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Core B Description

Core B Regulatory Compliance & Subject Safety

I. OVERVIEW
The regulatory issues faced by institutions performing clinical research have become increasingly more complex, placing greater demands on investigators for timely and complete compliance to federal and institutional guidelines. While accepted as serving an important function to safeguard subjects, the process of obtaining regulatory approvals to conduct clinical trials is generally regarded as cumbersome and time-consuming. Most investigators do not have an expert on staff that understands the regulatory issues involved in managing investigational research and who knows the institution’s obligations under the federal rules. Although technically covered by the auspices of the Institutional Review Board (IRB), Institutional Biosafety Committee (IBC) Data Safety Monitoring Board (DSMB) and Office of Contracts & Grants, these entities have institution-wide responsibilities and have limited resources or focused expertise for individual research projects.
Our recent experience in dealing with newly instituted regulatory and compliance regulations from NIH related to federally-funded trials with human subjects/samples (e.g. R01 A150467-01 Anton (PI), P30 AI-28697 CFAR Chen (PI), 5 U01 AI46749 HPTN056) is that it has quickly become onerous, complicated with multiple, overlapping and often non-communicating oversight groups with few guidelines and no allocated funding to ensure a responsive infrastructure.
The growing recognition of lapses in the oversight and conduct of clinical research, increasing federal regulatory activities, and published reports and studies on a number of aspects of the oversight system have brought this issue to the forefront of the public’s attention. That clinical trials have grown in number and complexity since the institutionalization of IRBs by the federal clinical research regulation, the so-called Common Rule, serves to heighten the magnitude of the problem. Modern IRBs are facing increased demands and expectations as the burden of federal regulatory requirements and the number of clinical trials are increasing. This results in increased burdens on the investigative team to assume regulatory responsibilities. An added complexity is the diversity of sites at which clinical research is performed. As is often the case, the emergence of a challenge provides a genuine opportunity to re-examine the oversight system and identify ways that it can be improved. This novel Core addresses this challenge.
The objective of the Regulatory Compliance and Subject Safety Core is to provide an infrastructure of regulatory and technical expertise to facilitate management of and maintain compliance with the regulatory responsibilities of the U-19 Projects while acting in an efficient and cost effective manner to facilitate conducting the clinical trial aspects of the four projects in the Microbicide Development Program (MDP).
Institutional Relationship Interfaces:
  1. UCLA Institutional Review Board (UCLA IRB)
  2. Johns Hopkins Institutional Review Board (JHU IRB)
  3. AIDS Research Alliance (ARA)
  4. University of Washington (UW)
  5. NIH Prevention Science Review Committee (PSRC)
  6. U.S. Food and Drug Administration (FDA)
  7. Contract Research Organization (CRO: Westat or PPD)
  8. Data Safety Monitoring Board (DSMB)
  9. Pharmaceutical/biotechnology research sponsors
  10. Data Management and Biostatistics Core (Core C)
II. RELEVANCE AND ROLE
Investigators in clinical trials have an obligation to take appropriate steps to protect both the integrity of the clinical trial and the subjects who participate in research studies. Ensuring the integrity of research cannot be stressed enough because of its seminal connection to the advancement of scientific research and clinical treatment. Detailed plans and systems are needed to assure protocol and regulatory adherence while maintaining human subject confidentiality and safety. In many phases of trials sponsored by the pharmaceutical industry, the sponsor provides oversight and monitoring of the research. This system has generally proven to be an effective means of maintenance of the integrity of the research. By and large, no parallel system exists when studies are sponsored by other entities, leaving the oversight to the investigative team. The details and rigor now involved in regulatory compliance often exceed skills of junior and non-MD investigators as well as experienced MD investigators. The lack of experience and expertise often leads to unfortunate delays in timetables and milestones while requisite standards of good clinical practice are met.

The intricate regulatory and subjects’ safety issues are further complicated when conducting a multi-institutional project. Increasingly complex and costly oversight mechanisms, often working independently and with conflicting advisories, can impede the ability of researchers to conduct clinical investigations in a timely, efficient and compliant manner. In this grant, it is being proposed that a single reporting regulatory mechanism (the “Regulatory Compliance and Subject Safety” Core) oversees all projects to reduce duplication of effort and ambiguity in regulatory interpretation. This will be done in an advisory and collaborative/assisting manner as direct responsibility for proper trial conduct remains with the relevant investigator/institution.

Given that multi-site studies require multiple approvals, and informed consents require explicit and careful documentation, the Core will also provide model IRB applications to all sites participating in a specific study protocol. The Core will review the site-specific documents prior to submission to the site’s institutional review. Our experience is that centralization and pre-review of such work increases the efficiency and timeliness of the submissions while providing basic oversight of adherence to the regulations regarding conduct of research with human subjects. The Core will also gain experience with the various IRBs involved in the studies, keep track of common issues in obtaining study approval, and improve the efficiency of the ethical review process. Forms developed for specific studies will be checked to ensure that they contain the required elements of informed consent. Local submissions and amendments will occur at the sites, but the Core will keep a record of all IRB approvals and consent forms used in respective studies in the website library. The Core will also codify the requirements for source documentation of consent forms, and appropriate storage of such forms for future audits and will promulgate standards for confidentiality, ensuring that each participating site has policies and procedures in place guaranteeing such confidentiality.

The Regulatory Compliance and Subject Safety Core will be charged with organizing and maintaining an on-going, comprehensively based review of federal regulations with interval updates to MDP investigators; implementing changes to meet new regulatory demands; collating and disseminating safety information from all projects; and, monitoring and assisting in timely federal and institutional submissions, approvals, adverse event reporting and inter-institutional communications. The Core will ensure standardized responses to similar inquiries from IRBs, PSRCs, CROs, and the FDA as well as assist in preparing standardized formats for case report forms (CRFs), reporting of adverse experiences (AEs) and DSMB reports. The Core will serve as the project home for the MDP-wide DSMB comprised of representatives from UCLA (Medical Director and Biostatistician), JHU (Medical Director), an expert in veterinary science, and a community representative.

The Regulatory Compliance and Subject Safety Core will also be responsible for maintaining adherence to local institutional policies regarding conflict of interest with regard to research support and publication, in accordance with Federal regulations. The Principal Investigator (PI) and MDP investigators understand their responsibility in maintaining objectivity in research by ensuring that the selection of products for testing (Projects 1, 4) and the design and conduct, as well as the reporting of research are not biased by competing financial interests. The Core will maintain a registry of disclosures by MDP investigators regarding financial interests and other conflicts that may influence objectivity or the perception thereof. In the case of positive disclosures, information on management of the conflict will be recorded.

III. CORE SERVICES
The Regulatory Compliance and Subject Safety Core will direct and coordinate three components of the MDP: regulatory compliance, subject safety, and resource allocation. Much of this will be facilitated by close coordination of this Core’s administration with that of Core C (Data Management and Biostatistics) for electronic document and data review and storage, AE report notification, filing and storage and other standardized entry forms such as questionnaires used in Project 3, and CRFs used in Project 4. The Core will also be jointly responsible with Core C in preparing the Data Monitoring Reports (DMR) to be presented to the DSMB.

A. Regulatory Compliance
i. Organize and track all protocol and informed consent submissions, approvals, amendments and renewals (both in real time to ensure timely turnaround with tracking and as a dated repository in the “regulatory library” for site reviews), FDA and PSRC communications, and IRB submissions and approvals. (Projects 1, 2, 3, 4)
ii. Assist in all IND preparation, submissions and FDA correspondence. (Projects 2, 4)
iii. Utilize appropriately qualified individuals both centrally- and site-based for oversight of the overall conduct of the trials, to handle data, to verify the data, and to prepare the project reports. (Projects 2, 3, 4)
iv. Ensure Protection of Human Subjects Training and HIPAA certifications remain current for all appropriate present research personnel and training is mandated for all new personnel. Training logs will be maintained on all key personnel as well as a master file for any changes in staff and delegation of responsibilities. (Projects 1, 2, 3, 4)
v. Establish and maintain a web-based data system, in conjunction with Core C, to produce reports and track existing and evolving information related to regulatory responsibilities of the cores. (Projects 1, 2, 3, 4)
vi. At study completion, Core B will work closely with the respective Project Leader/Team and Core C to clean the data set, lock down the final data set, produce final outcome results, and prepare a final report. (Projects 1, 2, 3, 4)
vii. Ensure that animal studies are being conducted according to federal and international guidelines (Animal Welfare Act and The Animals (Scientific Procedures) Act of 1986 respectively). (Project 1)
viii. Maintain registry of disclosures by MDP investigators regarding conflict of interests. (Projects 1, 2, 3, 4)

B. Subject Safety
i. Establish and maintain a web-based, real-time information system in conjunction with Core C for serious adverse experiences (SAEs) and adverse experiences (AEs). (Projects 2, 3, 4)
ii. File and track SAE and AE reporting to all appropriate regulatory bodies for the projects, providing a common site for tracking all MDP-related safety events. (Projects 2, 3, 4)
iii. Assist in the development of an independent Data Safety Monitoring Board (DSMB) and be jointly responsible with Core C in the preparation of Data Monitoring Report (DMR) and in coordinating interval meetings. (Projects 1, 2, 3, 4)
iv. Maintain records and oversight of recruitment, accrual, retention and demographic profiles for each study. (Projects 1, 2, 3, 4)

C. Resource Allocation
i. Develop standard operating procedures (SOPs) for the core use to clarify flow and responsibilities, including documentation requirements regarding study protocol versions and receipts, reviews and amendments, consent form records.
ii. Centrally coordinate and provide technical expertise to write IND submissions, protocol review summaries and related reports for the projects.
iii. Coordinate and prepare for meetings, conference calls and site visits with the FDA, NIH, CRO or other groups collaborating in the MDP proposal.
iv. Develop and coordinate IRB-approved clinical trial subject database with HIPAA compliance, confidentiality maintenance and 6-monthly interrogatories as to whether the subjects wish to remain contactable.
v. Quality assurance and quality control will be maintained by computer-assisted (Core C) daily monitoring of data uploaded into the site-specific website. Normative ranges will be described and discrepancies will be automatically flagged. The site will be contacted for clarification or correction. All changes will be tracked and an audit trail will be maintained. This novel feedback system will ensure timely interventions, corrections and preservation of scientific integrity.
Additionally, each project will perform a bimonthly internal quality assurance assessment of the uploaded data on the website. A 10% audit of randomly selected data fields will be verified for accuracy.

IV. CORE MANAGEMENT
A. Prioritizing
A quality assurance/regulatory compliance Master Audit Plan will be designed for each project that will define timelines for both the project’s overall progress as well as tracking renewals for regulatory documents. This will be achieved by the Core Director/Co-Director meeting soon after funding, with each project leader and team to define the Core’s role in each AIM of each Project over the 5-year period. A master GANT chart will be prepared for each Project as well as the MDP overall. Core C will assist in all IRB-related, clinical trial timeline features of the GANTT chart and will maintain and make the charts accessible on the appropriate portions of the website. These timelines will be reviewed independently every two months by Core B and, subsequently, on scheduled teleconferences with each project leader. The Master Audit Plan will also assist in the prioritizing of resources to meet proposed timeline deadlines.

B. Monitoring Core Usage
A tracking system will be developed to document each project’s time demands and resource usage of the Regulatory Compliance and Subject Safety Core services. In addition, recording of the number of visits to the relevant Core-related websites (managed by Core C) by each project will be monitored to determine the utility of this novel aspect applied to multi-site trials.

C. Data Safety Monitoring Board (DSMB)
The core, in preparation for DSMB reviews, will review non-confidential reports to the DSMB prepared by Core C, in order to ensure the highest quality review by that body. These preliminary reviews will ordinarily be handled by conference call, with the format starting with a session with the Executive Committee of the Administrative Core and the Director/Co-Director of the Regulatory Compliance and Subject Safety Core to discuss the presentation and prepare the items needed for DSMB review. Reports will be prepared with the assistance of the core (in terms of formatting and data acquisition) and the project leaders. The prepared reports will be circulated to the DSMB members, followed within 2-3 weeks by the formal closed DSMB meeting (in person or by teleconference). This will be followed by interaction with the investigators to answer questions and clarify issues, followed by an executive DSMB session during which the major recommendations are formulated.

The DSMB will be a single group appointed and recruited with a charge to oversee all MDP-related projects for the entire 5-year period. This will ensure continuous oversight and benefit both the subjects and the investigators by having review boards familiar with the nature of the related research efforts. Membership in the DSMB will be constituted by having a medical officer at UCLA and JHU, an expert in veterinary science from the Health Protection Agency, Porton Down, a biostatistician (UCLA) capable of reviewing all Projects’ data as well as a Community Representative. The specific member’s descriptions and qualifications are listed below under Core Personnel. The DSMB members, along with key personnel from each project, will develop a DSMB charter and SOPs regarding their data reviews. Setpoints for guidance regarding recommendations for modification/termination of individual projects will be incorporated into each final project protocol based upon relevant information provided by Core C in consultation with individual project teams. DSMB members are reimbursed $1500 per year for their time in reviewing reports and participation in meetings. It is anticipated that the DSMB will meet on a quarterly basis. The frequency of DSMB meetings may be subject to change based upon individual project recruitment and any safety issues that arise.

D. Interfacing with Data Management and Biostatistics Core (Core C )
As discussed throughout this proposal, there will be an interdependent collaboration between Regulatory Compliance and Subject Safety Core (Core B) and Core C. Core C will provide the infrastructure by which Core B will be able to conduct its regulatory oversight. Core B will ensure the integrity of the data provided so that the reports and analyses performed by Core C are accurate and sound. The Core Directors/Co-Directors (Denny for Core C and Fuerst for Core B) will be responsible for communication between the Cores to ensure the integration of the data.

E. Quality Control/Quality Assurance
Related to overall study conduct: The Regulatory Compliance and Subject Safety Core will also interface with study medical officers and externally contracted clinical monitors to translate monitoring reports into actionable items. We understand that the NIH will employ external monitors to work with us, evaluating the performance sites for good clinical research practice (including appropriate case history contents, source data documentation, chart notes, visit checklists, product dispensing and accountability records), regulatory compliance, accurate protocol implementation, internal quality assurance, HIV testing and counseling, and test agent accountability. Problems and issues identified by monitors will be related to the Executive Committee of the Administrative Core and back to the relevant project leader and team members as well as incorporated into the DMR. Relevant lessons for other studies will be confidentially extracted and included in the interval memoranda sent by the Core to all MDP investigators.

V. CORE PERSONNEL
A. Regulatory Compliance and Subject Safety Core Director
Ian M. McGowan, M.D., Ph.D. will function as the Regulatory Compliance and Subject Safety Core Director. Prior to taking up his current post at UCLA he spent a total of five years in the pharmaceutical industry as a Director of Clinical Research. His area of expertise is in antiretroviral drug development and he worked on the development programs for abacavir and amprenavir at GlaxoWellcome and tenofovir DR (TDF) at Gilead Sciences. While at Gilead Sciences he was responsible for the TDF development program. This included the development, execution, safety monitoring, and regulatory oversight of the Phase II / Phase III studies in Europe, North America, and Latin America. More specifically, he was responsible for producing the TDF investigator brochure, writing the TDF Phase II/III protocols including the informed consent forms, and assuring the TDF investigators were conducting the TDF clinical studies in compliance with FDA and local regulations. In addition, he established the data safety monitoring board (DSMB) for the TDF development program and was responsible for organizing the DSMB meetings. Although he was supported by colleagues in the regulatory division at Gilead Sciences, he was responsible for leading discussions with the FDA and European regulatory authorities including the presentation of the end of Phase II TDF meeting with the FDA. Throughout his career in the pharmaceutical industry Dr. McGowan received extensive training in GCP/ICH and while at GlaxoWellcome attended the Postgraduate course in Pharmaceutical Medicine run the University of Wales, UK. More recently he has received additional training in GCP (ACRP GCP course, September 2002) and HIPAA regulations. He currently has active human research certification from the David Geffen School of Medicine at UCLA.
The role of the Core Director will be to maintain overall responsibility for the Regulatory Compliance and Subject Safety Core. Dr. McGowan will provide scientific expertise in the development of INDs, serve as project leader on Project 1 of the MDP proposal and Co-Director of the Administrative Core (Core A.).

B. Regulatory Compliance and Subject Safety Core Co-Director
Amy Adler R.N., M.S.N., F.N.P. (Core B, Co-Director) Ms. Adler is the clinical trials coordinator for the Center for HIV and Digestive Diseases (CHADD). She will serve as the Co-Director of the Regulatory Compliance and Subject Safety Core. Ms. Adler is a master' s prepared registered nurse and board certified family nurse practitioner. Her experience spans from the "bench to the bedside".

Ms. Adler's began her career as a research biologist with a large pharmaceutical company working under GLP conditions. She was the clinical trial coordinator and data manager of clinical research trials in GI Oncology at the University of California- San Francisco from 1997 to 2001. Her work at UCSF included the development of a translational research database, accounting and financial tracking/oversight, IRB preparation/submission and approval maintenance as well as the managing the conduct of clinical trials. She was recruited to UCLA to be the Clinical Nurse Coordinator of the Center for HIV & Digestive Diseases in July 2004. At UCLA, she is responsible for overseeing all regulatory aspects of clinical trials and research for CHADD as well as recruiting and maintaining all study subjects. She manages the clinical research efforts at CHADD in coordination with the basic science efforts. Ms. Adler maintains her clinical skills as a nurse practitioner by serving the community as a primary care provider at a community clinic 10 hours/week.

Ms. Adler's familiarity with the various roles in this novel translational project, will allow her to act as a liaison between the investigators, sponsors, and regulatory bodies. Her diverse skill set includes developing and managing multidisciplinary clinical research groups as well as maintaining regulatory compliance.

Ms. Adler will oversee all activities of the Regulatory Compliance and Subject Safety Core in conjunction with the Core Director, Dr. McGowan, and be responsible for the daily operation of this Core and management of ancillary personnel.

C. DSMB
i. Ronald Mitsuyasu, MD (UCLA, Medical Director, Committee Co-Chair)
Dr. Ronald Mitsuyasu is Professor of Medicine and the Director of the UCLA Center for Clinical AIDS Research and Education (CARE Center) at the University of California, Los Angeles. Dr. Mitsuyasu is associate director for clinical programs of the UCLA AIDS Institute and heads the UCLA AIDS Clinical Trials Unit. He is the past chair of the Immunology Research Agenda Committee (IRAC) of the NIAID Adult AIDS Clinical Trials Group (AACTG) and has served on the Steering Committees of the AACTG and the NCI’s AIDS Malignancy Consortium (AMC). He has been a member of several DSMBs including the NHLBI’s DSMB for the Transfusion in HIV study. Dr. Mitsuyasu helped establish one of the nation’s first Kaposi’s sarcoma clinic in the USA at UCLA in 1984. His research interests include clinical trial investigations of cytokines, immune-based therapies, biologic response modifiers, vaccines and gene therapies for HIV and treatments for AIDS-related malignancies. He will serve as a member and Medical Officer for the DSMB for this proposal.

ii. Paul Lietman, MD, PhD (Johns Hopkins University, Medical Director, Committee Co-Chair)
Paul S. Lietman, MD, PhD, is a Clinical Pharmacologist and Pediatrician with decades of clinical trial experience and service on institutional review boards that are ample qualification to serve on the DSMB proposed. Dr. Lietman directed the Division of Clinical Pharmacology at Johns Hopkins University for 28 years. In this capacity, he created the Drug Development Unit to rigorously implement clinical studies of drugs in development that has now completed over a hundred clinical investigations of drugs in development, including many first in human studies. He has decades of experience in clinical intervention studies, most often early in the human clinical development (phase I or phase II), with special emphasis in anti-infectives, including significant work in the antiretroviral arena. He has served in related leadership roles, including service as the first Chairman of the Pharmacology Committee of the AIDS Clinical Trials Group. He is recipient of the Oscar B. Hunter Award for Therapeutics from the American Society of Clinical Pharmacology for a meritorious career in drug research. He has served on the institutional review board (IRB) at Johns Hopkins University School of Medicine for over 20 years and is currently the chairman of one of 5 IRBs at Hopkins. He has also served as consultant to the pharmaceutical industry and the FDA for his expertise in clinical drug development, including numerous safety investigations (e.g., Bendectin congenital anomalies and FIAU-related deaths).

iii. Graham Hall, FRCPath, MRCVS
Dr Graham Hall is a Scientific Leader at the Health Protection Agency, Porton Down where he provides expertise in veterinary science and pathology to research projects and where he is “Named Veterinary Surgeon” under the Animals (Scientific Procedures) Act 1986, having responsibility for the health and welfare of animals in experiments. He has over 40 years of research experience, 21 of which were spent at what is now the BBSRC Institute for Animal Health where he developed his expertise in experimental veterinary pathology, investigating the pathogenesis of bacterial and viral diseases of cattle and pigs. During 11 years at CAMR (now HPA Porton Down) he has been responsible for the health and welfare of rhesus macaques infected with simian immunodeficiency virus and has investigated the pathogenic processes associated with SIV infection in macaques, particularly the enteropathy that develops. He has contributed to studies of experimental anthrax in pigs, tuberculosis in guinea pigs as models for evaluation of new vaccines and other animal models of human infections. Dr Hall has co-authored 90 publications and is an editor of the journal Research in Veterinary Science.

iv. Christina Kitchen, PhD (UCLA, Biostatistician)
Dr. Christina Kitchen is an Assistant Professor in Residence in the Department of Biostatistics, UCLA School of Public Health. Dr. Kitchen is a member of the American Statistical Association and has received various honors in her field. She was the recipient of the National Institutes of Health Predoctoral Individual National Research Service Award, the National Institutes of Health AIDS Training Grant, UCLA AIDS Institute Seed Grant, and recently elected member of Delta Omega, Public Health Honor Society. As a Co-Investigator for the NIH/NIAID P30 CFAR, Biostatistics Core H, Dr. Kitchen has provided biostatistical advice to AIDS researchers at UCLA. She is also the Principal Investigator for UCLA AIDS Institute Center for AIDS Research, “Evolution of HIV-1 Coreceptor Utilization and Diversity.” Dr. Kitchen’s has previously served as the biostatistician member of the DSMB for Dr. Anton’s vaccine trial R01 (#AI50467; Role of Immunization Site in Eliciting Mucosal Immunity).

v. John Slovick (Community Representative)
John Slovick began educating people about HIV as a volunteer for AIDS Project Los Angeles' Southern California HIV/AIDS Hotline. Joining the Hotline staff in 1996 as a referral specialist, his responsibilities involved researching, coordinating and updating referrals for all of Southern California, as well as scheduling a large volunteer base. Moving to the position of Treatment Advocate, Mr. Slovick counseled hundreds of people on all aspects of HIV disease. This was accomplished through individual sessions, physician visits, community education forums and conference presentations. In addition, under a grant from the Office of AIDS Programs and Policy, he designed and executed the 'Treatment Advocacy Training'. Held three times a year, the training brought Treatment Advocates in contact with a wide variety of experts in the field of HIV to allow them to better serve their clients. He has also worked closely with Dr. Anton for the past 2 years on their present HIV vaccine trial (AI50467), acting as the community liaison and lay educator to ensure full understanding of the consent form (each visit = 2 hours).