Phase II-IV Clinical Trials:
Clinical Trial Management and Monitoring

Project Management
Through strong team structures, close communication, and detailed tracking and measurement, the Project Management group delivers consistent high quality services to customers. RCRS provides its project management services in India as well as in UK and Poland.

Projects vary based on size, complexity, therapeutic area and specific customer requirements. All projects conducted by RCRS, whether with a single service scope of work or a full-service global program, follow a common project management methodology that provides sponsors with a standardized and disciplined approach to project management. This methodology provides each Project Manager with a set of standards and guidelines to manage projects in the most effective manner.

Project Managers work closely with the sponsor project team from project kick-off and start-up through completion of the final study report or contract closure to meet their objectives. This team approach to project management ensures that the project will be completed according to specific study requirements and timelines. RCRS provides detailed timely tracking of each project to make sure that sponsors consistently know the status of their project. RCRS tracks key metrics and milestones for every project, and by agreeing on these milestones ahead of time with the sponsors, it lays a foundation for effective communication, reporting, continual improvement, and demonstration of success.

Project Managers have the background and skills necessary to effectively manage the following important project management components:

Customer relationships and communication
Developing and executing customer-specific requirements
Effective project planning and scheduling
Project resource planning and allocation
Project risk planning and analysis
Project budgeting
Project communication
Project tracking and status reporting
Proactive issue identification and resolution

The Project Manager serves as a primary resource and central point of communication for the project team and provides leadership and direction, including identifying and assembling training opportunities, to build a performing project team. RCRS assigns the right staff for each project, assembling a highly motivated, integrated team that best suits the needs of the study and the sponsor, based on factors such as therapeutic experience, prior site performance and location. Project teams typically consist of a Project Director (who supervises the team and oversees quality and training), a Project Manager (who co-ordinates communication and study activities, and manages timelines and budgets), a Team Leader within each operational area (e.g. a clinical team leader provides tracking, support, consistency of monitoring and support for the regional monitoring team), Site Monitors (who co-ordinate the trial at site), Clinical Trial Assistant to co-ordinate the documentation and communication in the study and other operational team members depending upon the scope of work.

Co-ordination of Investigator Meetings
Investigator meetings co-ordinated by RCRS are geared towards creating a dynamic environment for the interaction of individuals with a common purpose. These interactive meetings are designed to be both informative and thought provoking, and enable investigators to develop a dialogue with sponsors on best practices for managing the study and gathering clinical trial data. The meetings also include training in key areas including trial protocol, current Good Clinical Practice (GCP) guidelines and study-specific procedures.

A successful investigator meeting helps to build stronger relationships with key target audiences and provides a platform to launch enduring materials to broader audiences. From scientific presentations to program management, meeting services, creative design and production, RCRS aims to conduct meetings that are engaging, dynamic and effective.

RCRS utilizes proactive processes for management of diverse investigative sites, including onsite visits to ensure necessary standards for conducting the study, training of site personnel, identifying and offering customized solutions to logistic issues faced at sites, and coordinating resolution of non-compliance issues in a speedy manner. Throughout each clinical trial, the group works closely with sites to upgrade infrastructure to fulfill trial and current regulatory requirements. The RCRS team works closely with investigators to accelerate patient recruitment and ensure patient compliance. RCRS applies real-time site performance metrics that track the progress of studies at each site.

Clinical Trial Site Qualification and Monitoring
RCRS provides Clinical Monitoring services via office-based and regional Clinical Research Associates with a smooth flow of active communication amongst project team members. We provide monitoring services in India, Poland and Romania. The Site Monitors are ICH-GCP trained and provided with trial specific and Sponsor's SOP training (if required). The approach of each site monitor is for 'site oversight'- they are responsible for the efficient supervision of the site team, site team personnel training , the resources available at the site and the timelines set for the study milestones at the site.

The site qualification process ensures that the site meets the necessary requirements of the trial prior to study site initiation. RCRS has an extensive database of investigators in several disease domains that consist of physicians with extensive clinical trial experience. These investigators have the appropriate facilities and qualified support personnel, and are audited and approved by RCRS and thoroughly trained in Good Clinical Practices as well as on trial procedures and requirements.

RCRS offers high quality solutions driven by the combination of clinical trial expertise and resources that facilitate the collection and review of paper or electronic patient data in clinical trials.

Study monitoring services offered by RCRS are tailored to meet the objectives, design and requirements of Sponsors, and are characterized by planning, versatility, reliability, scalability, and the ability to interface with other participating vendors, all in compliance with stringent confidentiality and applicable local regulatory standards.

Clinical Trial Supplies Management
RCRS offers facilities and consultation for drug storage, inventory, and temperature-controlled transport for clinical trial supplies such as pharmaceuticals, vaccines, biologicals, devices, laboratory kits and equipment. These services are also compatible with the use of centralized randomization, drug assignment, and blinding techniques.

Clinical supplies are stored under customer-specified conditions with complete access control and disaster management and recovery processes. Supply distribution is tracked through delivery to sites in accordance with RCRS SOPs. Storage areas designated for drugs and biologicals are maintained at ambient, refrigerated or frozen conditions with 24x7 temperature monitoring and back-up power supply. RCRS also arranges for return and/or destruction of expired, unused and damaged trial supplies under customer-specified conditions.

RCRS also has readily available storage for samples at the following temperatures: ambient, refrigerated, and frozen at -20^oC, -70^ooC or -80^oC. Samples and materials that RCRS can store include genomic DNA, Plasma, serum, CSF, bone marrow, tissue specimens and biopsies.

Grant & Investigator Payments
The familiarity with the local legal and regulatory environments allows RCRS to efficiently create and manage Investigator contract and payment schedules that abide by local laws and appropriate agencies. RCRS also distributes and monitors Investigator grant and payment schedules for the Sponsor.

Central Pharmacy Services
The Central Pharmacy at RCRS provides Investigational Product storage facilities as per requirement for drugs in solid and liquid dosage forms, vaccines and other biologicals at controlled temperature (maintained at 2-8^oC and refrigerated -20^oC, -70^oC).

The services offered by the central pharmacy include:

Packaging, dispensing and bar-coding of each sample as per randomization
Dedicated pharmacy services and dispensing facilities for solid, liquid and parental dosage forms
Abundant sample archival facilities with temperature monitoring systems and back-up generators

Pharmacovigilance
Through a team of dedicated and experienced pharmacovigilance associates, RCRS provides a comprehensive and reliable 'Safety Services Portfolio' which includes;

Study and Sponsor specific, dedicated Pharmacovigilance associates
24x7 receipt and processing of Serious Adverse Events (SAEs)
Capability to enter data directly into Sponsor's safety database
Rapid medical & regulatory assessments of SAEs for reportability
Established pharmacovigilance follow-up and management practices
Timely transmission of safety issues to sponsors, Regulatory Affairs and Ethics Committee (EC)/Institutional Review Boards (IRBs)
Liaison between investigators and medical monitors at sponsor groups across varying regions and time zones .
Coding of medical terms and medications using MedDRA & WHO-DD
Narrative writing
Designing & conducting Post Marketing Safety (Phase IV) studies & safety data collection
Site safety audits for compliance
Management of safety issues associated with Medical Devices & Product Technical (Quality) Complaints
Medical literature search for regulatory submission
Training Sponsors / Investigators in Safety reporting infrastructure & processes

Biometrics
The RCRS Biometrics Group encompasses the functions of Data Management, SAS Programming, and Statistics. Our Biometrics staff is located in India (Bangalore, Mumbai). The Group is currently implementing CDISC standards and is compliant with ICH guidelines.

Data Management:
RCRS Clinical Data Management offers the full complement of Data Management services with experience in clinical trials ranging from Phase I - Phase IV. Data Management Services are dedicated to the highest Quality, Excellence, and Client Satisfaction through Project Management, Communication, and Execution of studies.

RCRS has developed a comprehensive Data Management Plan template which allows for rapid development of databases with our partners and encompasses the following:

Database design and validation
User access rights
Data processing
Query processing and resolution
Coding and Quality Control (QC) guidelines
Data transfers and data handling instructions
Global conventions

During project execution RCRS focuses on full team involvement and communication so that the end result is a clean database delivered on time.

Our core Data Management system is Oracle Clinical. The team is fully trained on this application and experienced in its use. Services provided by the team include:

Protocol Review
Case Report Form (CRF) Review
CRF Design, Printing, Distribution, Collection, and Analysis
Data Validation Specifications
Database Design
Data Receipt, Logging, and Tracking
Data Entry
Query Management
Medical Coding
Data Quality Assurance
Data Transfer
SAE Reconciliation
Data Management Reporting
Data Review Meeting
Data Management Plan (DMP) Development
DMP Review Meeting
Electronic Data Capture (EDC) Consulting

Statistics and Programming:
As with Clinical Data Management Services, the RCRS Statistical and Programming team offers the full complement of statistical services with experience in clinical trials ranging from Phase I-IV. Our statisticians work with clients from protocol design and sample size calculation through CSR writing and review. We have strong expertise in the full range of statistical methods including descriptive statistics, linear and nonlinear models, generalized linear models, categorical data analysis, time-to-event analysis, nonparametric methods, equivalence and non-inferiority methods and data imputation. Our statisticians and programmers have worked on protocols varied in size and complexity, across multiple therapeutic areas and study phases. RCRS can handle work as part of a full service project or take on discreet assignments for projects such as CDISC submission datasets and program validation.

The RCRS leadership team has a median of 15 years of experience in the industry, and has participated in numerous regulatory submissions. The core programming language used is SAS.
Services provided by the team include:

Protocol design
Sample size estimation
Statistical methods for protocols
Protocol and CRF review
Randomization schedules
Statistical analysis plan development for individual studies and ISS/ISEs
Programming of statistical tables, listings and graphs
CDISC dataset creation
Interim analyses
Data Monitoring Committee support
Independent programming verification
Support for marketing
Exploratory analysis
FDA and other regulatory body consulting
Analyses for manuscript preparation

Regulatory Affairs
The RCRS Regulatory Affairs team has considerable global experience in drug development and regulatory strategy. This enables its clients to most efficiently develop their new drugs and to achieve timely and successful regulatory submissions. RCRS has experience in drug development throughout the world, with focus on the US, EU, India, Middle East, and other Asia-Pacific countries. RCRS is able to provide regulatory liaison services including agency interactions of all types such as responses to agency requests for information, planning and preparations for successful scientific advice development meetings, and preparation and submission of documentation for clinical trial and marketing applications that meet all international requirements.

Based on the extensive knowledge of the regulatory environment and the changing requirements in many countries and regions, RCRS is able to provide strategic input, advice and services that are valuable to companies of all sizes. RCRS can provide input on documentation and agency interactions regarding exploratory INDs, fast track development, orphan drug classification, priority review, conditional approvals, regulatory gap analysis of development plans, labeling negotiations, risk management plans, and Advisory Committee Meeting support.

RCRS also has considerable global experience in clinical trial support including interactions with ethics committees, import and export licenses of trial materials, certified qualified staff for manufacturing and drug supply issues, legal representation where the company does not have a country office, submission of required trial documentation, investigator packages, Investigator's Brochure development (to ICH GCP standards), safety reporting, and annual reports.

RCRS is also able to provide significant lifecycle management support for its clients, including regulatory strategy to expand the market for an approved product by identifying new indications and dosage forms, and aiding the client in meeting all regulatory requirements such as submission of spontaneous adverse event reports to regulatory authorities, submission of Periodic Safety Update Reports, review of promotional materials to meet agency requirements, review of label changes, marketed product annual reports, manufacturing changes, and submission of post-approval commitments.

In summary, RCRS serves the entire spectrum of regulatory needs for its clients, based on experience and knowledge.

Quality Assurance (QA)
QA Personnel:

The hallmark of the RCRS QA team is international training and experience in clinical research, with a mandate to ensure compliance to international standards, ethics and GCP. The team focuses more on preventive than corrective actions to minimize issues that may arise from non-compliance. Our staff is experienced in Phase I-IV studies in drugs, devices and biologicals for both innovator and generic products and strives to continually improve internal systems to exceed sponsor expectations. The team members contribute in an advisory capacity to the Indian Society for Clinical Research (ISCR) and the Indian Forum for GCP (InfoGCP)

Services and experience:
The QA team has been providing study audit services to its existing clients with the goal being to avoid regulatory deficiencies. Our team has wide experience of working at the site, sponsor and CRO environments and thus has a high understanding of the local cultural intricacies in the various countries and regions we serve. Advice from the Regulatory team is an added feature of the services provided by the QA team to its clients. Our auditors have an eye for detail, capabilities for re-construction of study events and gap identification with regard to non-compliance to SOP, GCP and applicable regulations. RCRS lists its audit observations in confidential reports which are provided to the sponsor along with advice for immediate corrective action and systems improvement. Corrective Action Plans are reviewed for adequacy and evidence prior to closing audit findings. Audit observations are presented to sponsors by classifying them into minor, major and critical findings with specified timelines for reporting each of these classifications.

The following services are provided by the QA team:

Clinical Investigator Site Audits
Sponsor Audits
Systems Audits
Central Laboratory Audits
Clinical Trial Supply Audits
Adverse Event Reporting System Audits
Computer Systems Validation Audits
Database and Data Management audits
GLP Audits