Trial.

     

    Sponsor
      is required to inform and provide in a timely manner to MDSPS all necessary
      information relative to a change in the Protocol and will discuss such changes
      in accordance with article 2.2.

     

    In
      addition to the forgoing, Sponsor will provide MDSPS with the following:


     

    
      	 	
              (i)

            	
              sufficient
                amount of all required Study Materials;


            


    

     

    
      	 	
              (ii)

            	
              safety
                data sheets for the Study Materials, where
                available;

            


    

     

    
      	 	
              (iii)

            	
              sufficient
                and comprehensive data as may be required by MDSPS concerning the
                stability of the Study Materials, storage and safety
                requirements;

            


    

     

    
      	 	
              (iv)

            	
              final
                version of the Clinical Trial Protocol in force on the Effective
                date
                indicating the title and date of Clinical
                Trial;

            


    

     

    
      
        
        

      

      
        4

        
          

        

      

      
        
        

      

    

     

    
      	 	
              (v)

            	
              names
                and contact information of all key
                personnel;

            


    

     

    
      	 	
              (vi)

            	
              written
                communication of any eventual bans or suspensions of the Clinical
                Trial by
                any applicable government or
                organization.

            


    

     

    
      	 	
              4.2

            	
              RESOURCES
                AND RESPONSIBILITIES OF
                MDSPS

            


    

     

    MDSPS
      shall appoint for the Clinical Trial the responsible person in charge of the
      work to be performed.

     

    MDSPS
      will provide Sponsor with the following:

     

    
      	 	
              (i)

            	
              Materials
                (other than the Study Materials described in Section
                3.1);

            


    

     

    
      	 	
              (ii)

            	
              labor
                necessary to conduct the Service as requested by
                Sponsor;

            


    

     

    
      	 	
              (iii)

            	
              data
                generated from each Service, where
                appropriate;

            


    

     

    
      	 	
              (iv)

            	
              a
                final report setting forth a full summary of the results of each
                Service,
                as requested;

            


    

     

    
      	 	
              (v)

            	
              necessary
                professional and support personnel for each Study or service
                requested.

            


    

     

    
      	 	
              4.3

            	
              IDENTITY
                OF PROJECT MATERIALS

            


    

     

    Sponsor
      attests that all Study Materials provided to MDSPS are identical to the
      description provided in the Protocol or Service Plan. Sponsor will furnish,
      on
      request, the Study Materials identification and content tests on the clinical
      supplies used for the Clinical Trial where appropriate.

     

    
      	 	
              4.4

            	
              DELAYS

            


    

     

    If
      delays
      in performance of a particular Service are experienced because of regulatory
      approval delays, Sponsor’s request or inability to supply MDSPS with materials
      or information required to perform the Service, MDSPS will be entitled to
      reallocate resources otherwise reserved for the performance of such
      Service.

     

    
      	5	
              CONDUCT
                OF SERVICE

            


    

     

    
      	 	
              5.1

            	
              MDSPS
                COMPLIANCE

            


    

     

    MDSPS
      agrees to perform each Service in accordance with all regulations that are
      applicable to the Services conducted under this Agreement and any applicable
      regulations or laws in force in the countries where the Clinical Trial is
      carried out, including, but not limited to the federal regulations pertaining
      to
      investigational drugs, including but not limited to the regulations set forth
      in
      FDA Form FD 1572, 21 CFR, parts 50, 56 and 312, Good Clinical Practice
      requirements as may be published by the FDA from time to time, and ICH
      Guidelines. MDSPS will perform all laboratory analyses in accordance with
      applicable industry standards, Sponsor’s specifications and the Standard
      Operating Procedures as set forth in the documents attached. In the event of
      a
      change in regulatory requirements, MDSPS will make every reasonable effort
      to
      satisfy any new requirements.

     

    
      
        
        

      

      
        5

        
          

        

      

      
        
        

      

    

     

    
      	 	
              5.2

            	
              SPONSOR
                COMPLIANCE

            


    

     

    Protocol
      specifications shall not be changed without prior notice to MDSPS and any
      changes must be documented as numbered amendments, properly dated and signed.
      Unless designated as an MDSPS responsibility, an Investigational New Drug
      Application (IND), or equivalent approval to conduct clinical research, has
      been
      filed with the FDA or the appropriate country regulatory authorities with
      respect to the study drug and no applicable law, rule or regulation prohibits
      the conduct of the Project;

     

    All
      data,
      information, drug, facilities and equipment which are to be supplied by Sponsor
      under this Agreement and are necessary for MDSPS’ effective performance of the
      Services contracted, shall be made available to MDSPS and/or the Investigators
      in accordance with the Time Lines as defined in this Agreement and shall be
      in
      full compliance with all applicable regulations.

     

    
      	 	
              5.3

            	
              QUALITY
                CONTROLS

            


    

     

    MDSPS
      shall install appropriate quality controls in order to monitor Investigator
      compliance with the Protocol or Service Plan. MDSPS shall comply with the
      Standard Operating Procedures as set forth in the above-mentioned documents,
      as
      appropriate. MDSPS shall train those personnel associated with this Agreement
      to
      assure compliance with such Standard Operating Procedures.

     

    
      	 	
              5.4

            	
              AUDITS
                AND FACILITIES
                EXAMINATION

            


    

     

    Upon
      request by any properly authorized officer or employee of any Government or
      Regulatory Authority to have access to or verify any record, report,
      documentation or data in MDSPS’ possession, custody or control, MDSPS shall
      promptly inform the Sponsor and MDSPS shall arrange access by such officer
      or
      employee to MDSPS for the purpose of verifying and or copying any record,
      report, documentation or data pertaining to the Clinical Trial.

     

    Upon
      notification of impending inspection by any Regulatory Authority at MDSPS’
premises or at any Investigator Site related to the Clinical Trial, the Sponsor
      shall be notified by MDSPS within three (3) business days. The Sponsor shall
      notify MDSPS within three (3) business days upon receiving notice of an
      impending inspection of the Sponsor’s premises, MDSPS facility or Investigator
      site by any Government or Regulatory Authority, relating to the Clinical
      Trial.

     

    During
      the term of this Agreement, MDSPS will permit Sponsor’s representatives to
      examine or audit the work performed hereunder, and the MDSPS facilities at
      which
      the Service will be conducted. Sponsor shall provide reasonable notice, not
      less
      than ten (10) business days, of its intent to audit and shall conduct the audit
      during regular business hours. During such examination, Sponsor’s
      representatives may verify documents, facilities, records and results of all
      quality assurance inspections performed by MDSPS, methodology, procedures and
      any other relevant item relating to the Services performed. Sponsor’s
      representatives may also visit MDSPS’ premises upon reasonable notice, not less
      than ten (10) business days, at reasonable times and frequency, during normal
      business hours, to observe the progress of each Study. Should Sponsor wish
      to
      retain a third party to conduct the audit, it will not retain a CRO to conduct
      the audit without first obtaining the permission of MDSPS, which permission
      shall not be unreasonably withheld. Auditors, including third party auditors,
      shall be identified (including, any affiliations) to MDSPS Quality Assurance
      Director prior to scheduling and conducting the audit.

     

    
      
        
        

      

      
        6

        
          

        

      

      
        
        

      

    

     

    
      	 	
              5.5

            	
              DEBARMENT
                CERTIFICATION

            


    

     

    MDSPS
      certifies that it has not been debarred, and has not been convicted of a crime
      that could lead to debarment, under the Generic Drug Enforcement Act and that
      it
      will use its best efforts not to employ any person or entity that has been
      so
      debarred or convicted to perform any Services under this Agreement. Sponsor
      represents that it shall not request MDSPS to perform assignments or tasks
      that
      violate any applicable law or regulation.

     

    
      	6	
              OWNERSHIP

            


    

     

    
      	 	
              6.1

            	
              WORK
                PRODUCT AND INVENTIONS

            


    

     

    MDSPS
      shall assign, at Sponsor’s request, all rights, title and interest in all data,
      discoveries, inventions, improvements, new uses, processes, copyrights, trade
      secrets, techniques and compounds (“Inventions”), whether patentable or not,
      arising from work performed under this Agreement (excluding all know how,
      confidential and/or proprietary information, systems, programs and processes
      owned or developed by MDSPS prior to, or independent of this Agreement, and
      any
      software, written material, design, documentation or improvement licensed by
      MDSPS from any third party) and directly linked to Sponsor’s Study Materials.
      Sponsor shall request such assignment within one (1) year of notification by
      MDSPS of such Inventions.

     

    MDSPS
      shall timely communicate in full detail and disclose to Sponsor all data,
      information, reports, results and other work product collected, generated,
      prepared or derived by MDSPS during the course of Services performed under
      this
      Agreement.

     

    
      	 	
              6.2

            	
              PATENTS

            


    

     

    If
      Sponsor requests and at Sponsor’s expenses, MDSPS will provide Sponsor with
      reasonable assistance to obtain patents. MDSPS, its employees, agents, and
      consultants shall fully cooperate with Sponsor in obtaining and maintaining,
      at
      Sponsor’s sole cost and expense, any patent protection as may be available with
      respect to such Inventions, and shall execute all documents reasonably deemed
      necessary by Sponsor for purposes of procuring and maintaining such patent
      protection, and all documents necessary for assigning Inventions to Sponsor.
      Sponsor shall be free to exploit both the patents it holds as a result of the
      Services as well as any unpatented results of the Services without any
      additional compensation to MDSPS. All works authored by MDSPS under this
      Agreement shall be deemed or treated as “works for hire” to the extent permitted
      under the applicable Copyright Law.

     

    
      
        
        

      

      
        7

        
          

        

      

      
        
        

      

    

     

    
      	 	
              6.3

            	
              PUBLICATIONS

            


    

     

    Sponsor
      shall retain title to and the right to publish all documentation, records,
      raw
      data, specimens or other work product generated in connection with the
      performance of the Services provided by MDSPS as defined in the applicable
      Protocol or Study Plan. Such publications shall not be made by MDSPS without
      the
      prior written consent of Sponsor.

     

    
      	 	
              6.4

            	
              USE
                OF NAMES

            


    

     

    Neither
      party will use the other party’s name in connection with any publication or
      promotion, without the other party’s prior written consent.

     

    
      	7	
              CONFIDENTIAL
                INFORMATION

            


    

     

    
      	 	
              7.1

            	
              DEFINITION

            


    

     

    “Confidential
      Information” shall mean any scientific, technical, trade or business information
      possessed, obtained by, developed for or given to any of the parties and which
      is treated by the Party as confidential or proprietary.

     

    
      	 	
              7.2

            	
              DISCLOSURE

            


    

     

    The
      Parties acknowledge that an exchange of Confidential Information is necessary
      in
      order to enable them to engage in meaningful business discussions and/or
      collaboration. With respect to such Confidential Information, the Parties agree
      to cause their officers, employees and other representatives to hold in strict
      confidence all Confidential Information obtained from each other and/or their
      officers, employees, and representatives, and not to use, disclose, or permit
      any third party access to such Confidential Information for any purpose, other
      than as may be required or permitted to perform any obligation under this
      Agreement or as directed in writing by authority of Sponsor.

     

    
      	 	
              7.3

            	
              EXCEPTIONS

            


    

     

    The
      obligation of confidentiality will not apply to Confidential Information which
      either Party can clearly demonstrate falls within any of the following
      categories:

     

    
      	 	
              (i)

            	
              Information
                that is or becomes available to the public at the effective date
                of the
                present Agreement through no fault of the other
                Party;

            


    

     

    
      	 	
              (ii)

            	
              Information
                that, as of the time of disclosure to one Party, was already known
                to and
                in the lawful possession of the other, as evidenced by written
                records;

            


    

     

    
      	 	
              (iii)

            	
              Information
                obtained after the Effective Date of this Agreement hereof from a
                third
                party lawfully in possession of and with no limitation upon disclosure,
                and having the right to disclose the
                same;

            


    

     

    
      	 	
              (iv)

            	
              Information
                that is required to be disclosed pursuant to operation of
                law.

            


    

     

    
      
        
        

      

      
        8

        
          

        

      

      
        
        

      

    

     

    
      	 	
              7.4

            	
              DURATION
                OF OBLIGATION

            


    

     

    The
      obligation of confidentiality under this Agreement shall survive the completion
      of the Services for 10 years.

     

    
      	8	
              PAYMENT

            


    

     

    
      	 	
              8.1

            	
              METHOD

            


    

     

    For
      performing the Services agreed upon pursuant to this Agreement, MDSPS shall
      be
      compensated in accordance with the Budget and the payment schedule annexed
      to or
      included as part of this Agreement. The payment schedule shall cover any and
      all
      of MDSPS costs and expenses for each Service.

     

    Final
      payment shall be upon completion of service, final deliverable or receipt of
      a
      final report issued pursuant to and in a format set forth within this Agreement.
      Terms of payment shall be net forty five (45) days after the receipt of the
      invoice. All wire transfers shall be made payable to the following bank
      details:

     

    Banca
      Intesa S.p.A.,

    Dip.
      Assago-Milanofiori,

    Centro
      Direzionale Milanofiori,

    Strada
      3,
      Palazzo B3,

    20090
      Assago (MI) (Assago),

    c/c218803235104,
      ABI 03069,

    CAB
      32465,

    Cod.
      SWIFT BCITIT22459,

    IBAN
      CODE
      IT 20 Y030 6932 4652 1880 3235 104.

     

    
      	 	
              8.2

            	
              LONG
                TERM STUDIES

            


    

     

    This
      agreement shall be subject to an inflationary adjustment review every 12 months.
      Any inflationary adjustment will be negotiated in good faith between the
      parties. The parties agree to use the Consumer Price Index (CPI) or the EU
      equivalent thereof as the marker of any inflationary adjustment.

     

    
      	 	
              8.3

            	
              CURRENCY
                - EXCHANGE RATE

            


    

     

    The
      currency to be used to invoice and for payment shall be set forth in the Budget
      attached. If MDSPS is to perform Services whereby it earns fees or incurs
      expenses in a currency differing from the invoice and payment currency
      (hereafter, “Foreign Currency(ies)”), the initial foreign currency exchange
      rates used as a basis for calculating the Budget (the “Budgeted Rates”) shall be
      stated in the Budget.

     

    Each
      calendar quarter, an average actual foreign exchange rate will be computed
      for
      each foreign currency exchange rate indicated in the Budget. The average actual
      foreign currency exchange rate will be calculated based upon the foreign
      currency exchange spot rates published in the Financial Times on the last
      business Friday of each month during the quarter under review (the “Current
      Rate”). At the end of each calendar quarter, MDSPS shall calculate a currency
      adjustment. If the amount invoiced during the calendar quarter calculated at
      the
      Current Rates is greater than the amount invoiced calculated at the Budgeted
      Rates by more than two percent (2%), MDSPS shall issue a separate invoice for
      the difference. If the amount invoiced during the calendar quarter calculated
      at
      the Current Rates is less than the amount invoiced calculated at the Budgeted
      Rates by more than two percent (2%), MDSPS shall issue a separate credit note
      for the difference.

     

    
      
        
        

      

      
        9

        
          

        

      

      
        
        

      

    

     

    
      	 	
              8.4

            	
              DUE
                DATE AND LATE FEES

            


    

     

    Payment
      is due within forty five (45) days of the date of each invoice provided by
      MDSPS. In the event of a late payment and unless MDSPS has been informed in
      writing of any dispute, MDSPS reserves the right to impose an interest charge
      upon the outstanding invoice(s) of 0.75% per calendar month on a compounded
      basis or as otherwise specifically provided in the Statement of
      Work,

     

    
      	9	
              INDEMNIFICATION

            


    

     

    
      	 	
              9.1

            	
              BY
                SPONSOR

            


    

     

    Sponsor
      shall indemnify, defend and hold harmless MDSPS its agents, employees, or
      subcontractors approved by Sponsor and designated in this Agreement hereunder,
      from and against any and all losses, damages, liabilities, reasonable attorney
      fees, court costs, and expenses resulting or arising from any claims, actions,
      proceedings, investigations or litigation (including personal injury or wrongful
      death) relating to or arising from or in connection with this Agreement, except
      for claims as set forth in section 9.2 hereunder.

     

    
      	 	
              9.2

            	
              BY
                MDSPS

            


    

     

    MDSPS
      shall indemnify, defend and hold harmless Sponsor and its agents and employees
      hereunder, from and against any and all losses, damages, liabilities, reasonable
      attorney fees, court costs, and expenses resulting or arising from any claims,
      actions, proceedings, investigations or litigation (including personal injury
      or
      wrongful death) relating to or arising from or in connection with this
      Agreement, and resulting from:

     

    
      	 	
              1.

            	
              Negligent
                or intentionally wrongful acts of MDSPS during the conduct of a service;
                or

            


    

     

    
      	 	
              2.

            	
              Any
                activity by MDSPS which is contrary to either this Agreement, written
                relevant and material recommendations, information, instructions,
                rules
                and guidelines furnished by Sponsor for use in administration of
                any
                procedure described in this Agreement, federal laws and
                regulations.

            


    

     

    
      	 	
              9.3

            	
              CONDITIONS
                FOR INDEMNIFICATION

            


    

     

    The
      indemnitee shall provide the indemnitor with prompt notice (including a copy
      thereof), of any claim or lawsuit served upon it that is related to this
      Agreement. The indemnitee shall fully cooperate with the indemnitor and its
      representatives in the investigation of any claim or lawsuit related to the
      Services provided in this Agreement. The indemnitee shall not unreasonably
      withhold its approval of the settlement of any claim, liability, or action
      covered by this indemnification provision.

     

    
      
        
        

      

      
        10

        
          

        

      

      
        
        

      

    

     

    
      	10	
              LIMITATION
                OF LIABILITY / DAMAGES

            


    

     

    Neither
      party, nor its Affiliates, nor any of its agents and employees, shall have
      any
      liability of any type, for any special, incidental, indirect or consequential
      damages, including, but not limited to the loss of opportunity, loss of use,
      or
      loss of revenue or profit, in connection with or arising out of this Agreement,
      except if resulting from the gross negligence or intentional or willful
      misconduct of the party against which relief is sought.

     

    
      	11	
              TERMINATION

            


    

     

    
      	 	
              11.1

            	
              BY
                EITHER PARTY

            


    

     

    
      	 	
              11.1.1

            	
              MATERIAL
                BREACH

            


    

     

    Either
      party may terminate this Agreement for material breach by giving written notice
      and specifying the nature of the breach. If the other party has not commenced
      to
      formulate and provide a plan to substantially cure the breach within thirty
      (30)
      business days of receipt of the notice of breach, then the Agreement shall
      be
      deemed terminated.

     

    
      	 	
              11.1.2

            	
              SAFETY
                OR EFFICACY HAZARD

            


    

     

    If
      accumulating evidence from a study causes any concern about the safety or
      efficacy as it relates to the safety of the compound, comparator or study design
      either Party may terminate this Agreement under this Section. Such termination
      shall be effective immediately upon notification by telephone, which shall
      then
      be followed by written confirmation.

     

    
      	 	
              11.1.3

            	
              INSOLVENCY
                AND/OR DISSOLUTION

            


    

     

    In
      the
      event that the other Party becomes insolvent or makes an assignment for the
      benefit of the creditors or bankruptcy proceedings are instituted against the
      other Party, any of which event shall be treated as default by the Party given
      the notice.

     

    If
      the
      other Party ceases or threatens to cease to carry on the whole or any relevant
      part of its business or trade.

     

    
      	 	
              11.2

            	
              BY
                SPONSOR

            


    

     

    Sponsor
      shall have the right at any time to terminate this Agreement prior to completion
      by giving thirty (30) days advance written notice to MDSPS. In the event of
      such
      written notice of termination, MDSPS shall immediately use its best efforts
      to
      reduce cost to Sponsor. In case of such termination, Sponsor shall pay MDSPS
      for
      work completed to the date of termination of service including any close down,
      uncancelable, or hand-over fees, or for work MDSPS is irrevocably obligated
      to
      complete.

     

    
      
        
        

      

      
        11

        
          

        

      

      
        
        

      

    

     

    
      	 	
              11.3

            	
              FORCE
                MAJEURE

            


    

     

    A
      Party
      shall be excused from performing its obligations under this Agreement if its
      performance is delayed or prevented by any cause beyond such Party’s control,
      including but not limited to, acts of God, fire, explosion, disease, weather,
      war, insurrection, riots, or power failure, strikes, lockouts, or other
      industrial action taken by the employees of any Party or of any third party
      (whether or not the Party against whom such action is taken could have avoided
      the same by acceding to the demands of the employees responsible for such
      action), civil commotion, embargo, governmental action, legislation or
      regulation, invasion, threat of or preparation of war.

     

    Performance
      shall be excused only to the extent of and during the reasonable continuance
      of
      such disability. Any deadline or time for performance specified in this
      Agreement or the Protocol which falls due during or subsequent to the occurrence
      of any of the disabilities referred to herein shall be automatically extended
      for a period of time equal to the period of such disability. In addition, the
      provision of this paragraph shall apply where the failure to perform is caused
      by the withdrawal of approval of the project by the relevant governing
      regulatory body including, but not limited to, the FDA, Therapeutic Products
      Directorate (TPD), and Medicines Control Agency (MCA), representing the
      respective regulatory agencies in the US, Canada and UK.

     

    
      	 	
              11.4

            	
              SURVIVAL
                OF OBLIGATIONS

            


    

     

    Termination
      of this Agreement shall not relieve either Party of its obligation to the other
      in respect of maintaining the confidentiality of information, (b) obtaining
      consents for advertising and publications purposes, (c) indemnification, (d)
      compensation for Services performed through the date of termination, (e) the
      obligation to maintain insurance, (f) work product and inventions and (g)
      dispute and arbitration.

     

    
      	 	
              11.5

            	
              RETURN
                OF ALL MATERIALS

            


    

     

    
      	 	
              11.5.1

            	
              RETURN
                OF SPONSOR’S MATERIALS

            


    

     

    Upon
      termination of this Agreement, MDSPS shall return to Sponsor upon request all
      documentation, data, reports and any other item related to the Services
      rendered, except for those materials or copies thereof, that are deemed
      reasonably necessary for regulatory or business purposes by MDSPS.

     

    
      	 	
              11.5.2

            	
              RETURN
                OF MDSPS’ MATERIALS

            


    

     

    The
      Sponsor agrees to return all the equipment provided by MDSPS at the conclusion
      of the Clinical Trial. Such equipment shall be returned in working order wear
      and tear excepted. If any equipment is not returned in working order, MDSPS
      will
      invoice the Sponsor an indemnity corresponding to repair fees of the material
      supplied. If any equipment is not returned, MDSPS will invoice the Sponsor
      an
      indemnity equivalent to the unit replacement value (catalogue value) of the
      equipment supplied.

     

    
      
        
        

      

      
        12

        
          

        

      

      
        
        

      

    

     

    
      	12	
              TRANSFER
                OF OBLIGATIONS

            


    

     

    
      	 	
              12.1

            	
              BETWEEN
                THE PARTIES

            


    

     

    MDSPS
      shall perform its Services as an independent contractor and shall have complete
      and exclusive control over its employees and agents. The Services rendered
      by
      MDSPS are those of an independent contractor and not those of Sponsor. No
      Services rendered pursuant to this Agreement shall be construed to deem MDSPS
      an
      employee, agent or joint-venturer with Sponsor.

     

    
      	 	
              12.2

            	
              ASSIGNMENT
                TO SUB-CONTRACTORS

            


    

     

    If
      MDSPS
      is obligated under this Agreement to contract with subcontractors, then any
      such
      contract shall bind the subcontractors to the terms and conditions of this
      Agreement. MDSPS shall not assign any obligations to subcontractors without
      Sponsor’s prior written authorization.

     

    As
      MDSPS
      is not a transport company, the transport will be entrusted to a professional,
      such as UPS, Go! or DHL, selected according to the normal business practices
      and
      in respect of the standard usually used in the industry. MDSPS reserves the
      right to change of transport company in order to execute in a satisfactory
      manner the transportation of the samples.

     

    Should
      MDSPS be required under this Agreement to contract with subcontractors other
      than courier companies, MDSPS will provide a list of the subcontractors which
      will be approved by Sponsor.

     

    The
      following Services are subcontracted and the subcontractor is
      selected:

     

    
      	 	
              -

            	
              Regulatory,
                administrative and monitoring activities in Sweden to CRO
                Norma.

            


    

     

    
      	 	
              -

            	
              Regulatory,
                administrative and monitoring activities in Israel to Yael Marmor
                (freelance CRA)

            


    

     

    The
      following Services are subcontracted and the subcontractor is almost
      selected:

     

    
      	 	
              -

            	
              Import
                license and drug supply in France to
                LC2

            


    

     

    
      	 	
              -

            	
              Import
                license and drug supply to Utrecht Hospital in the Netherlands France
                to a
                Pharmacist in the Utrecht Hospital Import License and drug supply
                to four
                sites in Sweden to a Pharmacist in
                Sweden

            


    

     

    
      	13	
              INSURANCE

            


    

     

    Each
      Party will maintain, for the duration of this Agreement, insurance in an amount
      reasonably adequate to cover its obligations hereunder, and, upon request,
      each
      Party will provide to the other party a certificate of insurance showing that
      such insurance is in place.

     

    
      
        
        

      

      
        13

        
          

        

      

      
        
        

      

    

     

    
      	14	
              LANGUAGE

            


    

     

    The
      Parties hereto have requested that this Agreement and all notices given pursuant
      hereto be drafted in the English language.

     

    
      	15	
              NOTICES

            


    

     

    Any
      notice required or permitted to be given hereunder by either party shall be
      in
      writing and shall be deemed given on the date received if delivered personally
      or by reputable overnight delivery service, or three days after the date
      postmarked if sent by registered or certified mail, return receipt requested,
      postage prepaid to the following addresses:

     

    
      	 	
              To
                MDSPS:

            	
              Manuela
                Leone

              General
                Manager, Europe

              MDS
                Pharma Services s.r.l.

              Assago
                (MI),

              Centro
                Direzionale Milanofiori,

              Strada
                4,

              Palazzo
                A4

              Italy

            
	 	 	 
	 	
              Copy
                to:

            	
              Vice
                President, Legal Services

              MDS
                Pharma Services 

              621
                Rose Street 

              Lincoln,
                NE 68502

            
	 	 	 
	 	
              To
                Gentium:

            	
              Massimo
                Iacobelli

              Piazza
                XX Settembre, 2,

              22079
                Villa Guardia (CO) - Italy

            
	 	 	 


    

     

    
      	16	
              SEVERABILITY

            


    

     

    In
      the
      event that any provision contained herein is held to be invalid or unenforceable
      whether by reason of legislation or by reason of any decision of a regulatory
      body of judicial authority having jurisdiction over the subject matter of this
      Agreement and the Parties, such affected provision shall be deemed severable
      and
      deleted from all other provisions contained in this Agreement and the latter
      shall remain enforceable to the fullest extent permitted by law.

     

    
      	17	
              DISPUTE
                AND ARBITRATION - APPLICABLE
                LAW

            


    

     

    This
      Agreement shall be construed, governed, interpreted, and applied in accordance
      with the laws of Italy.

     

    Any
      disputes arising in connection with, or arising out of the existence, validity,
      interpretation, performance and/or termination of this Agreement shall be
      settled amicably. In case of disputes for which no amicable solution is
      possible, the parties shall submit to the exclusive jurisdiction of the
      competent courts of Milan, including in case of co-defendants.

     

    
      
        
        

      

      
        14

        
          

        

      

      
        
        

      

    

     

    IN
      WITNESS WHEREOF, the parties have caused this Agreement to be executed in
      duplicate original copies, by their duly authorized representatives, as of
      the
      last date written below.

    


    
      	
              MDS
                PHARMA SERVICES

            	 	 	
              GENTIUM

            
	 	 	 	 	 
	
              By:

            	
              /s/
                Manuela Leone

            	 	
              By:

            	
              /s/
                Laura Iris Ferro    

            
	 	Signature	 	 	Signature
	 	 	 	 	 
	 	
              April
                12, 2006

            	 	 	
              March
                17, 2006

            
	 	Date	 	 	Date
	 	 	 	 	 
	 	
              Manuela
                Leone

            	 	 	
              Laura
                Iris Ferro

            
	 	Name	 	 	Name
	 	 	 	 	 
	 	
              European
                General Manager

            	 	 	
              Chief
                Executive Officer 

            
	 	Title	 	 	Title


    

    


    


    
      	
              GENTIUM

            	 	 	
              GENTIUM

            
	 	 	 	 	 
	
              By:

            	/s/
              Cary Grossman 	 	
              By:

            	/s/
              Massimo Iacobelli
	 	Signature	 	 	Signature
	 	 	 	 	 
	 	April
              6, 2006	 	 	
              March
                15, 2006

            
	 	Date	 	 	Date
	 	 	 	 	 
	 	
              Cary
                Grossman

            	 	 	
              Massimo
                Iacobelli

            
	 	Name	 	 	Name
	 	 	 	 	 
	 	
              Chief
                Financial Officer

            	 	 	
              Scientific
                Director

            
	 	Title	 	 	Title


    

     

    
 

    
      
        
        

      

      
        15

        
          

        

      

      
        
        

      

    

    


    APPENDIX
      1 

    


     

    PROTOCOL
      OF THE CLINICAL TRIAL

     

    


    


    


    
      
        
        

      

      
        16

        
          

        

      

      
        
        

      

    


    APPENDIX
      II 

    


     

    BUDGET

    


    


    


    


    
      
        
        

      

      
        17

        
          

        

      

      
        
        

      

    



    

     

    


     

    GENTIUM

    


    Massimo
      Iacobelli

    Piazza
      XX
      Settembre, 2

    22079
      Villa Guardia (CO) - Italy

    Email:
      miacobelli@gentium.it

    


     

    VOD
      - Defibrotide Study

     

    


     

    Proposal
      n° AA2618420 - Version 8 - 21st February 2006

     

    prepared
      by

    Jérôme
      Zakka-Bajjani

    Proposals
      & Contracts Manager

    Tel:
      +33.1.46.90.24.21 

    e-mail:
      jerome.zakka-bajjani@mdsinc.com

    


    Alessandra
      Consonni 

    Business
      Development Manager

    Tel:
      +39.2.57.51.47.68 

    e-mail:
      aconsonn@mdsinc.com

     

    MDS
      Pharma Services Italy 

    Strada
      4
      - Palazzo A/4

    20090
      Assago (Ml) 

    Fax:
      +39.2.57.79.06.71

    


    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

    


    
      	
              GENTIUM
                - VOD - Defibrotide Study - Proposal no. AA2618420 - Version
                8

            	
              

            


    


    Table
      of
      Contents

    

      
        	
                EXECUTIVE
                  SUMMARY

              	
                3

              
	
                1.

              	
                PROJECT
                  DEFINITION

              	
                3

              
	 	
                1.1.

              	
                Study
                  Title

              	
                3

              
	 	
                1.2.

              	
                Study
                  Design

              	
                3

              
	 	
                1.3.

              	
                Study
                  Objectives

              	
                3

              
	 	
                1.4.

              	
                Patient
                  / Centre Numbers

              	
                3

              
	 	
                1.5.

              	
                Study
                  Timelines

              	
                3

              
	2.	
                
                  STUDY
                    MANAGEMENT

                

              	
                4

              
	 	
                2.1.

              	
                Division
                  of Responsibilities

              	
                4

              
	 	
                2.2

              	
                Project
                  Team Approach

              	
                6

              
	 	
                2.3.

              	
                Project
                  Team Structure

              	
                7

              
	
                3.

              	
                SERVICES

              	
                8

              
	 	
                3.1.

              	
                Study
                  Set-up

              	
                8

              
	 	 	
                3.1.1.

              	
                Project
                  Definition Meeting

              	
                8

              
	 	 	
                3.1.2.

              	
                Project
                  Team Training

              	
                8

              
	 	
                3.2.

              	
                Document
                  Management

              	
                8

              
	 	 	
                3.2.1.

              	
                Protocol
                  / Informed Consent Form (ICF) familiarisation

              	
                8

              
	 	 	
                3.2.2.

              	
                Protocol
                  Synopsis Translation in Sweden

              	
                8

              
	 	 	
                3.2.3.

              	
                ICF
                  Adaptation and Translation

              	
                8

              
	 	 	
                3.2.4.

              	
                Case
                  Report Form (CRF) Development

              	
                9

              
	 	 	
                3.2.5.

              	
                Operations
                  Manual

              	
                9

              
	 	 	
                3.3.

              	
                Investigator
                  Recruitment

              	
                9

              
	 	 	
                3.3.1.

              	
                EBMT
                  - Investigators

              	
                9

              
	 	 	
                3.3.2.

              	
                Investigator
                  Contracts / Hospital Conventions

              	
                9

              
	 	
                3.4.

              	
                Central
                  Pharmacy / Import Supply

              	
                9

              
	 	
                3.5.

              	
                Ethics
                  Committee / Regulatory Submissions

              	
                9

              
	 	 	
                3.5.1.

              	
                Organization
                  of Regulatory Resources

              	
                10

              
	 	 	
                3.5.2.

              	
                Ethics
                  Committees Amendment Submissions

              	
                11

              
	 	
                3.6.

              	
                Study
                  Initiation

              	
                11

              
	 	 	
                3.6.1.

              	
                Investigator
                  Meeting

              	
                11

              
	 	 	
                3.6.2.

              	
                Site
                  Initiation Visits

              	
                11

              


      

       

      
        
          
          

        

        
          
          

          
            

          

        

        
          
          

        

      

      
        


        
          	
                  GENTIUM
                    - VOD - Defibrotide Study - Proposal no. AA2618420 - Version
                    8

                	
                  

                


        

         

      

      
        	 	
                3.7.

              	
                Monitoring
                  Activities

              	
                12

              
	 	 	
                3.7.1.

              	
                Monitoring
                  Visits

              	
                12

              
	 	 	
                3.7.2.

              	
                Telephone
                  Contacts

              	
                13

              
	 	 	
                3.7.3.

              	
                Correspondence

              	
                14

              
	 	 	
                3.7.4.

              	
                e-CRF
                  Review and Query Management

              	
                14

              
	 	 	
                3.7.5.

              	
                COSMOS
                  Set-up / Updates

              	
                14

              
	 	 	
                3.7.6.

              	
                Study
                  File and Documentation Maintenance

              	
                14

              
	 	 	
                3.7.7.

              	
                Serious
                  Adverse Event (SAE) Reporting to Sponsor and Documentation

              	
                15

              
	 	 	
                3.7.8.

              	
                Hospital
                  Fee Payments (Optional)

              	
                15

              
	 	
                3.8.

              	
                Study
                  Close-out

              	
                15

              
	 	 	
                3.8.1.

              	
                Site
                  Close-out Visits

              	
                15

              
	 	 	
                3.8.2.

              	
                Drug
                  Reconciliation

              	
                15

              
	 	
                3.9.

              	
                Project
                  Management

              	
                16

              
	 	 	
                3.9.1.

              	
                Project
                  Team Co-ordination

              	
                16

              
	 	 	
                3.9.2.

              	
                Reporting
                  to Sponsor

              	
                16

              
	 	 	
                3.9.3.

              	
                MDS
                  Pharma Express TM

              	
                16

              
	 	 	
                3.9.4.

              	
                Co-monitoring
                  Visits (Optional)

              	
                19

              
	 	 	
                3.9.5.

              	
                Sponsor
                  Contact

              	
                19

              
	 	 	
                3.9.6.

              	
                Project
                  Management of Austria, Germany and Switzerland (Optional)

              	
                19

              
	
                4.

              	
                SERVICE
                  CHARGES

              	
                20

              
	 	
                4.1.

              	
                Project
                  Assumptions

              	
                20

              
	 	
                4.2.

              	
                Professional
                  Fees

              	
                20

              
	 	
                4.3.

              	
                Optional
                  Costs

              	
                24

              
	 	
                4.4.

              	
                Variable
                  Costs

              	
                25

              
	 	
                4.5.

              	
                Estimate
                  of Pass-through Costs

              	
                26

              
	 	
                4.6.

              	
                Payment
                  Schedule

              	
                27

              
	
                APPENDIX
                  1 - CURRICULUM VITAE

              	
                27

              


      

    

    
       

      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

    


    
      	
              GENTIUM
                - VOD - Defibrotide Study - Proposal no. AA2618420 - Version
                8

            	
              

            


    


    Executive
      Summary

     

    MDS
      Pharma Services is pleased to provide GENTIUM
      with our
      proposal and preliminary budget estimate Version
      8
      for a
      Phase III study which aim is the “Study
      of the Incidence and Outcome of Veno-occlusive Disease (VOD) with the
      Prophylactic Use of Defibrotide (DF, GENTIUM, Italy) in Paediatric Stem Cell
      Transplantation.”

     

    MDS
      Pharma Services has identified the following factors that will be crucial for
      the successful delivery of the project in accordance with GENTIUM’s
      requirements.

     

    TEAM
      STABILITY

     

    MDS
      Pharma Services’ human resource management is based on the four core values of
      Mutual Trust; Genuine Concern and Respect for People; Integrity and Commitment
      to Excellence. These core values, combined with the regular training our CRAs
      receive, allows MDS Pharma Services to have one of the lowest staff turnovers
      in
      the CRO industry (8% in Europe).

     

    PROJECT
      TEAM EXPERIENCE

     

    We
      propose allocating an experienced International Project Director (IPD), based
      at
      our Italian
      office,
      who
      will be responsible for the whole project team, and will act as GENTIUM
      main
      contact. We propose allocating Agostino
      Lazzaro
      as the
      IPD (Please
      refer to his CV in appendix for more detail).

     

    The
      project team will be selected from a large pool of experienced CRAs. This is
      an
      important asset for the successful conduct of such a project.

     

    MDS
      Pharma Services places a significant emphasis on Operational Management support
      of all projects. This level of support is available to the Project Team to
      assist in the rapid resolution of issues.

     

    PROJECT
      COMMUNICATION

     

    The
      importance of establishing the right communication channels at the start of
      any
      project cannot be over-emphasised. The MDS Pharma Services team always
      demonstrates a responsive, open and collaborative approach, as evidenced by
      a
      recent CenterWatch report in which Investigators rated MDS Pharma Services
      as
      one of the top three CROs in Europe and North America.

     

    In
      addition to the use of integrated and innovative IT-based management tools,
      MDS
      Pharma Services will utilise MDS Pharma Express, a state-of-the-art web access
      tool that will allow GENTIUM
      access
      to real-time study data via the Worldwide Web. This provides significant study
      management benefits for important studies.

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

      
        


        
          	
                  GENTIUM
                    - VOD - Defibrotide Study - Proposal no. AA2618420 - Version
                    8

                	
                  

                


        

         

      

    

    KEY
      FACTS

     

    
      	
              Countries
                

            	
              ITALY,
                FRANCE, UK, NETHERLANDS, SWEDEN, ISRAEL, IRELAND

            
	
              Services
                

            	
              CLINICAL
                OPERATIONS, REGULATORY
                AFFAIRS

            
	
              N°
                Centres 

            	
              13

            
	
              Total
                N° Patients for ClinOps 

            	
              117

            
	
              Budget
                (excluding VAT and Pass-Through
                costs) 

            	
              562
                741 €

            


    

    


    MDS
      Pharma Services will be pleased to discuss this bid with GENTIUM
      team.

     

    
      
        
        

      

      
        2

        
          

        

      

      
        
        

      

    

    


    
      	
              GENTIUM
                - VOD - Defibrotide Study - Proposal no. AA2618420 - Version
                8

            	
              

            


    


    1.
      Project Definition

     

    1.1.
      Study Title

     

    VOD-DF
      Study:
      Prospective Study of the Incidence and Outcome of Veno-occlusive Disease (VOD)
      with the Prophylactic Use of Defibrotide (DF, GENTIUM,
      Italy)
      in Paediatric Stem Cell Transplantation.

     

    1.2.
      Study Design

     

    Phase
      III, multicenter, open label, randomised study to evaluate prophylactic DF
      in a
      paediatric patient population at high risk for VOD. Approximately 270 patients
      will be enrolled in European centres. MDS Pharma Services will be responsible
      for 13
      centres
      (117
      patients) in 7 countries.

     

    1.3.
      Study Objectives

     

    Evaluation
      of the Incidence and Outcome of Veno-occlusive Disease (VOD) with the
      Prophylactic use of Defibrotide in Paediatric Stem Cell
      Transplantation.

     

    1.4.
      Patient / Centre Numbers

     

    
      	
              COUNTRY

            	
              N°
                CENTRES

            	
              N°
                PATIENTS

            
	
              United
                Kingdom 

            	
              2

            	
              18

            
	
              Ireland
                

            	
              1

            	
              9

            
	
              Italy
                

            	
              3

            	
              27

            
	
              Sweden
                

            	
              4

            	
              36

            
	
              Netherlands
                

            	
              1

            	
              9

            
	
              France
                

            	
              1

            	
              9

            
	
              Israel
                

            	
              1

            	
              9

            
	
              TOTAL
                

            	
              13

            	
              117

            


    

    


    1.5.
      Study Timelines

    


    
      	 	
              Timelines

            
	
              w Set-up
                Activities 

            	
              End
                October 2005

            
	
              w Regulatory
                / EC Submissions 

            	
              End
                October 2005

            
	
              w First
                Patient Included 

            	
              End
                January 2006

            
	
              w Last
                Patient Included 

            	
              End
                January 2009

            
	
              w Last
                Patient Last Visit 

            	
              End
                August 2009

            
	
              w Study
                Close-out 

            	
              End
                October 2009

            


    

    


    NB
      These timelines assume that Ethics Committee and Regulatory Authority approvals
      are granted, and that the study drug is available on-site before
      First Patient In.


     

    
      
        
        

      

      
        3

        
          

        

      

      
        
        

      

    

    
      


      
        	
                GENTIUM
                  - VOD - Defibrotide Study - Proposal no. AA2618420 - Version
                  8

              	
                

              


      

       

    

    2.
      Study
      Management

     

    2.1.
      Division Of Responsibilities

     

    
      	
              Responsibilities

            	
              GENTIUM

            	
              MDS
                Pharma

              Services

            
	
              Project
                Definition Meeting 

            	
              ü

            	
              ü

            
	
              Project
                Team Training

            	 	
              ü

            
	
              Protocol
                / Informed Consent Form (ICF) Development

            	
              ü

            	 
	
              Protocol
                / ICF Familiarisation

            	 	
              ü

            
	
              Protocol
                Synopsis Translation 

            	
              ü

            	
              ü

              (Sweden
                only)

            
	
              ICF
                Adaptation 

            	 	
              ü

              (Ireland
                and Sweden only)

            
	
              ICF
                Translation 

            	
              ü

            	
              ü

              (Sweden
                only)

            
	
              Protocol
                Submission to MoH 

            	 	
              ü

              (France
                only)

            
	
              CRF
                Development 

            	
              ü

              (e-CRF
                development subcontracted

            	 
	
              Operations
                Manual 

            	
              ü

               

              (To
                be produced by a 3rd party CRO)

            	
              ü

               

              (Review
                only)

            
	
              Investigator
                Identification

            	
              ü

            	 
	
              Qualification
                Visits

            	
              ü

            	 
	
              Hospital
                Conventions

            	 	
              ü

            
	
              Regulatory
                Submissions 

            	
              ü

            	
              ü

              (Ireland
                and Sweden only)

            
	
              Ethics
                Committee Submissions 

            	
              ü

            	
              ü

              (Ireland
                and Sweden only)

            
	
              Ethics
                Committee Submissions Follow-Up 

            	 	
              ü

              (Support
                only for UK)

            
	
              Ethics
                Committee Amendment Submissions 

            	
              ü

              (Italy)

            	
              ü

              (Except
                Italy)

            
	
              Investigator
                Meetings: attendance and organisation 

            	
              ü

              (Organisation
                sub-contracted)

            	
              ü

              (Attendance
                and preparation)

            
	
              Study
                Drug Packaging / Labelling / Distribution 

            	
              ü

            	 
	
              Site
                Initiation Visits

            	 	
              ü

            


    

     

    
      
        
        

      

      
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              Responsibilities

            	
              GENTIUM

            	
              MDS
                Pharma

              Services

            
	
              Import
                License 

            	 	
              ü

              (The
                Netherlands, Israel, France and Sweden)

            
	
              Contract
                Negotiation with Central Pharmacy 

            	 	
              ü

              (The
                Netherlands and Sweden only)

            
	
              Import
                Supply Company 

            	 	
              ü

              (France
                (LC2) only)

            
	
              Routine
                Monitoring Visits

            	 	
              ü

            
	
              Telephone
                Contacts

            	 	
              ü

            
	
              Correspondence
                with Sites

            	 	
              ü

            
	
              E-CRF
                Review and Query Management 

            	 	
              ü

            
	
              COSMOS
                Set-up / Updates

            	 	
              ü

            
	
              Study
                File and Document Maintenance

            	 	
              ü

            
	
              Serious
                Adverse Event Reporting 

            	
              To
                Authorities

            	
              To
                GENTIUM

            
	
              Serious
                Adverse Event Documentation

            	 	
              ü

            
	
              Hospital
                Fee Payments (optional)

            	 	
              ü

            
	
              Site
                Close-out Visit

            	 	
              ü

            
	
              Project
                Team Co-ordination

            	 	
              ü

            
	
              Reporting
                to Sponsor

            	 	
              ü

            
	
              Sponsor
                Contact

            	 	
              ü

            
	
              Data
                Management 

            	
              ü
                (EBMT)

            	 
	
              Statistics
                Activities 

            	
              ü
                (EBMT)

            	 
	
              Clinical
                Study Report 

            	
              ü
                (EBMT)

            	 


    

     

    
      
        
        

      

      
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    2.2
      Project Team Approach

     

    Experienced
      MDS Pharma Services personnel from different disciplines and countries will
      be
      brought together to form a project team, which is specific to this individual
      project (see proposed organisation chart below). The project team will consist
      of an International Project Director (IPD)
      based
      in Italy,
      7
      Clinical Research Associates (CRA) and a Regulatory Affairs
      Manager.

     

    The
      project team will be led by the IPD, who will be GENTIUM’s
      primary
      contact throughout the course of the study. The IPD will report directly to
      senior management at MDS Pharma Services. Project team activities will be
      monitored by senior management to ensure that study requirements are fulfilled,
      and that the study is completed within the agreed budget and time
      frame.

     

    
      
        
        

      

      
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    2.3.
      Project Team Structure

     

    


     

    


    
      	
              FTE

            
	
              IPD

            	
              0,21

            
	
              CRA
                Italy

            	
              0,10

            
	
              CRA
                France

            	
              0,03

            
	
              CRA
                Netherlands

            	
              0,04

            
	
              CRA
                UK

            	
              0,07

            
	
              CRA
                Sweden

            	
              0,13

            
	
              CRA
                Ireland

            	
              0,04

            
	
              CRA
                Israel

            	
              0,03

            
	
              CTA

            	
              0,14

            


    

    


    Notes: 

    Ø The
      IPD
      will directly manage all countries.

    Ø The
      IPD
      and the Italian CRA will share the same CTA.

    


    
      
        
        

      

      
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    3.
      Services

     

    All
      MDS Pharma services will be provided in accordance with the MDS Pharma Services
      SOPs, which are compliant with ICH GCP guidelines. All project team activities
      are liable to be audited by the independent quality assurance division of MDS
      Pharma Services.

     

    3.1.
      Study Set-up

     

    3.1.1. Project
      Definition Meeting

     

    MDS
      Pharma Services IPD
      will
      organise and attend a meeting in GENTIUM’s office (Italy)
      with
GENTIUM
      to
      define and clarify the study objectives and general study procedures, and to
      ensure common understanding of responsibilities, timelines and reporting
      lines.

     

    3.1.2. Project
      Team Training

     

    MDS
      Pharma Services will participate to an international training meeting in
GENTIUM’s office,
      in
      order to ensure that all members of the project team are fully conversant with
      the technical requirements of the protocol, e-CRF and other study documentation.
      Representatives from GENTIUM
      will
      also attend this meeting in order to brief the MDS Pharma Services project
      team
      on the study drug and study objectives. A Webex training session will also
      be
      held for training purposes.

     

    3.2.
      Document Management

     

    3.2.1.
      Protocol / Informed Consent Form (ICF) familiarisation

     

    MDS
      Pharma Services will review the study protocol and Informed Consent Form (ICF)
      provided by GENTIUM
      in
      English, in order to familiarise themselves.

     

    3.2.2. Protocol
      Synopsis Translation in Sweden

     

    MDS
      Pharma Services will subcontract the translation of the protocol synopsis to
      be
      submitted to Ethics Committees and Regulatory Authorities, from English into
      Swedish, in accordance with local legislation. This document will then be
      distributed to all investigational site personnel, in order to facilitate local
      comprehension.

     

    3.2.3. ICF
      Adaptation and Translation

     

    MDS
      Pharma Services will adapt the ICF for Ireland and Sweden. MDS Pharma Services
      will also subcontract the translation of the Patient Information and Informed
      Consent Form (ICF), from English into Swedish, in accordance with local
      legislation, and in order to facilitate local comprehension.

     

    
      
        
        

      

      
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    3.2.4. Case
      Report Form (CRF) Development

     

    GENTIUM
      will
      manage the CRF development and select and manage an e-CRF supplier.

     

    3.2.5. Operations
      Manual

     

    MDS
      Pharma Services will participate to the preparation of an Operations Manual
      in
      English, in order to supplement the study protocol, with clear definitions
      of
      tasks, responsibilities, study-specific procedures, communication lines and
      timelines. The main responsibility for preparing this document is held by the
      3rd Party CRO involved in the study.

     

    3.3.
      Investigator Recruitment

     

    3.3.1. EBMT
      - Investigators

     

    All
      selected centres and investigators are members of the EBMT (European
      Group for Blood and Marrow Transplantation).
      GENTIUM
      has
      already identified the centres to be included in the study.

     

    MDS
      Pharma Services will manage no tasks related to investigators identification
      and
      selection.

     

    3.3.2. Investigator
      Contracts / Hospital Conventions

     

    MDS
      Pharma Services will not provide the investigators with contracts as they are
      all members of the EBMT and will not be paid for their
      participation.

     

    MDS
      Pharma Services will negotiate and draw up financial agreements with each
      hospital selected to participate in the study (except
      for The Netherlands),
      based
      on the fees agreed by GENTIUM.

     

    3.4.
      Central Pharmacy / Import Supply

     

    MDS
      Pharma Services will negotiate the contract with the Central Pharmacy in The
      Netherlands and Sweden.

     

    MDS
      Pharma Services will also liaise with LC2 in France to negotiate the contract
      for supplies importation.

     

    3.5.
      Ethics Committee / Regulatory Submissions

     

    The
      regulatory management of global clinical trials is a complex undertaking due
      to
      the large number of countries involved, and hence successful management is
      key
      to rapid project start-up in multiple countries. The following paragraphs
      outline the ways in which MDS Pharma Services operates to ensure efficient
      compliance with the regulatory requirements of each country (Only
      submissions in Ireland and Sweden will be managed by MDS Pharma Services. MDS
      Pharma Services will also support Gentium for the submissions in France and
      especially in UK).

     

    
      
        
        

      

      
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    3.5.1.
      Organization of Regulatory Resources

     

    MDS
      Pharma Services has regulatory affairs groups based in Europe, North America
      and
      Asia. These Regulatory Affairs Departments perform the following functions
      in
      relation to clinical trials:

     

    
      	 	
              Ø

            	
              Prepare
                core study documentation (e.g. investigator brochure, IMP dossier,
                IND) -
                if required.

            


    

     

    
      	 	
              Ø

            	
              Maintain
                a country-by-country database of national regulatory and ethics data
                requirements and processes.

            


    

     

    
      	 	
              Ø

            	
              Co-ordinate
                regulatory activities in conjunction with MDS project management
                professionals.

            


    

     

    
      	 	
              Ø

            	
              Disseminate
                emerging regulatory information to local regulatory advisers (see
                below).

            


    

     

    
      	 	
              Ø

            	
              Provide
                support to local regulatory advisers in responding to ethics committee
                and/or regulatory authority
                questions.

            


    

     

    
      	 	
              Ø

            	
              Delivery
                of training to local regulatory advisers when
                appropriate.

            


    

     

    In
      each
      country, MDS Pharma Services Clinical Operations teams will nominate an
      individual to have responsibility for regulatory aspects of clinical trial
      management. These local regulatory advisers network extensively with the
      Regulatory Affairs Department and have the following
      responsibilities:

     

    
      	 	
              Ø

            	
              Prepare
                and submit regulatory and ethics committee packages in the local
                country
                concerned.

            


    

     

    
      	 	
              Ø

            	
              Respond
                to any questions from the local ethics committees and/or regulatory
                authority.

            


    

     

    
      	 	
              Ø

            	
              Communicate
                changes in country-specific regulatory and/or ethics requirements
                to the
                Regulatory Affairs Departments.

            


    

     

    The
      above
      system provides an excellent platform for consistent, reliable delivery of
      efficient regulatory support to global clinical trials.

     

    Except
      for Israel, all the countries proposed for this trial and managed by MDS Pharma
      Services are EU members. Study initiation in most of these countries will
      proceed according to the requirements of the EU Clinical Trial Directive
      (2001/20/EC).

     

    In
      order
      to facilitate transparent status tracking for the countries for which MDS Pharma
      Services is responsible for the regulatory set-up, the MDS Pharma Services
      EU
      Regulatory Affairs Department will create a Regulatory Master File (RMF). This
      document will record all key regulatory events.

     

    Published
      data in conjunction with our own records show that regulatory and ethics
      timelines in the proposed countries are as follows:

     

    
      
        
        

      

      
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              Country

            	
              Approximate
                Regulatory and

              Ethics
                Timelines

            
	
              Ireland
                

            	
              2
                months

            
	
              Sweden
                

            	
              2
                months

            


    

    


    Experience
      in submitting clinical trial applications to these countries has highlighted
      a
      number of discrepancies between the published timelines and the actual
      timelines. Outlined below are some key points of regulatory intelligence
      gathered from our more recent applications.

     

    In
      Ireland and Sweden, The European Clinical Trial Directive (2001/20/EC) specifies
      a 60 day timeline for regulatory and ethics assessments, however, the actual
      timelines we are currently experiencing tend to be slightly longer especially
      with regard to EC approvals.

     

    3.5.2. Ethics
      Committees Amendment Submissions

     

    It
      is
GENTlUM’s
      expectation that amendments will be required for the study. Following receipt
      of
      a comprehensive and final amendment text from GENTIUM,
      MDS
      Pharma Services will submit the amendment to Ethics Committees in all countries
      involved except Italy, which will be directly managed by GENTIUM.
      For
      budget purpose, it has been assumed that one amendment will be submitted
      shortly.

     

    3.6.
      Study Initiation

     

    3.6.1.
      Investigator Meeting

     

    MDS
      Pharma Services’ IPD will participate to one
      Investigator Meeting,
      in
Germany.
      This
      meeting will be attended by MDS Pharma Services’ IPD, as well as representatives
      from GENTIUM.

     

    MDS
      Pharma Services will participate to the meeting documents preparation
      (slides/overheads, hand-outs, etc.).

     

    During
      the investigator meeting, GENTIUM
      will
      brief the investigators on the study drug and the aim of the trial, and
      participate in all discussions that ensue. MDS Pharma Services will present
      the
      protocol and e-CRF, and conduct a thorough review of the monitoring activities
      (including respective responsibilities and SAE reporting guidelines), ICH GCP
      and regulatory aspects of the study.

     

    3.6.2.
      Site Initiation Visits

     

    The
      critical and relevant study-related documents will be kept in the centralised
      Trial Master File at MDS Pharma Services. EBMT will compile an Investigator
      Site
      File and provide one to each centre, according to ICH GCP
      requirements.

     

    MDS
      Pharma Services will visit each of the selected sites, to ensure complete
      understanding of the protocol and associated study documentation. MDS Pharma
      Services will deliver all documentation and ensure careful storage of all study
      documents and clinical trial supplies, in accordance with ICH GCP
      guidelines.

     

    
      
        
        

      

      
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    MDS
      Pharma Services will ensure that study personnel are fully conversant with
      the
      requirements of the study and that they fully understand their
      obligations.

     

    During
      the visit the CRA will:

     

    
      	 	
               ̈

            	
              Review
                with the investigators the protocol and
                e-CRF,

            


    

     

    
      	 	
               ̈

            	
              Review
                with the investigators the conduct of monitoring visits, and confirm
                the
                monitor’s continued access to study-related source
                documents,

            


    

     

    
      	 	
               ̈

            	
              Review
                with the investigators the requirements for Adverse Event
                reporting,

            


    

     

    
      	 	
               ̈

            	
              Review with the investigators the requirements for drug storage and
                accountability,

            


    

     

    
      	 	
               ̈

            	
              Supply
                the investigators with a study file, in which all study-related documents
                and correspondence will be archived, in accordance with ICH GCP
                guidelines,

            


    

     

    
      	 	
               ̈

            	
              Retrieve
                any document missing from MDS Pharma Services’ study
                files,

            


    

     

    
      	 	
               ̈

            	
              Review with the investigators their responsibilities concerning local
                regulations,

            


    

     

    
      	 	
               ̈

            	
              Review
                with the investigators laboratory
                procedures,

            


    

     

    
      	 	
               ̈

            	
              Stress
                the importance of correctly obtaining informed consent from
                patients,

            


    

     

    
      	 	
               ̈

            	
              Review
                with the investigators their responsibilities for archiving study-related
                documents according to applicable
                regulations.

            


    

     

    Further
      to each visit, MDS Pharma Services will prepare a visit report, to be stored
      in
      the Trial Master File at MDS Pharma Services, and a copy made available to
      GENTIUM.

     

    3.7.
      Monitoring Activities

     

    3.7.1.
      Monitoring Visits

     

    Prior
      to
      each visit, MDS Pharma Services will make appointments with investigators and
      confirm in writing the date and time of the planned monitoring
      visits.

     

    MDS
      Pharma Services will visit all investigational centres 6
      times
      (about
      each 7,5
      month),
      in order to review study progress, and in particular will:

     

    
      	 	
               ̈

            	
              Verify
                all completed Electronic Case Report Forms (e-CRFs) and rectify any
                errors
                in accordance with ICH GCP
                guidelines,

            


    

     

    
      
        
        

      

      
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               ̈

            	
              Verify
                compliance with the protocol,

            


    

     

    
      	 	
               ̈

            	
              Verify
                critical study data,

            


    

     

    
      	 	
               ̈

            	
              Verify
                that patients have given their informed consent prior to inclusion
                in the
                study,

            


    

     

    
      	 	
               ̈

            	
              Verify
                documentation of all Adverse Events and compliance with the relevant
                procedures,

            


    

     

    
      	 	
               ̈

            	
              Conduct
                comprehensive source document verification (100% of demographic data,
                study entry criteria, Adverse Events, concomitant
                medication, key efficacy
                parameters),

            


    

     

    Further
      to each visit, MDS Pharma Services will prepare a monitoring visit report
      summarising the visit, to be stored in the Trial Master File at MDS Pharma
      Services, and a copy made available to GENTIUM.
      MDS
      Pharma Services will undertake follow-up activities to the monitoring visit,
      including written confirmation of action to be taken by
      investigators.

     

    MDS
      Pharma Services will keep track of study drugs, supplied and dispensed to all
      centres, and expiry dates of drug supplies (in view of possible requests for
      re-supply). MDS Pharma Services will keep appropriate records on standard forms,
      which will be filed in the Trial Master File.

     

    3.7.2. Telephone
      Contacts

     

    MDS
      Pharma Services will complement on-site monitoring with regular telephone
      contacts with investigators, and ancillary services, in order to ensure the
      smooth running of the study, and in particular, will verify: 

     

    
      	 	
               ̈

            	
              Study
                progress,

            


    

     

    
      	 	
               ̈

            	
              Queries,
                in case of issues needing clarification or incomplete data further
                to the
                monitoring visit,

            


    

     

    
      	 	
               ̈

            	
              Preparation
                of corrections to be signed off at the next monitoring
                visit,

            


    

     

    
      	 	
               ̈

            	
              Information
                on the overall study status,

            


    

     

    
      	 	
               ̈

            	
              Investigator’s
                motivation to deal with potential
                problems,

            


    

     

    
      	 	
               ̈

            	
              Adverse
                Events, exchange of information.

            


    

     

    MDS
      Pharma Services will report all telephone contacts on a telephone contact report
      to be stored in the Trial Master File.

     

    MDS
      Pharma Services will contact all participating centres by telephone
      approximately every month (i.e. 48
      contacts
      per centre), for the duration of the project.

     

    
      
        
        

      

      
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    3.7.3. Correspondence

     

    MDS
      Pharma Services will write to participating centres on a regular basis, to
      inform them of study progress, and any modifications to the study requirements,
      protocol amendments etc.

     

    3.7.4. e-CRF
      Review and Query Management

     

    In
      preparation for monitor visits, e-CRFs will be reviewed in-house, with
      particular reference to all medical data, such as SAEs, other patient safety
      items, patient suitability and protocol adherence. During monitoring and SDV,
      the MDS Pharma Services’ CRAs will ask the investigators for necessary
      clarifications, to rectify any errors or omissions detected and update the
      EDC
      system.

     

    MDS
      Pharma Services CRA will be also responsible for facilitating the resolution
      of
      all queries emitted by Data Management. These queries will be discussed with
      investigators during the course of a routine monitoring visit or by
      email/telephone.

     

    3.7.5. COSMOS
      Set-up / Updates

     

    MDS
      Pharma Services will set up the in-house Oracle® based tracking system (COSMOS)
      and tailor it to the project specifications (information to be tracked, formats
      of the print-outs).

     

    3.7.6. Study
      File and Documentation Maintenance

     

    MDS
      Pharma Services will manage the distribution and safe arrival of the study
      material including the investigator site file, and will collect the appropriate
      acknowledgement forms.

     

    MDS
      Pharma Services will track the study materials distributed to each site on
      the
      internal tracking system.

     

    MDS
      Pharma Services will ensure that all essential documents have been obtained
      for
      the study files and are correctly filed.

     

    3.7.7. Serious
      Adverse Event (SAE) Reporting to Sponsor and Documentation

     

    Investigators
      will report SAEs to GENTIUM.
      MDS
      Pharma Services will report SAEs to Gentium upon receipt only in case of
      findings during a routine monitoring visit. The MDS Pharma Services’ Safety
      department will
      not
      be
      involved in the study.

     

    Additional
      information required to fully document each SAE will be retrieved from the
      investigational site concerned by MDS Pharma Services during the course of
      a
      routine monitoring visit.

     

    GENTIUM
      will
      report all serious and unexpected Adverse Drug Reactions to the relevant
      regulatory authorities in each country involved in the study.

     

    
      
        
        

      

      
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    3.7.8. Hospital
      Fee Payments (Optional)

     

    MDS
      Pharma Services will administer payments (except
      for Italy)
      to all
      hospitals involved in the study, once the corresponding advance payment has
      been
      received from GENTIUM.

     

    MDS
      Pharma Services will issue and send fee schedules to all hospitals. On receipt
      of each signed schedule, MDS Pharma Services will pay the hospitals by cheque.
      MDS Pharma Services will notify the authorities of all payments issued, where
      appropriate.

     

    3.8.
      Study Close-out

     

    3.8.1. Site
      Close-out Visits

     

    Prior
      to
      each on-site closure visit, the CRA will make an appointment with the
      investigator and confirm in writing the date and time of the planned
      visit.

     

    Closeout
      visits will be conducted at all participating centres on completion of the
      study, in order to:

     

    
      	 	
               ̈

            	
              Verify
                the study documentation,

            


    

     

    
      	 	
               ̈

            	
              Verify
                the suitability of study archives,

            


    

     

    
      	 	
               ̈

            	
              Verify
                the signing off of drug dispensing
                logs,

            


    

     

    
      	 	
               ̈

            	
              Retrieve
                all unused study materials and return them to GENTIUM
                for destruction,

            


    

     

    
      	 	
               ̈

            	
              Confirm
                with investigators that the study may be subject to
                inspection.

            


    

     

    The
      CRA
      will prepare a closure visit report, summarising the visit, to be stored in
      the
      Trial Master File at the local MDS Pharma Services office, a copy of which
      will
      be made available to GENTIUM
      on
      request. The report will provide written confirmation of action to be taken
      by
      investigators.

     

    3.8.2.
      Drug Reconciliation

     

    Throughout
      the study, MDS Pharma Services will keep track of the study drugs, supplied
      and
      dispensed to all centres by GENTIUM,
      and
      track the expiration dates of drug supplies (in view of possible requests for
      re-supply).

     

    MDS
      Pharma Services will maintain up-to-date drug reconciliation records (to be
      kept
      in the Trial Master File), as completed by the investigators.

     

    At
      the
      end of the study, MDS Pharma Services will verify that the drug dispensing
      logs
      have been correctly completed and collect a copy from each investigational
      site
      to be filed in the Trial Master File.

     

    
      
        
        

      

      
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    3.9.
      Project Management

     

    3.9.1.
      Project Team Co-ordination

     

    The
      IPD
      will maintain overall control of the set-up and monitoring activities, and
      in
      particular will:

     

    
      	 	
               ̈

            	
              Allocate
                the appropriate resources to complete the study within the agreed
                timelines,

            


    

     

    
      	 	
               ̈

            	
              Co-ordinate
                and supervise MDS Pharma Services’ project
                team,

            


    

     

    
      	 	
               ̈

            	
              Motivate
                MDS Pharma Services’ project team and investigators involved in the study,
                

            


    

     

    
      	 	
               ̈

            	
              Respond
                to recruitment rates from site to site, and initiate / co-ordinate
                any
                remedial action required to achieve the overall study recruitment
                target
                within the defined timelines,

            


    

     

    
      	 	
               ̈

            	
              Oversee
                the local distribution of study material and
                documentation.

            


    

     

    3.9.2. Reporting
      to Sponsor

     

    The
      IPD
      will provide GENTIUM
      with a
      written 16
      report,
      regarding the study status, including centralised information on; 

     

    
      	 	
               ̈

            	
              Start-up,
                regulatory status,

            


    

     

    
      	 	
               ̈

            	
              Number
                of investigators recruited into the
                study,

            


    

     

    
      	 	
               ̈

            	
              Inclusion
                per site,

            


    

     

    
      	 	
               ̈

            	
              Comparison
                of planned and actual inclusions,

            


    

     

    
      	 	
               ̈

            	
              Number
                of drop-outs,

            


    

     

    
      	 	
               ̈

            	
              Number
                of protocol deviations,

            


    

     

    
      	 	
               ̈

            	
              Number
                of SAEs / AEs,

            


    

     

    
      	 	
               ̈

            	
              Number
                of monitoring visits performed,

            


    

     

    
      	 	
               ̈

            	
              Number
                of clean e-CRFs acquired,

            


    

     

    
      	 	
               ̈

            	
              Outstanding
                administrative issues.

            


    

     

    3.9.3. MDS
      Pharma Express TM

     

    In
      addition, MDS Pharma Services offers a comprehensive service that would allow
      GENTIUM
      real
      time access to the clinical trial data maintained in these management tools
      via
      a customized, secure, web based interface known as MDS
      Pharma Express TM.

     

    
      
        
        

      

      
        16

        
          

        

      

      
        
        

      

      
        
          


          
            	
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                      8

                  	
                    

                  


          

           

        

      

    

    

      
        	
              	·	
                An
                  intuitive and user-friendly service that allows you to keep current
                  on
                  your studies without any delay. 

              


      

      


      
        	
              	·	
                Provides
                  real-time access to investigator and subject summary information
                  with
                  drill-down features, print-ready study status reports, site visit
                  reports
                  and site visit schedules.

              


      

      


      
        	
              	·	
                All
                  study status information is extracted from MDS Pharma Services’
                  operational systems and automatically published via a web
                  interface.

              


      

    

     

    MDS
      Pharma Express is available to GENTIUM
      through
      a service agreement defining the terms and conditions of this service offering.
      With your authorization, MDS Pharma Services will activate the availability
      of
      your project status, activity and contact reports related to your particular
      study or studies, through MDS Pharma Express. Authorized users are defined
      by
GENTIUM
      and are
      assigned access to your studies available through this web service.

     

    Financial
      management is achieved through accurate projections and monitoring at all
      levels. The Project Leader is able to review costs against projections that
      are
      made on a monthly basis, enabling them to flag any anomalies to take remedial
      action at an early stage. Costs reviewed will also include pass-through charges,
      thus enabling us to keep a tight control continuously over all aspects of the
      project budget.

     

    As
      a
      valued sponsor, MDS Pharma Services offers you PharmaExpressTM - an added value
      to your clinical trials (see below for sample screen shots of
      PharmaExpressTM).

     

    
      
        
        

      

      
        17

        
          

        

      

      
        
        

      

      
        
          


          
            	
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                      8

                  	
                    

                  


          

           

        

      

    

    Sample
      Overview of MDS PharmaExpressTM Reports:

     

    

     

    Sample
      MDS On-line Monitoring Report:

     

    

     

    
      
        
        

      

      
        18

        
          

        

      

      
        
        

      

    

    
      


      
        	
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                  8

              	
                

              


      

    

     

    3.9.4. Co-monitoring
      Visits (Optional)

     

    The
      IPD
      will perform 7
      co-monitoring visits, one
      in each
      country involved in the study, in order to verify coherence of monitoring
      procedures, and as a QC of the CRAs’ work.

     

    3.9.5. Sponsor
      Contact

     

    The
      IPD
      will meet GENTIUM 5
      times
      during the course of the study, in order to discuss study progress, and resolve
      any problems that may have arisen.

     

    The
      IPD
      will contact GENTIUM
      approximately 2-3
      times per month
      during
      the course of the study, to discuss the study status, and resolve any pending
      issues. The IPD will communicate more during the set-up and closeout periods
      and
      less during the rest of the study.

     

    3.9.6. Project
      Management of Austria, Germany and Switzerland (Optional)

     

    If
      requested by GENTIUM,
      MDS
      Pharma Services IPD could manage Austria,
      Germany
      and
Switzerland,
      assuming that one CRA per country will be allocated by the CRO selected by
      GENTIUM.

     

    We
      assumed that the IPD will directly manage the CRAs (no PM in the local CRO).
      We
      would like to put stress on the training session. In order to have the local
      CRO
      CRAs working in accordance with MDS Pharma Services’ SOPs and procedures, it
      might be necessary to have more than one training session or a closer
      management. Please note that our optional budget could be updated according
      to
      the actual CRAs’ need for training.

     

    
      
        
        

      

      
        19

        
          

        

      

      
        
        

      

    

    
      


      
        	
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                  8

              	
                

              


      

       

    

    4.
      Service Charges

     

    4.1.
      Project Assumptions

     

    All
      calculations have been made according to the following assumptions:

    


    
      	
              General
                Assumptions

            
	
              Total
                number of patients 

            	
              117

            
	
              Total
                number of centres 

            	
              13
                (in 7 countries)

            
	
              Number
                of CRF pages 

            	
              40

            
	
              Total
                number of estimated SAEs 

            	
              TBD

            
	
              Total
                study duration (months) 

              -
                Set-up 

              -
                Recruitment 

              -
                Treatment and follow-up 

              -
                Close-out 

            	
              48
                

              3
                

              36
                

              7
                

              2

            


    

    


    4.2.
      Professional Fees

     

    
      	 	
              No
                of Units

            	
              Type
                of Unit

            	
              Unit
                Price (EUR)

            	
              TOTAL
                (EUR)

            	
              Comments

            
	Study
              Set-up	 	 	 	
              21
                328

            	 
	
              Project
                Definition Meeting 

            	
              1

            	
              meeting

            	
              1
                704 

            	
              1
                704 

            	
              This
                one-day meeting will take place in GENTIUM’s office in Italy. MDSPS’ IPD
                will attend. Travel and accommodation costs not
                included.

            
	
              Project
                Team Training 

            	
              1

            	
              meeting

            	
              17
                485 

            	
              17
                485 

            	
              This
                one-day meeting will take place in GENTIUM’s office in Italy. MDSPS’ IPD
                and CRAs will attend. Travel and accommodation costs not
                included.

            
	
              Team
                Training (Webex) 

            	
              1

            	
              training

            	
              1
                855 

            	
              1
                855

            	 
	
              Import
                Supplier Company 

            	
              1

            	
              contract

            	
              284
                

            	
              284
                

            	
              In
                France. IPD coordination only for contract negotiation.

            
	
              Document
                Management 

            	16
              881	 
	
              Study
                Document Familiarisation / Regulatory Master File Set-up 

            	
              1

            	
              dossier

            	
              1
                387 

            	
              1
                387

            	 
	
              Protocol
                Familiarisation 

            	
              15

            	
              team
                members

            	
              291
                

            	
              4
                359 

            	
              MDSPS
                Team is composed of 1 IPD, 7 CRAs and 7 CTAs.

            
	
              Protocol
                Synopsis Translation (Sweden only) 

            	
              1

            	
              language

            	
              230
                

            	
              230
                

            	
              MDSPS
                will subcontract the translation in Swedish to a professional agency.
                Fees
                are for coordination and review
                only.

            


    

     

    
      
        
        

      

      
        20

        
          

        

      

      
        
        

      

    

    
      
        


        
          	
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                    8

                	
                  

                


        

         

        
           

          
            	 	
                    No
                      of Units

                  	
                    Type
                      of Unit

                  	
                    Unit
                      Price (EUR)

                  	
                    TOTAL
                      (EUR)

                  	
                    Comments

                  


          

        

      

    

    
      	
              ICF
                Adaptation and Translation 

            	
              2

            	
              adaptation
                with/without translation

            	
              550
                

            	
              1
                099 

            	
              MDSPS
                will adapt the ICF in Ireland and Sweden. Additionally, MDSPS will
                subcontract the translation in Swedish to a professional agency.
                Fees are
                for coordination and review only.

            
	
              CRF
                Familiarisation 

            	
              15

            	
              team
                members

            	
              291
                

            	
              4
                359 

            	
              MDSPS
                Team is composed of 1 IPD, 7 CRAs and 7 CTAs.

            
	
              Operations
                Manual 

            	
              1

            	
              manual

            	
              5
                447 

            	
              5
                447

            	
              MDSPS
                IPD will participate to the Operating Manual development by the German
                CRO. MDSPS’ CRA/CTA will also familiarise with the Operating
                Manual.

            
	
              Investigator
                Recruitment

            	20
              316	
              All
                Investigators are EBMT members. MDSPS will neither be responsible
                for
                investigators identification and
                qualification.

            
	
              Hospital
                Contracts / Conventions 

            	
              12

            	
              contracts

            	
              1
                061 

            	
              12
                727 

            	
              MDSPS
                will not be responsible for hospitals contracts/conventions in The
                Netherlands (not required).

            
	
              Central
                Pharmacy Contract 

            	
              3

            	
              contracts

            	
              885
                

            	
              2
                655 

            	
              Negotiation
                of the central pharmacy contracts in The Netherlands and
                Sweden.

            
	
              Investigator
                Meeting Preparation 

            	
              1

            	
              meeting

            	
              2
                662 

            	
              2
                662

            	 
	
              Investigator
                Meeting Attendance 

            	
              1

            	
              meeting

            	
              2
                272 

            	
              2
                272 

            	
              IPD
                travel and attendance only.

            
	
              EC
                / Regulatory Submissions

            	34
              545	
              We
                assumed that the IMP Dossier, the core EU application form and the
                Investigator Brochure will be provided by
                GENTIUM.

            
	
              CTA
                Documentation Preparation (IMP
                Dossier etc.) 

            	
              1

            	
              dossier

            	
              4
                624 

            	
              4
                624 

            	
              Corresponds
                to time to compile the information from other submissions and to
                support
                GENTIUM during the regulatory process.

            
	
              Teleconferences
                

            	
              32

            	
              hours

            	
              124
                

            	
              3
                983 

            	
              As
                the number of teleconferences is not clearly defined, we allocated
                a
                certain number of hours for this task.

            
	
              Ethics
                Committee 

              Submissions
                

            	
              2

            	
              submissions

            	
              1
                932 

            	
              3
                863 

            	
              MDSPS
                will manage EC submissions in Ireland and Sweden only.

            
	
              Ethics
                Committee Submissions
                Follow-Up 

            	
              2

            	
              submissions

            	
              764
                

            	
              1
                529 

            	
              MDSPS
                will support GENTIUM submissions in UK (follow-up
                only).

            


    

     

    
      
        
        

      

      
        21

        
          

        

      

      
        
        

      

    

    

      
        
          	
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                    8

                	
                  

                


        

         

        
           

          
            	 	
                    No
                      of Units

                  	
                    Type
                      of Unit

                  	
                    Unit
                      Price (EUR)

                  	
                    TOTAL
                      (EUR)

                  	
                    Comments

                  


          

        

      

    

    
      	
              Ethics
                Committee Amendment Submissions 

            	
              10

            	
              submissions

            	
              795
                

            	
              7
                946 

            	
              GENTIUM
                will provide MDSPS with the final text of the amendment. MDSPS will
                not
                perform the submission in Italy.

            
	
              Regulatory
                Submissions 

            	
              2

            	
              submissions

            	
              5
                767 

            	
              11
                533 

            	
              MDSPS
                will manage Regulatory submissions in Ireland and Sweden
                only.

            
	
              Protocol
                Submission to
                MoH (France) 

            	
              1

            	
              submission

            	
              1
                067 

            	
              1
                067 

            	
              Cost
                to be adjusted according to the actual work performed.

            
	Study
              Initiation	
              24
                722

            	 
	
              Site
                Initiation Visits 

            	
              13

            	
              visits

            	
              1
                711 

            	
              22
                247

            	 
	
              Import
                Licence Negotiation 

            	
              4

            	
              licence

            	
              341
                

            	
              1
                362 

            	
              Negotiation
                of the import licence for France, The Netherlands, Sweden and Israel.
                Cost
                for this task in UK and Ireland can be found in option
                section.

            
	
              Drug
                / Supplies Shipment Tracking 

            	
              13

            	
              shipments

            	
              86
                

            	
              1
                113 

            	
              MDSPS
                assumed 1 shipment per site.

            
	
              Monitoring
                Activities

            	224
              384	 
	
              Monitoring
                Visits 

            	
              78

            	
              visits

            	
              1
                679 

            	
              130
                927 

            	
              Corresponds
                to 6 monitoring visits per site.

            
	
              Site
                Communication 

            	
              624

            	
              months
                x sites

            	
              52
                

            	
              32
                202 

            	
              Corresponds
                to 13 sites during 48 months.

            
	
              e-CRF
                Review / Query Management 

            	
              117

            	
              CRFs

            	
              172
                

            	
              20
                126

            	 
	
              COSMOS
                Set-up / Updates 

            	
              117

            	
              patients

            	
              54
                

            	
              6
                349

            	 
	
              Filing
                

            	
              48

            	
              months

            	
              725
                

            	
              34
                780 

            	
              GENTIUM
                will manage the TMF. MDSPS will only forward the essential documents
                on a
                regular basis to GENTIUM.

            
	
              Study
                Close-out

            	19
              138	 
	
              Close-out
                Visits 

            	
              13

            	
              visits

            	
              1
                472 

            	
              19
                138

            	 
	
              Project
                Management

            	201
              427	 
	
              Project
                Team Interaction 

            	
              48

            	
              months

            	
              2
                480 

            	
              119
                019 

            	
              Includes
                IPD time to manage each country ( 1 hour per month per country managed)
                and general on-going communication with CRAs (2 hours per CRA FTE).
                Includes also between 0,5 and 1,5 CRA hours per month for interaction
                with
                the rest of the team.

            
	
              Project
                Team Teleconferences 

            	
              16

            	
              teleconferences

            	
              999
                

            	
              15
                976 

            	
              Corresponds
                to 1-hour teleconferences. The IPD will spend 1 hour for minutes
                writing
                after each teleconference. We assume monthly teleconference during
                set-up
                and closeout and 3-monthly teleconferences during the rest of the
                study.

            


    

     

    
      
        
        

      

      
        22

        
          

        

      

      
        
        

      

    

    
      
        


        
          	
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                    - VOD - Defibrotide Study - Proposal no. AA2618420 - Version
                    8

                	
                  

                


        

         

        
           

          
            	 	
                    No
                      of Units

                  	
                    Type
                      of Unit

                  	
                    Unit
                      Price (EUR)

                  	
                    TOTAL
                      (EUR)

                  	
                    Comments

                  


          

        

      

    

    
      	
              Status
                Reports 

            	
              16

            	
              reports

            	
              1
                489 

            	
              23
                832 

            	
              The
                IPD will provide GENTIUM with 16 reports. This assumes 3 reports
                during
                the set-up, 2 reports during the closeout and 11 during the rest
                of the
                study.

            
	
              Sponsor
                Meetings 

            	
              5

            	
              meeting

            	
              1
                704 

            	
              8
                520

            	 
	
              Sponsor
                Communications 

            	
              48

            	
              months

            	
              710
                

            	
              34
                080 

            	
              The
                IPD will contact GENTIUM approximately 1,25 hours per week (2 hours
                per
                week during the set-up and close-out period and 1 hour per week during
                the
                rest of the study).

            
	
              TOTAL
                (excluding
                VAT and all pass-through costs)

            	562
              741	 


    

    


    Notes
      on Cost:

     

    
      	
            	 ̈	
              Due
                to the particular setting of this study, MDS Pharma Services would
                like to
                inform GENTIUM
                that the budget provided before is estimated.
                MDS Pharma Services will invoice the actual production to GENTIUM,
                in order to match the study specifications (competitive recruitment,
                etc.).

            


    

     

    
      	
            	 ̈	
              All
                costs in this proposal exclude VAT and pass-through
                costs.

            


    

     

    
      	
            	 ̈	
              Unit
                costs are for information purposes
                only.

            


    

     

    
      	
            	 ̈	
              These
                fees will be valid for 60 days from the date of this proposal, after
                which
                they may be subject to change.

            


    

     

    
      	
            	 ̈	
              If
                this proposal is accepted within a 60-day period, the fees will be
                valid
                until 21st
                April 2007.
                After this date, the fees will be subject to an annual increase not
                to
                exceed the “Indice Syntec.”

            


    

     

    
      	
            	 ̈	
              MDS
                Pharma Services would be prepared to begin preliminary activities
                on this
                project immediately upon receipt of a Letter of Intent from GENTIUM,
                containing all the agreed terms and conditions, including an initial
                fee
                payment. A formal agreement will be negotiated and executed within
                60 days
                of receipt of the Letter of Intent, in order for MDS Pharma Services
                to
                proceed with the project.

            


    

     

    
      	
            	 ̈	
              The
                currency to be used for invoicing and payments is detailed in the
                budget
                attached. Where MDS Pharma Services incurs Pass-Through Expenses
                or
                Investigator Grants in a currency differing form that used for invoicing,
                these will be translated using the exchange rates prevailing at the
                invoice date. The initial exchange rates used as a basis for calculating
                MDS Pharma Services’ professional fees (the “Budgeted Rates”) are: 1,44 €
                for 1£ and 0,77 € for 1 $US. Each calendar quarter, the average actual
                exchange rate (the “Current Rate”) will be computed for each currency,
                based on the spot rates on the last day of each of the 3 months in
                the
                quarter under review, as quoted by the website, www.oanda.com.
                If the amount invoiced for professional fees during the calendar
                quarter
                calculated at the Current Rates differs from that calculated at the
                Budgeted Rates by more than two percent (2%), MDS Pharma Services
                shall
                issue a separate invoice or credit note for the
                difference.

            


    

     

    
      
        
        

      

      
        23

        
          

        

      

      
        
        

      

      
        
          


          
            	
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                      8

                  	
                    

                  


          

           

        

      

    

    4.3.
      Optional Costs

     

    
      	 	
              No
                of Units

            	
              Type
                of Unit

            	
              Unit
                Price (EUR)

            	
              TOTAL
                (EUR)

            	
              Comments

            
	
              Hospitals
                Payments costs

            	 
	
              Payments
                

            	
              1

            	
              payment

            	
              95
                

            	
              -
                

            	
              Per
                payment, except for Italy (directly managed by
                Gentium).

            
	
              Annual
                Safety Reports

            	 
	
              Preparation
                and submissions of annual reports to authorities 

            	
              1

            	
              report

            	
              TBD
                

            	
              TBD

            	 
	
              Training

            	 
	
              Team
                Training (Webex)

            	
              1

            	
              training

            	
              1
                855

            	
              1
                855

            	 
	
              Investigator
                Meeting

            	 
	
              Investigator
                Meeting Organisation 

            	
              1

            	
              meeting

            	
              -

            	
              1
                680 

            	
              MDSPS’
                IPD will liaise with a meeting planner to organise a unique investigators
                meeting in Germany. 2 investigators per site, MDSPS’ IPD and Gentium team
                members will attend this one-day meeting. Please refer to pass-through
                costs for meeting budget.

            
	
              Investigator
                Meeting Preparation 

            	
              1

            	
              meeting

            	
              -

            	
              2
                662

            	 
	
              Investigator
                Meeting Attendance 

            	
              1

            	
              meeting

            	
              -

            	
              2
                272

            
	
              Project
                Management (Extra)

            	 
	
              CoSMOS
                updates and 

              Filing
                

            	
              -

            	
              -

            	
              -

            	
              9
                837

            	
              We
                assumed 153 patients for CoSMOS updates and 48 months for
                filing.

            
	
              Project
                Team Training

            	
              1

            	
              meeting

            	
              1
                704 

            	
              1
                704

            	
              We
                assumed the preparation of one meeting to be held in MDSPS’ office in
                Italy. All 3 (assumption) CRAs will participate.

            
	
              Project
                Team Interaction

            	
              48

            	
              months

            	
              1
                142 

            	
              54
                800

            	
              We
                assumed a 3 CRA team and monthly teleconferences. The cost includes
                teleconference minutes. Monthly teleconferences are required to manage
                these additional countries (not MDSPS CRAs).

            
	
              Reports
                Review 

            	
              136

            	
              reports

            	
              71
                

            	
              9
                656

            	
              We
                assumed 6 monitoring, 1 initiation and 1 close out visits per site
                (17
                sites in total).

            
	
              Co-monitoring
                visits 

            	
              3

            	
              visits

            	
              2
                130 

            	
              6
                390

            	
              One
                visit per country/CRA. Pass-through costs not included.

            
	
              Additional
                cost for Status
                Report writing 

            	
              16

            	
              reports

            	
              207
                

            	
              3
                312

            	
              Additional
                time for IPD and CTA, to be included in line item Status Reports.
                Monthly
                reports will be required to manage these additional countries (not
                directly monitored by MDSPS).

            


    

     

    
      
        
        

      

      
        24

        
          

        

      

      
        
        

      

    

    
      
        


        
          	
                  GENTIUM
                    - VOD - Defibrotide Study - Proposal no. AA2618420 - Version
                    8

                	
                  

                


        

         

        
           

          
            	 	
                    No
                      of Units

                  	
                    Type
                      of Unit

                  	
                    Unit
                      Price (EUR)

                  	
                    TOTAL
                      (EUR)

                  	
                    Comments

                  


          

        

      

    

    
      	
              Co-monitoring
                visits

            	 
	
              Co-monitoring
                visits 

            	
              7

            	
              visits

            	
              2
                130 

            	
              14
                910

            	
              1
                co-monitoring visit per country.

            
	
              EC
                Amendment Submission

            	 
	
              Italy
                

            	
              1

            	
              submission

            	
              731
                

            	 	
              Gentium
                will provide MDSPS with the final text of the
                amendment.

            
	
              France
                

            	
              1

            	
              submission

            	
              737
                

            	 	
              Gentium
                will provide MDSPS with the final text of the
                amendment.

            
	
              Netherlands
                

            	
              1

            	
              submission

            	
              821
                

            	 	
              Gentium
                will provide MDSPS with the final text of the
                amendment.

            
	
              UK
                

            	
              1

            	
              submission

            	
              760
                

            	 	
              Gentium
                will provide MDSPS with the final text of the
                amendment.

            
	
              Sweden
                

            	
              1

            	
              submission

            	
              836
                

            	 	
              Gentium
                will provide MDSPS with the final text of the
                amendment.

            
	
              Ireland
                

            	
              1

            	
              submission

            	
              760
                

            	 	
              Gentium
                will provide MDSPS with the final text of the
                amendment.

            
	
              Israel
                

            	
              1

            	
              submission

            	
              761
                

            	 	
              Gentium
                will provide MDSPS with the final text of the
                amendment.

            
	
              ICF
                Adaptation

            	 
	
              Italy
                

            	
              1

            	
              adaptation

            	
              360

            	 	 
	
              France
                

            	
              1

            	
              adaptation

            	
              380

            	 	 
	
              Netherlands
                

            	
              1

            	
              adaptation

            	
              460

            	 	 
	
              UK
                

            	
              1

            	
              adaptation

            	
              409

            	 	 
	
              Israel
                

            	
              1

            	
              adaptation

            	
              380

            	 	 


    

    


    4.4.
      Variable Costs

     

    
      	 	
              No
                of Units

            	
              Type
                of Unit

            	
              Unit
                Price (EUR)

            	
              TOTAL
                (EUR)

            	
              Comments

            
	
              Study
                Initiation

            	 
	
              Drug
                / Supplies Shipment Tracking 

            	
              1

            	
              shipment

            	
              86

            	 	
              Corresponds
                to each additional shipment (1 per site costed in global
                budget).

            
	
              SAEs
                Reporting to Sponsor / SAE notification to EC
                and Investigators

            	 
	
              Italy
                

            	
              1

            	
              SAE/
                Notification

            	
              180

            	 	 
	
              France
                

            	
              1

            	
              SAE/
                Notification

            	
              190

            	 	 
	
              Netherlands
                

            	
              1

            	
              SAE/
                Notification

            	
              230

            	 	 


    

     

    
      
        
        

      

      
        25

        
          

        

      

      
        
        

      

    

    
      
        


        
          	
                  GENTIUM
                    - VOD - Defibrotide Study - Proposal no. AA2618420 - Version
                    8

                	
                  

                


        

         

        
           

          
            	 	
                    No
                      of Units

                  	
                    Type
                      of Unit

                  	
                    Unit
                      Price (EUR)

                  	
                    TOTAL
                      (EUR)

                  	
                    Comments

                  


          

        

      

    

    
      	
              UK
                

            	
              l

            	
              SAE/
                Notification

            	
              205

            	 	 
	
              Sweden
                

            	
              l

            	
              SAE/
                Notification

            	
              230

            	 	 
	
              Ireland
                

            	
              l

            	
              SAE/
                Notification

            	
              205

            	 	 
	
              Israel
                

            	
              1

            	
              SAE/
                Notification

            	
              190

            	 	 
	
              Project
                Management

            	 
	
              Sponsor
                Meeting 

            	
              l

            	
              meeting

            	
              1
                704

            	 	
              This
                half-day meeting will take place in Gentium office in Italy. MDSPS’ IPD
                will attend (2 hours for preparation, 4 hours for attendance and
                2 hours
                for meeting minutes). Travel and accommodation costs not
                included.

            
	
              Monitoring
                visits

            	 
	
              Italy
                

            	
              l

            	
              visit

            	
              1
                511

            	 	
              Includes
                report review by the IPD.

            
	
              France
                

            	
              1

            	
              visit

            	
              1
                211

            	 	
              Includes
                report review by the IPD.

            
	
              Netherlands
                

            	
              l

            	
              visit

            	
              1
                911

            	 	
              Includes
                report review by the IPD.

            
	
              UK
                

            	
              l

            	
              visit

            	
              1
                175

            	 	
              Includes
                report review by the IPD.

            
	
              Sweden
                

            	
              l

            	
              visit

            	
              1
                911

            	 	
              Includes
                report review by the IPD.

            
	
              Ireland
                

            	
              1

            	
              visit

            	
              1
                175

            	 	
              Includes
                report review by the IPD.

            
	
              Israel
                

            	
              l

            	
              visit

            	
              1
                401

            	 	
              Includes
                report review by the IPD.

            


    

    


    4.5.
      Estimate of Pass-through Costs

     

    
      	 	
              No
                of

              Units

            	
              Type
                of

              Unit

            	
              TOTAL

              (EUR)

            	
              Comments

            
	
              Translations

            	 
	
              Protocol
                Synopsis Translation (Sweden only) 

            	
              1

            	
              language

            	
              TBD

            	 
	
              ICF
                Adaptation and Translation 

            	
              2

            	
              adaptation
                with/without translation

            	
              TBD

            	 
	
              Travel
                (accommodation not
                included)

            	 
	
              Project
                definition meeting 

            	
              1

            	
              meeting

            	
              110

            	
              This
                one-day meeting will take place in Gentium office in Italy. MDSPS’ IPD
                will attend.

            
	
              Sponsor
                meeting 

            	
              1

            	
              meeting

            	
              110

            	
              This
                half-day meeting will take place in Gentium office in Italy. MDSPS’ IPD
                will attend.

            
	
              Project
                team training 

            	
              1

            	
              meeting

            	
              6
                864

            	
              This
                one-day meeting will take place in MDSPS’ office in Italy. MDSPS’ IPD and
                CRAs will attend.

            
	
              Initiation
                and close-out visits
                

            	
              26

            	
              visits

            	
              25
                000

            	
              13
                sites, 1 initiation and 1 close-out visit per site. 1 co-monitoring
                (optional) visit per country.

            
	
              Monitoring
                and co-monitoring visits 

            	
              85

            	
              visits

            


    

     

    
      
        
        

      

      
        26

        
          

        

      

      
        
        

      

    

    
      
        


        
          	
                  GENTIUM
                    - VOD - Defibrotide Study - Proposal no. AA2618420 - Version
                    8

                	
                  

                


        

         

        
           

           

        

      

    

    
    

     

    
      	
               

            	
              No
                of 

              Units

            	
              Type
                of Unit

            	
              Total

              (EUR)

            	
              Comments

            
	Monitoring
              Activities	 
	
              Hospitals
                fees 

            	
              13

            	
              sites

            	
              TBD

            	 
	
              Meeting
                Planner

            	 
	
              Investigator
                meeting 

            	
              TBD

            	
              TBD

            	
              TBD

            	
              MDSPS’
                IPD will liaise with a meeting planner to organise a unique investigators
                meeting in Germany. 2 investigators per site, MDSPS’ IPD and Gentium team
                members will attend this one-day meeting.

            
	
              EC/Regulatory
                Fees

            	 
	
              Sweden
                

            	
              -

            	
              -

            	
              10
                298

            	 
	
              UK
                

            	
              -

            	
              -

            	
              TBD

            	 
	
              Ireland
                

            	
              -

            	
              -

            	
              2
                350

            	 
	
              Courier
                and document shipments

            	 
	
              Investigators
                file 

            	
              13

            	
              sites

            	
              TBD

            	 
	
              Extra-ordinary
                courier 

            	
              -

            	
              -

            	
              TBD

            	 
	
              Import
                Drug Company 

            	
              -

            	
              -

            	
              TBD

            	
              France
                only.

            
	
              Central
                Pharmacy 

            	
              -

            	
              -

            	
              TBD

            	
              The
                Netherlands and Sweden only.

            


    

    


    These
      pass-through costs will be invoiced to GENTIUM
      as
      incurred, plus a 5% handling charge. List for information only and not
      exhaustive.

     

    4.6.
      Payment Schedule

     

    Professional
      Fees

     

    MDS
      Pharma Services has invoiced to Gentium an upfront payment (55
      685
      Euros) at Letter of Intent signature. Once the upfront payment balances the
      production, MDS Pharma Services will invoice the actual monthly
      production.

     

    Variable
      / Optional costs and Pass-Through Costs

     

    These
      costs will be invoiced as incurred, on a monthly basis.

     

    Appendix
      1 - Curriculum Vitae

     

    Agostino
      Lazzaro
      has more
      than 20
      years of
      experience in the medical environment and more than 10
      years of
      experience in clinical research. He has already participated to 23
      clinical
      studies and managed many of them. Based in our Italian office, he will be
GENTIUM’s
      main
      contact during this study.

     

    

     

    Please
      double click on the icon to open the file.

     

    
      
        
        

      

      
        27