Neuro-Ophthalmology Research Disease Investigator Consortium (NORDIC) POLICIES

Summary

The Neuro-Ophthalmology Research Disease Investigator Consortium (NORDIC), stands as a specialized clinical research organization, created to facilitate the performance of multi-site observational and treatment trials aimed at addressing the many crucial yet unanswered questions concerning risk, diagnosis, treatment and management of Neuro-ophthalmological conditions.  Consciously devised to provide organization and operational capacity to researchers in academia, industry, government and non-profit institutions, NORDIC promotes the pursuit of innovative clinical research through the connection of resources that historically stood as a barrier to the performance of such trials.  With the planned inclusion of nearly 100 certified clinical trial sites located throughout the US and Canada (and future expansion to Europe, Israel and Australia), NORDIC unites the most esteemed specialists and sub-specialists devoted to the research of scientific and medical issues affecting vision, eye movements, pupil function, and visual quality of life. 

Neuro-ophthalmology is a subspecialty of Neurology and Ophthalmology that is concerned with scientific and medical issues that bridge both specialties.  Neuro-ophthalmologists consult, diagnose, and manage subjects with disorders that are problems for other physicians and, as such, this subspecialty is the repository for most complex systemic and neurological diseases that affect vision.  Almost no prospective information exists on a myriad of Neuro-ophthalmologic disorders; and with the lack of precise historical data on the visual and systemic health, ophthalmologists, neurologists, internists and family practitioners continue to perform many unnecessary, expensive, and potentially invasive tests and to treat subjects without evidence-based medicine guidance.  This can result in initiating therapies that can be hazardous without a clear rationale.

Many of these Neuro-ophthalmologic illnesses, although uncommon, have devastating affects on affected individuals.  Individual or small groups of Neuro-ophthalmologic investigators typically do not evaluate enough subjects with most of these disorders to recruit an adequate number of subjects to answer the many unanswered questions about visual outcome, relation to systemic illness, and effectiveness of current and future therapeutic interventions that require multi-site observational and treatment trials.  Establishing a consortium with a formal organization, single data coordination and biostatistics center and a network of investigators will permit the majority of Neuro-ophthalmologists to participate in multi-site observational and treatment trials, facilitate the integration of new medical/scientific concepts, and ensure recruitment of the necessary number of subjects for each study.  Moreover, this consortium and network will allow long range observational studies to be included, in order to collect prospective data so that the more expensive and focused treatment trials will be designed or provide answers without a more expensive single purpose clinical trial.

The precision of measuring visual outcomes can be used to pilot test many agents used to treat central nervous system disease or adversely affect the brain.  The efficiencies and cost-savings of using one data coordination and biostatistics center and having one organizational framework to foster, develop, and administer multiple studies are obvious.  Investigators will be trained, certified for participation in treatment trials and observational investigations, and update on procedures and study results at an investigator meeting at least once a year.  Additionally, we will have a single quality of life subcommittee to extend existing vehicles and develop new approaches that address visual disability.

Background

To establish an independent open organization, it was decided that NORDIC should be created as an entity.  The NORDIC Executive Committee (EC) was formed in November 2002. The EC included several members of the Research committee, with Dr. Karl Kieburtz appointed as Director of the Data Coordination and Biostatistics Center for NORDIC, and Dr. Kupersmith was named Network Chairman.  The EC members were chosen by the Network Chair, co-Chair, President of NANOS, and President Elect of NANOS based their on experience, research skills, and interest demonstrated during the initial planning period.  Dr. Deborah Friedman was added to the EC to help in the preparation of the various manuals of procedures and assist the DCBC.  All EC members agreed to develop the proposed structure for the consortium research network.

The EC chooses a Study Director (SD) for each protocol and guides the composition of each Study Steering Committee (SSC) for the first three proposed studies. The EC has designated two core NORDIC reading centers, Visual Field Reading Center (VFRC) at the University of California at Davis under the direction of John Keltner, MD and a Photography Reading Center (PRC) at the University of Rochester under the direction of Steven Feldon, MD, MBA.

Organizational Structure

The organizational structure of the NORDIC Network (see below) is composed of the Executive Committee, with Chairperson Mark J. Kupersmith, M.D. at Roosevelt Hospital, Beth Israel Medical Center and New York Eye and Ear Infirmary, Network Co-Chair Neil Miller, MD at Wilmer of Johns Hopkins Medical Center, and representation from three additional entities: the Data Coordination and Biostatistics Center (DCBC), an NEI appointed Data and Safety Monitoring Committee (DSMC) that will oversee all studies and the network operations in conjunction with the DCBC, and certified NORDIC Investigators/Sites.  Each major protocol has a Study Steering Committee and a Study Director (ad hoc members of EC) to develop and direct each study.  The directors of the NORDIC Visual Field Reading Center and Photography Reading Center will are also ad hoc members of the EC.  The DCBC for NORDIC is located at University of Rochester, Department of Neurology, under the direction of Karl Kieburtz, MD, MPH (DCBC Director) with Michael McDermott, PhD as the DCBC Co-Director, directing the biostatistics group and Deborah Friedman, MD as co-investigator.

A.  Executive Committee of NORDIC Network (EC)

The Executive Committee (EC) will have overall responsibility for developing, maintaining and directing all of the activities and organization of NORDIC, directed by the NORDIC Network Chairman.  The EC will have a strong commitment to expand program development, encourage new investigator participation, and bring new concepts for implementation in the Network.

The Executive Committee is responsible for formulating general NORDIC policies. Included in its responsibilities are the following:

  • Develop requirements for Investigators to be members of NORDIC. In concert with DCBC and Steering Committee for a Specific Study, develop requirements to give temporary status for Investigators for that Study.
  • Develop uniform examination and history protocols for NORDIC that can be adapted for each study
  • Train and certify Investigators with assistance of the Study Steering Committee in new evaluation methods.
  • Solicit ideas for new studies from Investigators and other sources
  •  Host an annual Investigator meeting to accomplish the four goals above
  • Critique and guide protocol development
  • Provide guidance in prioritizing new protocols or studies that should be developed
  • Select Study Planning/Steering Committee members and a Study Director (SD) for each major protocol to be developed
  • Review the topics for any new trials that are generated by NORDIC members or a specific Study Steering Committee, or by the EC members themselves
  • Review and approve all ancillary studies
  • Review problems that develop for which a Study Steering Committee requests guidance
  • Develop and maintain a program of quality assurance in the study*
  • Monitor the performance of participating Investigators*
  • Assist Investigators in developing data collection studies not requiring funding
  • Enforce the NORDIC Editorial Policy/Critique major manuscripts prior to their submission to a journal
  • Supervise the dissemination of results and guidance from NORDIC studies
  • Identify potential funding sources
  • Identify and select DCBC, Visual Field Reading Center (VFRC), Photography Reading Center (PRC), and other institutions necessary to assist in conducting NORDIC studies
  • Appoint necessary standing committees that include NORDIC EC members, Investigators, and experts for specific studies (e.g., the Health Related Quality of Life Committee)
  • Pay Investigators/Sites on a quarterly basis for their work using performance information provided by DCBC.  As deemed appropriate, sites will be paid upon successful completion of recruitment, completion of study visits as demonstrated by paper or electronic case report form submission to the DCBC, resolution of all outstanding queries and proper study closeout procedures.
  • Find and contract with consultants for clinical research development
  • Contract with central IRB, New England Institutional Review Board (NEIRB), for sites without a local IRB
  • Identify and hire Regional Project Coordinators to provide site coordination and site monitoring
  • Implement the recommendations of the DSMC for each study

* In conjunction with the DCBC and Study Director for each study

 

Other functions of the Executive Committee will be defined once the committee is formed.

The EC is composed of:

  • Chairperson (voting only to break tie)
  • Co-Chairperson (voting)
  • DCBC Director (voting)
  • DCBC Co-Director (Biostatistician) (nonvoting except in the absence of the Director)
  • Co-investigator of DCBC (nonvoting)
  • Program officer from the NEI (voting)
  • A minimum of three additional Neuro-ophthalmologist (with clinical trial or prospective research experience) (voting) – elected by the current members of the EC
  • Each Study Director of funded studies (for the duration of each study) (non-voting)
  • Director of Visual Field Reading Center (nonvoting)
  • Director of Photography Reading Center (nonvoting)
  • Directors of additional Core Reading centers (nonvoting)
  • Additional members as needed for specific studies (nonvoting)

* Term limits for EC members will be determined as NORDIC evolves.

A.1 Network Chairperson

The NORDIC Network Chair is responsible for coordinating the activities and contributions from Study Directors, NORDIC Investigators and DCBC, and will report to the NEI program officer.  The Chair will serve as chairperson for the EC, establishing agendas and directing meetings of this committee.  The Chair will regularly interact with the NEI Program Official, Coordinators and Investigators from participating sites, the DCBC, granting agencies, foundations and companies.  In addition, the Network Chair facilitates site compliance with Federal (HHS / NEI / FDA) regulations.  The DCBC will be the central repository of all IRB files for the Network.  The Chair Headquarters will be provided with a regulatory document tracking spreadsheet from the DCBC on a regular basis, summarizing the status of IRB approvals and collection of all necessary regulatory documents from all participating sites for each study.  The Chair will adjudicate disputes among Investigators or the DCBC, recommend Study Directors, review all proposed protocols prior to meetings, encourage submission of new studies and proposals, seek funding from government and private sources, and vote in Executive Committee meetings only to break a tie.  The Network Chair and the DCBC will develop criteria with each Study Director for Investigator/Site participation and certification for each funded protocol.  The Chair will review every proposal and potential project, and assign a member of the EC to assist in further exploration and development prior to a formal EC recommendation to pursue a new study.  The Network Chair or Co-Chair will interview every candidate seeking to be a NORDIC Investigator to detail their responsibilities (i.e., educating their personnel, recruiting subjects to NORDIC studies, participating in subcommittees of NORDIC, and attending meetings for updates, training, and certification).  The Network Chair will establish and maintain a NORDIC email system to notify Investigators of potential new studies, solicit pilot data, keep Investigators informed, answer Investigator inquiries, set up Investigator meetings, and disseminate updates and changes.  The Network Chair and the Executive Committee will address issues that arise during ongoing studies if the Study Steering Committee is unable to provide a definitive answer. The Network Chair will head the certification committee.

The Network will provide Regional Project Coordinators (RPCs) for studies that do not require a coordinator at each site. The Network will provide fiscal and budgetary structure, and controls to administer funds for studies to Investigators, reading centers, and research laboratories. The Network will contract with a central IRB for sites without a local IRB.

A.2 Network Co-Chair

The NORDIC Network Co-Chair will report, depending upon the issue, to the Network Chair or the Director of the DCBC.  In collaboration with the Network Chair and the NEI Program Officer, the Network Co-Chair participates in the development and overall program management of the Network.  The Co-Chair will assist the Chair in his duties as needed. The Co--Chair will co-direct the Credentials Committee. The Co-Chair will be primarily responsible for recruiting Neuro-Ophthalmologists to participate in the Network.  The Co-Chair and the Chair will divide equally between themselves participation on Study Steering Committees.

* The Chairman, Co-Chairman, and DCBC staff will have a bi-weekly conference call (or more often if needed), with the other members participating as needed.  The full EC will have a monthly conference call.

A.3 Meeting Attendance

The EC is convened quarterly.  Dates for these meetings are scheduled a year in advance.  Attendance at quarterly EC meetings must be given the highest priority by all EC members.  The input of each EC member and Study Director is fundamental to the progression and advancement of the Network.  Should an EC member or Study Director find it impossible to attend an EC meeting, he or she is required to notify the Network Chair of the expected absence. 

Study Directors are permitted to invite other clinical site professionals, who have special interest and expertise that are relevant to the meetings, pending approval from the Network Chair or Program Officer.  In many instances, an Investigator from a participating site may regularly attend EC meetings to update the EC on the particular Network study that the Investigator leads.  Special consultants and guests may be invited to attend EC meetings at the invitation and approval of the Program Officer.  Additionally, the professional staff from the DCBC is invited to attend EC meetings at the approval of the Network Chair or Program Officer.

Agenda

Before each meeting of the NORDIC EC, the Network Chair will establish a draft agenda for review by the committee.  EC members will notify the Network Chair concerning any changes or modifications to the agenda.  For each ongoing study, it is standard for the Study Director taking the lead on that protocol to give a brief verbal progress report.  Expert consultants or invited guests may be added to the agenda at the request of the Program Officer or EC members.  If an Investigator would like to obtain approval to make a presentation (concept, mini-protocol, protocol, proposed collaboration, etc.) at an EC meeting, the following should occur:

  • Notify the Network Chair and Program Officer at least 4 weeks before the EC meeting.
  • Forward (preferably electronically via e-mail) a copy of the presentation (concept, mini-protocol, protocol, proposed collaboration, etc.) to the Network Chair and Program Officer three weeks before the EC meeting for review and distribution to the EC members.  If this deadline is not met, the presentation will be allowed at the discretion of the Network Chair or Program Officer; however the EC vote may be delayed (two weeks following the EC meeting) to afford the EC the opportunity to review the printed material.

B.  Data Coordination and Biostatistics Center (DCBC)

For each Study, the staff in the DCBC, in conjunction with each Study Steering Committee, has the responsibility for overseeing the development of the protocol, development of operational and analytical methodology, the conduct of each study according to the protocol, and analysis of all data.  The DCBC serves as an administrative resource for study investigators.  It is actively involved in facilitating initial IRB approvals, yearly renewals, amendment approvals and tracking centrally of all of the final approval documents etc... 

The DCBC has a multidisciplinary staff necessary to manage multiple projects.  For each study a complete project team is formed including a member from each core functional area within the DCBC.  These project teams work in close communication to ensure all aspects of the study conduct are completed in a proper and timely manner.  A typical project team is composed of the following types of individuals and may include more of less individuals depending on the size/scope of the project

  • DCBC Director
  • DCBC Co- Director (Biostatistician)
  • DCBC Co-Investigator
  • Program Manager
  • Senior Project Coordinator
  • Associate  Project Coordinator
  • Database Manager
  • Information Analyst
  • Technical Programming Staff
  • Data Entry & Support Staff
  • Help Desk Support
  • Consultants

B.1 Responsibilities

The DCBC Director is responsible for the supervision and management of DCBC staff to ensure the successful completion of Network goals that fall under the DCBC's domain.  The DCBC Director, Co-Director (Biostatistician), and Co-investigator collaborate closely with each Study Steering Committee, Site Investigators and NEI staff on biostatistical issues related to the design, implementation, conduct, and analysis of Network studies and provide communication performance feedback to all.  The DCBC will train and help with the supervision of the Regional Project Coordinators.  The Director participates on every established board and committee in the Network, and has coordinating and reporting responsibilities to the Data and Safety Monitoring Committee.  The Director is a voting member of the Executive Committee, Study Steering Committees, Study Planning Committees, and co-authors Network publications.  The DCBC is primarily responsible for the following areas:

B.2 Study Design and Planning

The DCBC advises and assists the EC and Study Steering Committee with the study design and planning for studies to be conducted in the Network, including the determination of sampling and randomization schemes, defining primary and secondary outcomes, and all biostatistical issues.  DCBC staff assists with protocol development, and prepares study materials, including the final protocol, the manual of procedures and data collection forms (electronic case report forms (eCRFs) for each study.  DCBC staff will train and certify site staff in electronic data capture [e.g., eCRFs completion], study drug and central laboratory procedures (if applicable), and all other administrative aspects of study procedures.

B.3 Study Conduct

The DCBC provides and maintains computerized data management systems, with capabilities for distributed and central data entry, editing, modifying, and reporting of data.  DCBC staff monitors and report on data quality, protocol adherence, and recruitment status, producing quarterly EC reports, and monthly status reports.  The DCBC staff assists in the coordination of site visits by Regional Project Coordinators, Study Steering or Executive Committee members and sets up data review visits, as required for quality assurance.  The DCBC is responsible for interim analysis for safety, efficacy and futility monitoring conducted by the Data and Safety Monitoring Committee.

B.4 Closeout and Analysis

The DCBC conducts statistical analyses of study results and assists investigators in the preparation of presentations and manuscripts for publication.  Study data reside centrally at the DCBC that is responsible for complete documentation of the study and archival of the dataset. 

B.5 Communication, Management and Organization

The DCBC collaborates with NEI to establish and refine organizational procedures to optimize the efficiency of the Network.  The DCBC often makes arrangements for external services and procurement of supplies for individual studies, including arrangements for acquisition of study drugs and placebos, coordination of masking methods, setting up subcontracts for diagnostic tests centrally analyzed and consultancy agreements with outside experts and the procurement and distribution of certain study equipment and supplies.  The DCBC is also responsible for maintaining and distributing study documents, including protocols, manuals of procedures and data collection forms.  A private NORDIC Network portal is maintained by the DCBC via eResearch Community, which is a component of the Clinical Data Management System (CDMS) suite of applications from eResearch Technology (eRT), including facilities for posting of pertinent research related documents for each study (e.g., protocol, model consent form, manual of procedures, eCRF completion instructions, frequently asked questions etc.) and containing contact information for all affiliated credentialed staff for the Network.

A separate publicly accessible website will be maintained by the Network Chair to keep subjects, families and the research community aware of NORDIC activities.  The website will be updated regularly with status of individual NORDIC projects, as well as Network news.  This website will be linked to the NANOS website (and possibly to the American Academy of Neurology and American Academy of Ophthalmology websites) to announce new studies.  Interested investigators can enter their credentials and data required to begin the certification process to become a NORDIC Investigator and a participant in a specific study.  The Network Chair and Co-Chair are responsible for credentialing procedures.  Once credentialed, investigators will then be provided with a user ID and password from the DCBC to gain access to eResearch Community for study specific information.

B.6   Procurement, Packaging, Labeling and Distribution of Study Drugs

The DCBC will be work closely with each Study Director and Steering Committee for each clinical drug study conducted by NORDIC to ensure an adequate supply of active and placebo drug is procured and that the supply has been manufactured following Good Manufacturing Principles (GMPs). The DCBC will provide packaging and labeling service to make certain that each study site has an adequate supply of study drug and matching placebo for each enrolled subject.  This will be accomplished via an established subcontract with a reputable drug packaging/distribution company or via the University of Rochester Investigational Drug Services (IDS) Unit, established in 1993, which packages, labels, and distributes study interventions.  The mission of the IDS is to provide clinical research scientists and investigators with the necessary support to assure safe and efficient conduct of clinical drug trials including compliance with federal, state, Joint Commission on Accreditation of Healthcare Organizations (JCAHO), and American Society of Health-System Pharmacists (ASHP) requirements regarding control of investigational drugs.  IDS has been responsible for the packaging, labeling and distribution of experimental medications for a variety of NIH-sponsored trials, including DATATOP, CARE-HD, QE2, and, most recently, the NET-PD studies.  The IDS is registered as a Wholesaler-Repacker of Drugs and Devices in the State of New York (Registration Number 024796).

Prior to the final selection of the drug packaging/labeling and distribution vendor the DCBC will conduct a vendor qualification audit which will consist of a complete tour of the facilities, a review of Standard Operating Procedures and training and certification records of employees, as well as reviewing the FDA website for any 483s. 

The DCBC will work closely with the Study Director, Study Steering Committee and the drug packaging vendor: to determine the best packaging schematic, re-supply mechanisms, plans for emergency disclosure envelopes, scratch-off labels or other mechanisms for emergency disclosure procedures, inventory tracking log; storage requirements, methods for drug supply return or destruction, and all other details related to proper handling, accountability and storage of investigational agents.  The DCBC will include written procedures regarding the drug supply in each Study Manual of Procedures.

C.  Study Planning/Steering Committee

For each major study, a Study Planning or Steering Committee will be designated.  This committee or a subset of the committee generally will serve as a Study Steering Committee during the conduct of the study.

Members of a Steering Committee will include a Study Director, the DCBC Director and/or DCBC Co-Investigator and a DCBC biostatistician, the NORDIC Network Chair and/or Co-Chair, and a representative of the NEI.  Additional members including site Investigators will be added depending on the specifics of the protocol.  The Study Planning/Steering Committee will convene by conference call and meet as needed.

Whereas the EC is responsible for issues related to NORDIC in general or to more than one study, the Study Steering Committee is responsible for issues specific to one protocol.  Specific functions of a Study Steering Committee include:

  • Develop final protocol, informed consent form, data forms, study procedures, and other study materials
  • Develop Manual of Procedures with DCBC
  • Develop budgets for startup and certification meetings and procedures, site reimbursement, steering committee costs to direct study, reading site costs, and new Site equipment.  The Network EC will develop the entire budget for the Study with Study Director and Steering Committee and DCBC for the EC to administer
  • Develop requirements for Investigators to be certified for the protocol
  • Secure drug supply (active and placebo) in conjunction with the DCBC
  • Pilot test case report forms and procedures prior to start of subject recruitment
  • Consider changes or modifications in the protocol as may be necessary or desirable
  • Advise the EC on operational matters
  • Prepare manuscripts and study documents
  • Develop study close-out procedures with the DCBC
  • Direct the study once approved and funded

D.  Study Director

The individual who conceives and develops the study concept, specific aims and significance, necessarily will automatically be designated the Study Director of the study unless there is a compelling reason for the EC to name another person.  A Study Director is designated for each major study.  The Study Director provides leadership to the Study Steering Committee for the protocol and works more directly with the DCBC than the other Steering Committee members in carrying out the functions listed above.  The Study Director serves as Principal Investigator (PI) for the study and can appoint a Co-Study Director (co-PI) and other Study Steering Committee members subject to approval of the EC.

A Study Director must be a certified NORDIC investigator.  An investigator can only serve as Study Director for one major Study at a time (generally defined as a project for which a specific grant proposal has been written).  This does not include unfunded data collections or pilot studies.

The Study Director may be asked to attend DSMC meetings. This generally will be required at the initial DSMC meeting to review the study protocol and the final meeting to review the data analyses of collected data.  Attendance at other meetings will depend on the stage of the study and whether data are presented in an open or closed session.

E.  Data and Safety Monitoring Committee (DSMC) – appointed by NEI

The DSMC has the responsibility for reviewing the ethical conduct of a study and for monitoring the data for evidence of adverse or beneficial treatment effects.  Results are not available to the participating Investigators who are treating or examining subjects until the DSMC recommends that this information be released.  The DSMC will be responsible for all major studies and will be kept abreast of, but will not be responsible for, ongoing unfunded data collections.

The DSMC should consist of one biostatistician, three Neuro-ophthalmologists, an internist, a visual assessment and/or quality of life expert, and a lay-person (e.g., a social worker) who will serve as a subject advocate.  It should also include the NEI representative as an ex-officio member.

Prior to the initiation of recruitment for a study, the DSMC will review the study protocol, including the model informed consent form and manual of procedures.  Each Study will require approval with respect to ethical and safety standards.  The DSMC periodically reviews the study progress (at least twice each year either at a meeting or a conference call) for efficacy, safety and futility as applicable.  Decisions made by this committee relating to protection of subject rights and/or resulting from data analyses are forwarded to the NEI, the Study Director/Study Steering Committee and the Network Chair.  The Study Steering Committee, in conjunction with the DSMC, will determine specific plans for evaluating adverse effects and efficacy, including stopping rules, for each protocol.  Subsequent to each DSMC meeting, the DSMC Chair will provide a written letter to the Network Chair for each study reviewed indicating the recommendation of the DSMC for continuation, modification or termination of the study.  The Network Chair will forward each letter to the appropriate Study Director and the DCBC for distribution to the participating study sites.  The sites will forward the letter to their IRB.

The DSMC reviews interim reports of subject accrual and outcome measures provided by the DCBC.  Interim reports typically include tabulations of study subject characteristics, major clinical events, and primary outcomes, arranged by site and by treatment group.  The decision to code or mask the treatment group is at the discretion of the DSMC.  If outcome data have accrued, the DCBC will also present a formal interim analysis of the primary outcome and hypothesis test based upon the group sequential method employed for the trial.  After reviewing each such report, the DSMC assesses the need to perform further in-depth evaluation of the benefits and risks of the study.  The DSMC has the authority and may agree to recommend termination or suspend a trial based on, but not limited to the following:

  • A clear advantage to an experimental group has been shown, in accordance with the planned statistical boundary for interim hypothesis testing;
  • Subject safety would be compromised by continuation of the study; and/or
  • Severe unanticipated problems occur regarding study conduct (i.e., inadequate recruitment or problems with drug supplies, etc.).

The DSMC’s recommendations are made to the NEI, which is responsible for the decision to terminate or suspend a study, although the decision may be discussed beforehand with the Study Steering Committee and the NORDIC Executive Committee.  The randomization codes of a masked study performed by the Network will remain intact until the completion of the study, including the follow-up period, with the exception of interim review by the DSMC.  Requests for restricted access to the study's status, e.g., for the analysis of ancillary studies performed in individual sites, will not be honored if they might lead to premature disclosure of the results of the primary study.  At the conclusion of individual studies, and at other times as may be deemed appropriate by the DSMC, the DSMC will recommend release of unmasked study data to the full Study Steering Committee for analysis and publication in scientific journals.  No other release of unmasked study data to the Study Steering Committee is authorized.  The DSMC, under the direction of its Chairperson, will prepare a written annual report for distribution to NEI.  This report will summarize important findings of the studies undertaken by the Network and may include recommendations for protocol or procedural changes.  Included in this report will be assessments of the performance of the DCBC, individual Study Steering Committees, the EC, and NEI in the overall management and conduct of the study.

 DSMC members are experts in and represent the following fields:

  • Neuro-ophthalmology
  • Medical safety issues
  • Ethics
  • Biostatistics/ Epidemiology/ Clinical Trials
  • Ad Hoc members as needed for special expertise

 

Current DSMC Members:

 

  • Maureen Maguire, PHD – Chair- University Pennsylvania
  • David Kaufman, MD – Michigan State University
  • John Selhorst, MD – St. Louis University
  • William Hart, MD – Washington University (emeritus)
  • Joanne Katz, PHD – Johns Hopkins University
  • Cynthia McCarthy, PHD – Independent Ethicist
  • Donald Everett, MS - NEI Program Officer
  • Eleanor Schron, PHD - NEI Program Officer

F.  Investigators

NORDIC membership is open to all who meet the qualifications below:

  • Neuro-ophthalmologists who are full members of NANOS or, if not, have completed a Neuro-ophthalmology fellowship or have comparable clinical experience
  • International NANOS members who (1) are English-speaking, (2) are able to obtain coverage from an Institutional Review Board (Human Ethics Committee), (3) use email and have internet access, and (4) for longitudinal studies, demonstrate the ability to maintain subjects in follow-up
  • General ophthalmologists or neurologists or optometrists who are experienced in Neuro-ophthalmologic diseases with an active Neuro-ophthalmology practice will be considered for each study if they can demonstrate to the EC basic knowledge of the clinical disorder under investigation, basic clinical skills required, and can follow the Study procedures and protocol.
  • · For a specific study that overlaps with another subspecialty research group such as the pediatric ophthalmologists (for an adult strabismus or juvenile glioma study) or the ocular plastic surgeons (for the Thyroid Eye Disease study), potential site investigators must agree to follow the NORDIC Network guidelines and may be granted Investigator status for the given Study.
  • Each Investigator must have a clinical facility and administrative staff that can support each study protocol including standardized light box, EDTRS charts, trial lens for refraction, examination lane (4 meters long), and a Humphrey computerized perimeter with SITA software, and a fundus camera approved by the Photo  Reading Center (PRC).  For specific studies, additional equipment will be required.
  • Clinical scientists, biostatisticians, or epidemiologists can contribute to protocol development and conduct but will not be study Investigators.
  • Because NORDIC studies will include a wide variety of systemic, ophthalmologic, and neurological disorders, for a specific study, Investigators who do not specifically have expertise in Neuro-ophthalmology may be included after certifying on the study protocol and procedures and all NORDIC policies.

Specific requirements will exist for an Investigator to participate in each protocol.  Each Study Steering Committee, in consultation with the Network Chair and the DCBC Director, is responsible for developing certification requirements and approving investigators for that protocol.  A NORDIC member can elect to participate in any or all studies for which he or she meets the certification requirements.  As NORDIC evolves, Investigators may be required to participate in at least one study to maintain active membership.

F.1  Credentials Committee

The Network Chair will lead this committee, which includes the Network Co-Chair and two or three senior Neuro-ophthalmologists, to review all potential candidates to be NORDIC Investigators.  For studies that include individuals who are not Neuro-ophthalmologists, the Study Director and members will participate in the certification process.  The Network chair will maintain a website that allows interested investigators to electronically submit the necessary paperwork to begin the credentialing process (see section B.5 above). The Credentials Committee will interview all applicants that meet the Investigator criteria for participating in the Network.  For specific studies these criteria will be altered as necessary.  Applicants who wish to join NORDIC when there is no upcoming Investigator meeting will give an alternative means to receive training on NORDIC procedures and policies and become certified (process to be developed).  The Committee will also be responsible for developing a policy and plan for addressing problem issues with NORDIC Investigators, methods for maintaining credentials, and termination.

F.2   Investigator Selection Process for Small Projects

For a protocol for which a smaller number of Investigators is needed, a competitive application process will be instituted.  The Study Steering Committee, in conjunction with EC members and/or a NEI-appointed committee, will review these applications as determined by the NEI program officer.  There will not be an established set of preferred sites that will participate in all trials to the exclusion of others who are qualified.  New site participation will be encouraged.  Pilot data collection and ability to recruit subjects for the proposed study will be paramount considerations.

G.  Ancillary Studies

A wealth of data can be collected on the subjects enrolled in the trials and the investigators will be encouraged to submit proposals for ancillary studies.  An ancillary study is defined as one that is performed concomitantly with the study in which (A) supplementary observations or procedures are performed upon all or a subgroup of the subjects according to a set protocol, or (B) additional work will be done by, or information obtained from, the DCBC.

Approval for an ancillary study by the Study Steering Committee and the DSMC is required to assure that no ancillary study will:

  • have an adverse effect on the completion of the study;
  • complicate the interpretation of the study results such as by tiring certain subjects so that they cannot complete the tests that are part of the study protocol as well as they might otherwise have;
  • adversely affect subject cooperation, in particular, affecting the reliability of subjects returning for follow-up visits;
  • jeopardize the public image of the study; or
  • create a serious diversion of study resources locally, at the DCBC, or at any other site involved in the study.

G.1   Procedure for Obtaining Ancillary Study Approval

The request for approval of an ancillary study should be in narrative form containing a brief description of the objectives, methods and significance of the study.  Full details should be given concerning any procedures to be carried out on any study subjects, such as visual function tests, imaging procedures, etc.  Details of any substances to be injected or otherwise administered to the subjects should be described.  Any observations to be made or procedures to be performed outside of the site should also be detailed.  For tests to be performed in the office, mention should be made of where in the sequence of tests performed as part of the protocol for the study the ancillary tests will be performed, and how much additional time will be needed for the ancillary studies.  Mention should also be made of whether additional visits, other than those included in the study protocol, will be needed for the ancillary study.

The Investigator should send his or her ancillary study request to the Study Director, who will distribute a copy to all members of the Study Steering Committee.  Each member of the Study Steering Committee should review the proposal and send a reply to the Study Director stating whether the proposal should be approved as is, revised and resubmitted, or rejected.  The report should list any concerns, questions or objections the reviewer may have.  The Study Director will review the report of each member of the Study Steering Committee within a reasonable time.  If there is a consensus for approval, he may send the Investigator a report indicating approval, including a summary of any concerns, objections or suggestions for changes made by the reviewers.  If there is a consensus for rejection, the Study Director should send the Investigator a report that indicates the reasons for rejection.  If approval for the ancillary study seems indicated with changes, this should be written to the Investigator with a summary of the reviewers' comments, questions and objections.  The Investigator may revise the proposal and resubmit it for review or may withdraw the proposal.  The DSMC must approve the final ancillary study proposal.

G.2 Implementation of Ancillary Studies

If no additional funds are needed, the Investigator may proceed with the ancillary study as soon as it has been approved by the Study Steering Committee.  If additional funding is necessary, the Investigator may prepare a new research grant application to NEI or any other potential funding source.  This should be reviewed by the Study Director or a member of the Study Steering Committee whom he/she designates prior to submission and a member of the EC.

If the ancillary study requires the involvement of more than one Site, any or all Sites in the study may be contacted about participating. Any Site has the right to refuse participation in any ancillary study.

The Investigator should not accept the grant or activate the ancillary study until approval has been received from the Study Steering Committee and the DSMC.  The finalized protocol for the ancillary study and a list of the participating sites should be sent to the Study Director, DSMC, EC, DCBC and the Site Investigator at each Site that will be participating in the ancillary study.

H. Funding

Major studies are funded through cooperative agreements between the National Eye Institute and the NORDIC Headquarters/Chair.  Funds will be distributed either from the Network Headquarters or DCBC to subcontracted steering committees, consultants, sites/investigators, central laboratories, central IRB, and reading centers for study operations including travel and organizational costsNEI will pay members of the DSMC directly.

Company or corporate sponsored studies are welcome.  These protocols and investigations will follow the guidelines established by NEI and NORDIC Network policies.

Other sources of funding may be sought to partially cover NORDIC costs for either conducting otherwise unfunded projects (see below) or to help support protocol development.

H.1 Funding for Investigators - paid to sites (institutions and practices)

In general, Investigators are compensated on a per-subject basis for each Study to cover the costs of the Investigator effort, ancillary personnel including coordinator, facilities use, and tests or procedures outside the normal standard of care.  A portion of the funding will be provided to support IRB submission and when a subject is enrolled, for follow up visits and study completion paid quarterly.  When appropriate, each Investigator/Site will receive funds to cover start-up costs for each study such as recruitment seminars, advertising, and study specific equipment purchases.  For some trials, salary support for the investigator and/or Site staff may be needed.

Each investigator must have an agreement between his/her institution or legal entity and NORDIC Headquarters or NEI.  The agreement will indicate the payment schedule for the study and the obligations of the Investigator and institution.

NORDIC Policy on Indirect Rates: For government supported research, 40% will be paid on non-patient care costs. For industry supported research, the institution rate will be applied on non-patient care costs.

H.2 Study Director

The Study Director for each Study will be supported through a subcontract between the NORDIC Headquarters and the Director’s institution.  Typically, the subcontract will cover the time for the director and a small amount for support staff.

H.3 Committees

Due to the amount work required, most EC members will be paid commensurate with their effort.  For other committees, members receive a per-day consulting payment from the DCBC or NORDIC Headquarters to partially compensate them for the time they devote to the Study while attending meetings, participating in conference calls, pilot testing study procedures, etc.

H.4 Subject Costs

Grant funds are intended to pay for assessments/procedures that are purely for the research and otherwise would not have been performed.  NORDIC will make every effort to ensure that the insurance companies or Medicare are not charged for tests or therapies are not considered an aspect of accepted clinical care.  Most NORDIC protocols will be established to conform to standard medical care as closely as possible.  The per-subject funding provided to the Investigator is expected to cover the additional time necessary on the part of the Investigator and his/her office staff.  This per-subject funding is also expected to cover the costs of maintaining an internet connection and usage time and study-directed time on the part of the Investigator in areas such as obtaining IRB approval, promoting recruitment, screening subjects who would otherwise not be examined, educating the eligible subjects about the trial and obtaining informed consent, responding to calls from the subjects during a Study, completing eCRFs, responding to edits and queries from the DCBC, and attending at least one Investigator meeting per year.

When an Investigator or staff member performs services that are considered routine care, independent of the study, it is appropriate to bill the subject's insurance company for these services.

Each Study will budget for some percentage of the cost for subjects without insurance (not including Medicaid) or insurance which will not pay for care at the Study participating site or with the Site investigator and who are unable to pay fees.

Research funds will be used to pay for supplies, medications, spectacles, etc., that would not be required as part of a subject’s routine care.

In some studies, subjects may be compensated to cover visit-related costs such as travel, meals, and parking.  Generally a distinction will be made between usual-care visits for which compensation, if any, may be nominal and protocol-required visits for which compensation may be greater.  In some studies, the compensation for usual-care and protocol-required visits may be averaged with the same amount of compensation then being offered for each visit.

H.5 Funding for IRB-Related Costs

For each funded study, the NORDIC structure will provide funds to pay for administrative effort by Investigators/staff to prepare and submit materials to the local IRB.  In addition, NORDIC will cover the cost of using a central IRB for investigators without access to a local IRB.  This funding will consider expenses for the initial review, annual reviews, and amendments.  NORDIC policy follows US government guidelines for not paying IRB fees for federally funded studies.

H.6  Unfunded Data Collection Projects

The NORDIC structure will provide for the opportunity to prospectively collect data using a standardized protocol outside of large randomized trials, particularly for conditions which are uncommon or which for other reasons do not have sufficient public health importance to garner funding.  Studies, which can reveal potential mechanisms of disease, emphasize novel approaches, or use molecular biological evaluations will be emphasized.

Individuals with ideas for such data collections should utilize the NORDIC study template to develop a brief study objective, rationale, and synopsis of a study design.  This can be expanded to no longer than four pages including preliminary data and citations of most relevant literature.  The EC will review the proposal and, if it is accepted, will work with the individual to develop a protocol, informed consent/assent form, and data collection forms.  The DCBC will be involved in establishing the database and implementing data quality control measures for these studies, internet data entry if indicated, maintaining the database, and analyzing the results.  It can automate a system to send reminders for overdue visits or data forms but will not be actively involved in tracking subjects.  It will be the responsibility of the Study Director and designee to ensure timely data collection.

I.  Subject Protection and Data Quality

I.1 IRB

Each Site must obtain approval from an IRB for each protocol in which it participates before it can begin to enroll subjects.  The Site must abide by reporting requirements of the IRB.  In some cases, the IRB may require official approval of study recruitment materials.  All changes in the research activities and all unanticipated problems involving risks to subjects must be immediately reported.  Protocol changes require IRB approval before implementation, except when required to eliminate apparent immediate hazards to subjects (in this case, the IRB must be notified immediately).  Modifications to study procedures, which do not constitute a meaningful change in the protocol and do not impact in any way on subject safety, may not require prior IRB approval, but often require that an amendment be submitted.  Any changes requested by the local IRB will be reported to the Study Steering Committee and DCBC.

IRB approval must remain current.  The DCBC will send a reminder to each site about two months prior to the expiration of IRB approval for a protocol (a protocol update for the IRB will be included).  If IRB approval lapses, the site cannot enroll any new subjects and cannot submit eCRFs to the DCBC for any established study subjects until IRB coverage is back in effect.

For some protocols, individuals who are not at institutions with IRBs may be permitted to use a private central IRB for NORDIC.  Generally, this will not be possible for surgical trials but may be approved for observational studies and randomized trials involving non-surgical therapies, which are already used routinely in clinical practice.

I.2 Informed Consent/Assent

An informed consent document must be signed before any procedures are performed that are specific to a study (e.g., not part of subject’s routine care, or information collected about the subject’s examination that may be analyzed for research purposes in the future).  The Informed Consent Document will contain information about the objectives of the study, the procedures followed during the study, and the risks and restrictions of the study, with special reference to possible side effects of the treatments.  The document will be in compliance with the requirement of each Site’s Office for Human Research Protections (OHRP) approved assurance and IRB.

I.2.1 Inclusion of Children

It is possible that the studies proposed within the research network will include children.  If children are included in any NORDIC study, the study will be conducted in accordance with the federal regulations 45 CFR46 subpart D “Additional Protections for Children Involved as Subjects in Research.”  This includes the requirement of parental permission for each child prior to participation in any given trial.  Youth assent will be obtained when appropriate.  A copy of the signed/dated parental permission forms/assent forms will be provided to the subject/parent/guardian and the originals will be maintained at the site.  All parental permission/assent forms will be fully HIPAA compliant. 

J.  Subject Data Form Completion

The subject electronic case report forms (eCRF) are to be completely filled out by the examining personnel and reviewed and signed by a certified Investigator and entered electronically via the internet.  Care must be taken to assure the subject eCRFs are completed in accordance with the source documents.  Any changes or corrections made on the subjects eCRFs once submitted must include a reason for change.  A full audit trail including the date and time of change, original entry, correct entry and reason for change will be maintain by the Clinical Data Management System (CDMS).

For those un-funded data collection studies where paper CRFs may be utilized, CRFs must be completed in a neat, legible manner to assure accurate interpretation of data.  A black pen is preferred to ensure clarity of any reproduced or faxed copies.  Any changes or corrections made to the subject CRFs must be made in black ink, and dated and initialed by the person making the change.  In such cases the original entry is crossed out with a single line but is not overwritten or erased; “white-out’ is never to be used.

K. Site Monitoring and Data Audits

The site monitoring policy may vary from study to study.  Site monitoring visits will not be performed on a routine schedule in view of the large number of Investigators and, for most protocols, the small number of subjects per Investigator.  In general, a Site monitoring visit will be performed (1) whenever there are concerns about data quality or (2) an Investigator (or Site, if there are multiple Investigators at the same site) enrolls or is projected to enroll at least 10% of the subjects in a protocol.  Other Investigators will be selected at random for site monitoring visits.  All Investigators are subject to site monitoring visits.  All NORDIC, Investigators must agree to cooperate with the Regional Project Coordinators or other Network or DCBC staff during site monitoring visits.

L.  Masking and quality control of data

These issues will be determined by each Study Steering Committee and the DCBC since the methods used will depend on the needs specific to each individual study.

M.  Scientific Fraud

Scientific fraud refers to the situation where data are actually fabricated.  Examples include (1) altering information collected from a subject that would have excluded them from a study, so that the subject appears to meet the eligibility requirements, (2) randomization of subjects prior to obtaining informed consent or changing the date on the informed consent form to conform with the randomization date, (3) changing examination dates so that they appear as being in the time windows specified in the protocol, and (4) altering outcome measurements. 

Perfect compliance with the protocol is not expected.  Subject adherence will never be 100%.  Some problems with medication compliance (where applicable) and missed visits are expected in any trial.  Some misclassification of outcome is also possible.  In fact, in determining a sample size estimate for the study, an adjustment is made to account for the expected losses to follow up, number of misdiagnosed subjects, and number of subjects who do not comply with their treatment assignment. 

Site staff does make mistakes.  Unintentional errors that occur in data collection are not scientific fraud.  They may be signs of poor Site performance and such errors are tabulated by the DCBC, but they do not imply fraud.  This is watched by the Study Steering Committee and the DCBC and becomes a concern when a site is making more mistakes than expected, particularly major ones (e.g., entering ineligible subjects). 

An Investigator has the responsibility of assuring that the protocol is carried out properly at his/her site and assumes responsibility for staff involved in the care of and data collection for study subjects.  An Investigator who suspects data irregularities should report this to the Network Chair and DCBC immediately.

N.  Confidentiality change to reflect new HPAA regulations

Individual subject medical information obtained as a result of participation in a NORDIC study is considered confidential and disclosure to third parties other than those noted in each study protocol is prohibited.   Medical information obtained during a study may be given to the subject’s personal physician or to other appropriate medical personnel responsible for the subject’s welfare with the subject’s permission.  Data generated as a result of this study are to be available for inspection upon request by the DCBC, the NEI, sponsors, and auditors of other regulatory agencies.

O.  Retention of Study Records

Each investigator will archive all relevant study data and keep them on file for the period of time specified by US law or by the institution of the Site Investigator, whichever is greater.  A study Investigator may not destroy NORDIC source documents or study data without prior written approval from the Study Director, the DCBC, or the Network Chair.  In the event that an Investigator is unable to procure a long-term document storage facility the Investigator should contact the Network chair.

P.  Communications (see Section B.5)

NORDIC will make extensive use of email for communications.  NORDIC Headquarters and the DCBC will maintain the necessary electronic databases and network for the electronic transfer of all information.  Email use will be required of all committee members and will be required for all Investigators.  For some protocols, internet access will also be required.  The DCBC Clinical Data Management System (CDMS) eResearch Technology (eRT) will be used in all studies for randomization, data entry, and viewing study documents.

Q.  Meetings of Investigators

NORDIC meetings will be held at least once a year, typically avoiding the major neurological or ophthalmic meetings to avoid conflicts.  Each Investigator is expected to attend at least one of these meetings yearly.

Generally, there will be a meeting for all NORDIC Investigators to discuss the status of current and planned protocols, and topics for possible future studies.  Separate meetings on the same day will be held for Investigators in specific protocols as indicated.  Opportunities will be provided to review basic and new NORDIC procedures and protocols and to instruct and certify new Investigators.

Prior to the start of each individual study, a protocol-specific training meeting will be held with the participating Investigators and Site Coordinators to review the protocol and procedures.  For veteran NORDIC Investigators participating in subsequent studies that use similar NORDIC protocols, a conference call to cover this information will be required as part of certification for a protocol.

R. Editorial Policy

R.1 Manuscripts and Presentations

All manuscripts to be written and presentations to be made related to any aspect of a NORDIC study including but not limited to the study protocol, study results, and study conduct must receive the approval of the EC.  The topic for a manuscript is initiated by each study by a Writing Committee appointed by the Study Director and Steering Committee or by any Investigator who may send a suggestion for a paper to the Study Steering Committee or EC for review.  The Study Steering and Writing Committees will develop a list of topics, questions, and investigations considered appropriate for publication and the DCBC will maintain this list.

Since it is impractical for every Investigator to have an active role in writing a paper, the Study Steering Committee will generally serve as a Writing Committee for major paper.  Investigators may volunteer for these writing assignments. 

The EC must approve all manuscripts about the study or any ancillary study prior to submission for publication. The manuscript will also be sent to all investigators in the specific study for review, comments, and approval prior to journal submission.  Abstracts must be submitted to the EC at least one month prior to the submission deadline. 

For major manuscripts, the Neuro-Ophthalmology Disease Investigator Consortium will be listed as the author on the title page with each Investigator who enrolled or followed at least one subject listed at the end of the paper as a contributor, in descending order from highest enrolling site to lowest enrolling site, if this meets with journal approval.  The Writing Committee for the manuscript will be listed.  Each manuscript must acknowledge sources of support for the study.

For secondary manuscripts, the investigators involved in writing the paper will be listed by name followed by “for the Neuro-Ophthalmology Disease Investigator Consortium” or “NORDIC.”

For the major manuscript of NEI-funded studies, the DSMC must approve the manuscript prior to submission.  A copy of the manuscript will be provided to the NEI for comment.  The DSMC will be sent secondary manuscripts for comment, but approval will not be required.

No investigator or other member of NORDIC can utilize any data or observations made on study subjects for press releases, published abstracts, presentations, or publications without approval of the NORDIC EC and Study Director.

R.2 Publications Committee

This committee will ensure that the preparation of the results of each study for abstract presentation or publication complies with NEI and NORDIC policies and guidelines and has appropriate analysis and conclusions. This committee will implement NORDIC data sharing policy (to be developed).  Manuscripts will be returned with tracked changes or written suggestions within one month of receipt.  Two members of the EC and two Investigators will comprise this committee.

S.  Publicity

The Study Steering Committee for a study must give approval prior of any press release or other publicity about the trial.  For NEI-funded studies, the DSMC and NEI also must approve release of study findings.  For studies using investigational agents, the pharmaceutical company, based on agreed to contractual terms, may also need to approve the press release or other publicity about the trial. 

T.  Conflict of Interest

Policies that follow NEI guidelines will apply to the members of the EC, DCBC, Study Steering Committees, Investigators, Coordinators and all participating staff in NORDIC studies.