CCTU TPL010 DMC charter

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CCTU TPL010 DMC charter Powered By Docstoc
					        The bold headings throughout the document should remain in the document.
        The information in red within the headings is for guidance only and should be
        deleted once the trial specific information has been inserted.



        Document Title:
        The document title should reflect the name and scope of the committee. Possible
        suggestions are:

                 Data Monitoring Committee Charter
                 Independent Data Monitoring Committee Charter
                 Data Monitoring and Ethics Committee Charter
                 Trial Monitoring Committee Charter
                 Data and Safety Committee Charter

        “Data Monitoring Committee Charter” is recommended.
        The acronym DMC is used throughout this template if a different title is used the
        template must be revised accordingly.




        Study Title
        Short Study Name
        R&D Number
        EUdract Number
        Sponsor
        Version of the Document
        Date of the current version




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                       INDEX



              1. Introduction to the DMC Charter

              2. Abbreviations

              3. Purpose of the DMC Charter

              4. Confidentiality

              5. Sponsor Confidentiality

              6. DMC Confidentiality

              7. Purpose of the DMC

              8. DMC Composition

              9. DMC Responsibilities

              10.       DMC Responsibilities Related to Trial Adaptation

              11.     DMC Meeting Structure and Communications

              12.     The Organisation of The Study Team

              13.     Responsibility of the The Study Team

              14.     The Composition of the Independent Statistical Center (ISC)

              15.     The Responsibilities of the ISC

              16.     Organizational Diagram of DMC, ISC, and Trial Steering
                       Committee

              17.     Information Available to DMC

              18.     Access to Data

              19.     Close Out Activities




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              1. Introduction to the DMC Charter

        GUIDANCE: The Introduction to the DMC Charter should contain a brief
        summary of the trial purpose and design, identify the trial’s sponsor(s), and
        state the purpose of the DMC charter itself.
        This section should include:
             The name and objectives of the clinical trial,
             A brief description of the study in the context of the overall development
               plan
             Whether there is a confirmatory component to the trial
             A brief description of the type of adaptive design, the owner(s) of the
               compound or device, and the sponsoring organization(s).
             The administrative structure should be briefly described identifying:
                   o The sponsor(s),
                   o The independent statistical centre (ISC),
                   o Other stakeholders,
                   o Participating contract research organization(s) (CROs),
                   o The steering committee, as appropriate.

           2. Abbreviations
        Add as appropriate
        CRO(s)           Contract Research Organization(S)
        DMC              Data Monitoring Committee
        FDA              Food and Drug Administration
        IRB              Institutional Review Board
        ISC              Independent Statistical Centre
        SAEs             Serious Adverse Events
        SAP              Statistical Analysis Plan




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              3. Purpose of the DMC Charter
        GUIDANCE: This section should briefly reiterate the purpose of the DMC Charter itself,
        namely to define the roles, responsibilities, and activities of the DMC trial, steering
        committee, sponsor, CRO(s), ISC, and other participating entities and/or individuals
        during the conduct of the planned adaptive clinical trial.


              4. Confidentiality
        GUIDANCE: This section should explicitly list information to be kept confidential above
        and beyond the usual standard confidentiality agreement.


              5. Sponsor Confidentiality
        GUIDANCE: The Charter should identify materials possessed by or available to the
        sponsor, either at the beginning of the trial or created during trial conduct (e.g., data
        reports), that are to remain confidential.
        In order to implement an adaptive trial, the sponsor may require access to information
        to which it would not normally have access and that, if released more broadly to study
        participants or clinical investigators, could compromise the integrity or feasibility of the
        trial. Further, different functional entities within the sponsor (e.g., the clinical trial team,
        statistical analysis team, drug supply team) may require access to information with
        different levels of blinding and, in such cases, the sponsor should define those personnel
        allowed access to unblinded or similar data and document their commitment to and
        procedures for maintaining data security and confidentiality.
        This section should identify:
            Categories of confidential materials related to the trial and the sponsor
               personnel authorized to access those materials (if any)
            Any functional units within the sponsor that will have access to
               confidential information
            Define whether the membership of the DMC will be considered confidential
               and, if so, identifying the non-sponsor entities to whom the DMC
               membership will be disclosed (e.g., clinical study sites, IRBs, FDA).

              6. DMC Confidentiality
        GUIDANCE: All DMC membership must maintain the confidentiality of proprietary
        information and other intellectual property, including both blinded and unblinded clinical
        trial data, as well as the content of DMC deliberations that occur during closed sessions.
        This section should include:
            Statements to the effect that all DMC members will sign standard
               confidentiality agreements
            That DMC members will not delegate their responsibilities to others or
               share access to data tables and results with persons outside the DMC, and
               that all user names and passwords will remain confidential
            The disposition of all confidential study materials (e.g., protocols, interim
               data reports) at the close of the study should be defined. For example, the
               DMC members might be instructed to destroy all paper and electronic
               documents, or to return paper documents to the sponsor, depending on
               applicable legal and regulatory considerations




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                 Describe the rights of DMC members to publish, present or communicate
                  trial-related information following completion of the trial

              7. Purpose of the DMC
              GUIDANCE: The recommendations of the DMC are advisory to the sponsor or the trial
              steering committee.
              The purposes of the DMC include:
               Providing oversight of the trial to ensure subjects are protected from
                 avoidable harm
               Maintaining trial integrity
               Providing review of planned or pending trial adaptations, including
                 verifying the face validity of the adaptations suggested by the predefined
                 trial design based on review of both unblinded safety and efficacy data;
               Making recommendations concerning further conduct of the trial, such as
                 the application of pre-specified adaptation rules (e.g. changes in
                 treatment allocation ratios, dynamic termination), or trial modification(s)
                 based on consideration of efficacy, safety, and/or futility.
               Consideration of disease specific issues
               Consideration of any regulatory issues
               Consideration of any ethical issues
               Consideration of any other issues specific to the treatments
              This section should briefly state:
               The overall purpose of the DMC, namely the protection of human subjects
                 and maintenance of trial integrity, and identify the purpose and role of the
                 DMC with respect to the review of interim data and the decision process to
                 implement planned trial adaptation(s)
               The advisory nature of DMC recommendations should be clearly
                 established

              8. DMC Composition
        GUIDANCE: This section should describe the membership of the DMC
            The required qualifications of the DMC members
            The relationship(s) of members to the sponsoring organization(s).
            In the setting of a confirmatory adaptive trial, DMC membership will generally
              exclude employees of the sponsor or other interested parties. However, to
              provide appropriate oversight of an adaptive trial, especially if the trial is
              particularly complex, innovative, or intended to span multiple phases in
              development, the DMC will need ready access to trial design and scientific domain
              expertise, which may only exist within the sponsoring organization.
             Types of adaptation decisions that might justify more direct sponsor/study team
             participation on the DMC include:
            The need to implement inherently complex decisions too challenging to put into
              an algorithm that could stand up to unexpected complexities arising in the data
            The need to implement decisions which, in traditional (non-adaptive) settings
              have been sponsor responsibilities (for example, selection of dosage or treatment
              formulation for confirmatory investigation, as might typically be done following
              the completion of Phase II)




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               The need to implement decisions for which there may be potential major
                commercial implications, giving the sponsor some unease about placing the
                decision entirely in external hands.
        Further, providing expert, timely, and specific information to the DMC may require that
        selected sponsor employees interact directly with the DMC and/or have access to
        unblinded DMC reports or other data.
        If such interactions are appropriate, then procedures need to be defined to prevent
        unblinded information from being shared with sponsor personnel involved in the conduct
        or administration of the trial
        In unusual circumstances, ensuring required DMC expertise and perspective may require
        that a sponsor employee or other interested party participate fully in DMC deliberations.
        In such a circumstance, the rationale for and risks of such a structure need to be fully
        explained, along with procedures to be used to prevent unblinded information from being
        shared with sponsor/study team personnel involved in the conduct or administration of
        the trial.
        In general, minimal sponsor/study team involvement in DMC activities is preferred to
        avoid both real and perceived loss of DMC independence. During planning the sponsor
        should consider how and why sponsor perspective might be relevant. The rationale for
        any substantive involvement in DMC activities should be explained in the DMC Charter.
        To minimise such involvement one possible approach would be to have only the external
        DMC members meet in a closed session to discuss safety or other issues without sponsor
        influence. A from the sponsor or study team representative would act as an “adjunct”
        member of the DMC, and would be given the least exposure to results and discussions
        necessary to complete his/her role relative to ensuring proper implementation of the
        adaptive decision.
        The DMC chairman should have previous experience serving on a data monitoring
        committee, should be familiar with regulatory concerns, and should be familiar with the
        FDA and EMEA DMC guidance documents. All DMC members, including the chair, should
        have significant clinical and/or drug development experience, and professional expertise
        that best suits the concerns of the study. The membership should include therapeutic
        area clinical experts and a statistician. Other professionals, such as a PK analyst might
        be included if so warranted. Members must have sufficient availability to attend all
        planned meetings and understand the time commitment required for data review for the
        duration of the trial. In particular, they must understand that efficiency of an adaptive
        design requires a speedy review and recommendation at decision points.
        If a formal algorithm is used to determine any adaptations then all members of the
        committee should demonstrate an understanding of the algorithm of the adaptation
        design.
        The statistician should be an individual who is competent in the relevant adaptive design
        methodology and all should be familiar with the general principles of study conduct
        necessary to maintain the integrity and validity of a study in an adaptive design setting.
        In this section, the Charter should state:
             The number of DMC members
             Whether the DMC is internal or external to the sponsor, or includes
                combination of internal and external members
             If any member is internal to the sponsor and, if so, describe the specifics
                of that person’s role and provide a specific justification
             The name and qualifications of the DMC chair
             The names and qualifications of the other DMC members




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               The requirements for the independence of DMC members and include a
                statement regarding conflict of interest
               An appendix containing any disclosures may be included as appropriate
               Procedures to be followed if a committee member needs to be replaced

              9. DMC Responsibilities
        GUIDANCE: The responsibilities of DMCs providing oversight of confirmatory, adaptive
        clinical trials include the usual responsibilities associated with providing oversight of non-
        adaptive confirmatory clinical trials.
        Traditional DMC responsibilities include:
            Making recommendations regarding the ongoing conduct of the trial based
               on unbiased and independent review of efficacy and safety data.
            Review serious adverse events (SAEs) and other pertinent safety and
               efficacy information, using the available data with clinical and statistical
               judgment, to make periodic recommendations to the appropriate body
               (e.g. trial steering committee or sponsor)
            Function independently of all other individuals and entities associated with
               the conduct of the trial
            Maintain documentation and state an expectation regarding the timeliness
               of DMC communications after each meeting

              10.      DMC Responsibilities Related to Trial Adaptation
        GUIDANCE: In addition to traditional DMC responsibilities, the DMC overseeing a
        confirmatory adaptive clinical trial must ensure the planned adaptation is implemented in
        a way that is faithful to the trial design. Is scientifically and ethically valid and maintains
        trial integrity. Attention needs to be paid to the degree with which consideration and
        implementation of adaptation may communicate interim efficacy and/or safety
        information to sponsor personnel and/or investigators at clinical sites, and whether this
        information may influence trial enrollment, the administration of treatments, or the
        assessment of trial outcomes.
        The rules for adaptations generally fall into one of four categories. The four categories of
        decision rules are:
        Allocation Rules: How will subjects be allocated to different arms in the trial?
        Example: Adaptive with the randomization ratio changing from stage to stage, based on
        accruing data. This would also include the decision to drop or add treatment arms.
        Sampling Rule: How many subjects will be sampled at the next stage?
        Example: Sample size re-estimation.
        Stopping Rule: When to stop the trial?
        Example: Stopping a trial for reasons of efficacy, harm, futility, or safety.
        Decision Rule: Design changes not covered by the previous three rules.
        Examples: Updating the model, changing the endpoint, modifying the initial design.
        This section should define:
            The role of the DMC in the context of the planned adaptations in the study
            The DMC is responsible for reviewing the data pertinent to the decision
               rule, and recommending the appropriate modification or adaptation to the
               clinical trial. In some cases, however, the adaptive nature of the trial
               involves the application of a well-defined rule (e.g., dose allocation) and
               the DMC simply verifies the ongoing appropriateness of utilizing the
               adaptation rule as defined in the protocol




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                 Identify the rules that apply to the trial in question, and indicate that they
                  should be carried out in accordance to the algorithm specified in the
                  protocol



              11.       DMC Meeting Structure and Communication
        GUIDANCE: The structure of DMC meetings and the flow of information between the
        DMC, sponsor, and other entities should be defined by the DMC Charter. The parties
        authorized to call a DMC meeting and those responsible for providing logistical support
        should be defined by the Charter.
        This section should:
            Define those responsible for calling a meeting of the DMC
            Agree how often or when meetings are expected to occur either:
                  o Calendar time
                  o Subject accrual
                  o Other trigger points (e.g. complete observations over pre-specified
                      time in a given number of patients)
            Define the responsibilities of:
                  o The DMC chair
                  o DMC members
                  o The sponsor
                  o Independent Statistical Centre (ISC)
                  o The study team as appropriate

        Meeting Structure
        GUIDANCE: DMC meetings will generally be divided into open, closed and occasionally
        executive sessions. These will differ in the number and type of individuals present, and
        the nature and confidentiality of the information being discussed.
        Open sessions may be attended by sponsor employees and other interested parties.
        During open sessions only information of a non-sensitive nature (e.g., fully blinded
        aggregate data) may be discussed.
        Closed sessions may only be attended by DMC members or in select circumstances by
        pre-identified sponsor personnel. Unblinded safety, efficacy, and other data may be
        discussed during closed sessions.
        Executive sessions are attended only by voting DMC members fully independent of the
        sponsor. These may be held to ensure full independence during discussions of sensitive,
        difficult, or particularly subjective issues.
                 Describe whether DMC meetings are to be entirely closed, or whether
                  there will be open sessions during which sponsor employees and other
                  interested parties may be present
                 Define whether executive sessions may be held and whether formal DMC
                  action requires discussion in executive session
                 Identify the DMC members and non-members who may be present at
                  each type of session. For example, will sponsor representatives attend any
                  part of the meeting in person, or are they to be available for contact? If a
                  sponsor representative or other non-DMC member is to participate in the
                  meeting, or be available to address questions, this section of the Charter
                  should discuss whether their involvement is restricted to open sessions



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                 The participation of the ISC statistician and/or study team should also be
                  defined
                  If the ISC statistician does not attend closed sessions, will he/she be
                  made readily available to address questions from the DMC?

        Voting
        GUIDANCE: The requirements for the conduct of DMC business should be defined in the
        Charter and should explicitly consider the potential absence of one or more DMC
        member(s), particularly at an unplanned “for cause” meeting. For example, what
        procedures will be followed if one or more DMC members cannot participate, especially if
        one of those members is the Chair or the DMC statistician? A quorum of the DMC must
        be defined, although the general expectation is that all DMC members be present at
        planned meetings. Even at unplanned meetings, it is highly desirable that both the chair
        and the DMC statistician be present.
                 This section should define who will be allowed to vote—typically voting is
                  restricted to DMC members fully independent from the sponsor.
                 A strong rationale must be provided if non-members, sponsor employees,
                  or other interested personnel are to be allowed to vote
                 A quorum of the DMC and a decision-making majority should be defined
                  An explicit statement of what decisions or advice must be provided by the
                  DMC as the conclusion of a DMC meeting

        Communication
        GUIDANCE: As the DMC must have access to privileged information DMC communication
        procedures should be defined by the Charter. In general, all DMC communications should
        be initiated by, and routed through, the Chair. Finally, the adaptive design may require
        certain specific communications from the DMC (e.g., the selection of a specific dose to
        carry forward) and such required communications should be identified in the Charter. In
        an adaptive design study, the DMC is expected to verify the face validity of adaptations
        proposed by the algorithm and, where appropriate, endorse the recommendation coming
        from the algorithm and pass the recommendation on to the trial steering committee or
        the sponsor for implementation, as defined in the Charter.
        Recommendations may include changes in treatment allocation, stopping of a treatment
        arm either for safety or futility, opening of a new treatment arm, or stopping of the
        entire trial for safety, futility or efficacy. All of these potential changes should be
        predefined in the trial protocol. To minimise potential bias, the recipient(s) of DMC
        recommendations must be limited to the individual(s) who will decide whether to
        implement the change(s).
        This section should define:
            Expected or acceptable pre-meeting communications, such as requests
               from the DMC for clarification or further information from a sponsor
               expert. Generally the DMC chair will initiate such communications
               How communication with the sponsor representatives or sponsor experts
               will occur while the meeting is in progress, and describe the DMC
               communications to the sponsor following the meeting. For example, how
               soon after a DMC meeting must a written recommendation be provided?
            List the person(s) who will receive communications from the DMC, and the
               relationship of those person(s) to the sponsor




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                 The route of communication and the identity of the authorized recipient of
                  DMC recommendations must be identified, especially when the DMC
                  recommendation to adapt or modify the trial may indirectly communicate
                  efficacy or safety information



        Meeting Minutes
        GUIDANCE: Meeting minutes must be prepared promptly, reviewed for accuracy by DMC
        members, and circulated according to the meeting structures (open, closed, executive).
        In general, minutes of open sessions may be distributed to the trial steering committee,
        other interested parties, and regulators. During the conduct of the trial, minutes of
        closed or executive sessions are distributed only to DMC members or only DMC members
        participating in executive sessions, depending on the structure of the DMC and the
        requirements of the trial. Once the trial is closed (i.e. the final database frozen), all DMC
        minutes (open and closed) should be made available to the sponsor.
        This section should define:
            The individual(s) who will prepare the minutes for the open and closed
               sessions
            The sponsor or CRO personnel will prepare minutes of open sessions
            The DMC Chair will prepare minutes of closed and executive sessions
            The timeframe within which minutes have to be prepared and circulated
            Frequently
            Who will receive minutes of executive, closed and open sessions, and who
               will receive minutes of open sessions only




              12.       The Organization of Study Team
        GUIDANCE: The purpose of this section is to describe the role of the study team in the
        clinical trial, and the structure of study team. The trial steering committee, the group
        that interacts with and receives DMC recommendations should be explicitly identified.
        This section should:
            Identify all organizations providing financial support for the trial
            Describe whether the trial steering committee only includes employees of
               the sponsor or study team, or includes external members
            The roles and titles of members of the trial steering committee should be
               listed
            Assert that members of the project team should remain blinded during
               trial conduct.

              13.       Responsibility of the Study Team
        GUIDANCE: List those activities in support of the DMC that are the responsibility of the
        study team. In an adaptive clinical trial, study conduct and data handling may be
        influenced, even unintentionally, by knowledge of actions taken as a result of interim
        results. Distance between the study team and these activities may lend credence to the
        integrity of the study. If the objective of a clinical trial is to confirm the benefit of a
        treatment for submission for regulatory approval, contracting all or part of these




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        activities to an independent organization should be considered as a way to avoid
        potential reviewer scepticism.
        This section should state that the study team is responsible for:
             The designation of the trial steering committee
             The conduct and operational monitoring of the trial
             The collection and quality assurance of trial data
             The provision of data and reports to the DMC in a timely fashion
             To ensure that treatment codes are handled in a manner to insure that
               the required level of blind remains intact
             The appointment of any independent external contract organization(s)
               that may perform any of the above activities on the sponsor’s behalf
             Provide regular updates to the DMC Chair on enrolment, study completion,
               and a projection of when the data review might occur
             Planning DMC meetings to occur at intervals defined by the amount of
               data available or the number of endpoint events, the members will need
               prior warning to schedule time for review and travel (if necessary)

              14.       The Composition of the Independent Statistical Centre (ISC)
        GUIDANCE: The ISC includes statistician(s) and programmer(s) who are independent of
        the study and unblinded during trial conduct. The ISC provides unblinded reports to the
        DMC. The DMC Charter should identify the individuals or organization providing
        independent statistical or programming services to the DMC and describe the
        relationship to the study team. Contact information and affiliation should be detailed in
        an appendix.
        The ISC can be set up as a function within the study team, as long as appropriate
        firewalls are put in place to ensure that no unblinded data are accessible by personnel
        involved in the conduct of the trial, or the ISC can be set up as a function external to the
        sponsor.
                 Identify the ISC members(s), the role of each
                 Describe the relationship of the ISC to the sponsor, and the level of
                  independence to the trial conduct. If the ISC is internal to the sponsor,
                  describe the organizational relationship, physical distance from those
                  directly involved in study conduct and the nature of the data firewall(s).
                 Discuss the participation of the ISC statistician at DMC meetings, including
                  attendance at open or closed sessions or alternative availability.
                 Describe how blinding in the study team will be maintained as
                  appropriate.

              15.       The Responsibilities of the ISC
        GUIDANCE: The DMC Charter should list the activities and expectations for the ISC.
        The Charter should state that:
            The ISC will maintain a file containing the unblinded treatment codes and
              will merge these with data received from the sponsor or the CRO(s)
            The ISC is responsible for the generation of data reports, summary tables,
              and statistical analyses for the DMC, subject to agreed timelines
            The ISC must produce any additional ad-hoc reports requested by the
              DMC




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                 Clarification from the sponsor about data in such a way as to avoid
                  communicating any patterns that may be evident in the unblinded data.
                 The DMC may ask the ISC to further search the data or provide
                  clarification when necessary
                 Whether the ISC statistician or other personnel are required to be
                  available at open or closed sessions of DMC meetings



              16.    Organizational Diagram of DMC, ISC, and Trial Steering
                 Committee
        GUIDANCE: Provide a diagram that identifies each organization involved in the DMC,
        including sponsor relationships, and the flow of communications.
        The Organizational Diagram in this section should illustrate:
            The flow of the data
            The level of blind
            The communications between the DMC and trial steering committee
            Denote whether the ISC is:
                 o Completely independent to the sponsor,
                 o Internal to the sponsor, or
                 o Internal to an organization managing the data or monitoring of the
                     sites.
            Identify all sources of information that the DMC will review.
                 o Affiliations,
                 o Contact information
                 o Details regarding the DMC members and Steering Committee
            The ISC will generally be part of an appendix, and need not be included in
              the organizational diagram.
        The organizational structure may vary from one trial to another.




        An example diagram to illustrate a suggested format. Delete from final
        document




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              17.      Information Available to the DMC
        GUIDANCE: In this section, the DMC Charter should describe the information to be made
        available to the DMC, the format(s), and delivery timings.
               List the documents that will be provided to the DMC before the trial
                begins.
                    o The study protocol,
                    o The DMC Charter,
                    o An adaptive design simulation report, and
                    o The Statistical Analysis Plan for the DMC (DMC SAP), including
                    o The agreed data presentation in the form of mock-up tables.
                    o Educational materials related to the specifics of the adaptive design,
                        as relevant for potential decision-making
               Specifically state when the DMC members should expect to receive reports
                in relation to scheduled meetings
               How reports will be delivered
               How unblinding will be managed
               Describe the secure delivery system by which the reports will be sent (e.g.
                encrypted email attachments, courier)
               Describe the level of data cleaning required by the DMC for interim
                reviews
               List the type of data to be included and the general format of tables and
                graphical displays




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               It is recommended, that with the exception of individual subject listings
                 for SAEs, data should be displayed as summary tabulations and graphical
                 displays by treatment group. As the trial is still in progress, displays
                 should present the number of subjects within each treatment group
                 currently at each visit, as well as the number entering and completing the
                 study phase
               Specifically mention the data, statistical analysis, tables and graphics that
                 the DMC will require to consider a recommendation for adaptation

              18.      Access to Data
        GUIDANCE: The purpose of this section of the Charter is to describe the flow of data,
        how access to the data is protected, and how the blind is protected. Confirmatory trials
        require strict restriction of access to data, results, and unblinded information.
        Describe the flow of data:
            Who will touch the data
            The level of blinding at each transfer point
            A flow chart is an effective mechanism to provide clarity for this
               potentially complicated process
            Discuss the role of individuals who touch the data, and strictly limit the
               access accordingly
            Include a description of procedures utilised to insure restricted access
            The Charter may refer to SOPs and documented firewalls where applicable

              19.      Close Out Activities
        GUIDANCE: The Charter should describe the actions required by the DMC once the
        clinical trial has been terminated and DMC data monitoring is no longer required.
        The Charter should:
            Provide a time frame by which the DMC Chair is required to send all
              meeting minutes
            Including closed minutes to the sponsor once the trial has officially
              terminated
            Also provide a time frame by which the DMC must return or verify
              destruction all confidential information including electronic information
        Suggested content of DMC open and closed reports

        Open Statistical Report: An Outline
           One page outline of the study design, possible with a schema
           Statistical commentary explaining issues presented in Open Report figures
             and tables
           DMC monitoring plan and summary of Open Report data presented at
             prior DMC meetings
           Major protocol changes
           Information on patient screening
           Study accrual by month and by institution
           Eligibility violations
           Basline characteristics (pooled by treatment group)
                 o Demographics



CCTU/TPL010                                              Version No.1   Approved: 07/03/2012   Page 14 of 15
                     o Laboratory values and other measurements
                     o Previous treatment usage and other similar information
                 Days between randomisation and initiation of treatment
                 Adherence to medication schedule (pooled by treatment group)
                 Attendance at scheduled visits (pooled by treatment group)
                 Reporting delays for key events(pooled by treatment group)
                 Length of follow-up data available (pooled by treatment group)
                 Participant treatment and study status (pooled by treatment group)

        Closed Statistical Report: An Outline
            Detailed statistical comment explaining issues raised by Closed Report
             figures and tables (by coded treatment group, with codes sent to DMC
             members by a separate mailing)
            DMC monitoring plan and summary of Closed Report data presented at
             prior DMC meetings
            Repeat of the Open Report information, in greater detail by treatment
             group
            Analyses of primary and secondary efficacy endpoints
            Subgroup analyses and analyses adjusted for baseline characteristics
            Analyses of adverse events and overall safety data
            Analysis of lab values, including basic summaries and longitudinal
             analyses
            Discontinuation of medications
            Information on crossover patients.




CCTU/TPL010                                           Version No.1   Approved: 07/03/2012   Page 15 of 15

				
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