Introduction to Clinical Research NCURA Region I Spring Meeting May 5, 2015
Agenda Introductions Brief History of Clinical Research Clinical Research in Context Clinical Research Compliance Clinical Research Management Selected Study Start-up Activities Monitoring Clinical Research Summary/Questions
Introductions Nick Repucci is the Director of the Clinical Trials Business Office (CTBO) at Boston Children s Hospital. He oversees contract and budget development and negotiation for corporate-sponsored clinical trials, investigatorinitiated studies, and other sponsored clinical research. He also provides oversight on other business requirements of engaging in clinical research at Children's, including making prospective insurance coverage determinations, coordinating charges for routine- and research-related care, invoicing sponsors, and ensuring compliance with state and federal billing regulations. Eric Tomasini is a Director in the Research Enterprise Solutions team at Huron Consulting Group. He has 17 years of experience in pharmaceutical, life science, contract research organization, academic medical center and management consulting environments. During that time Eric has worked across the research spectrum, to build and strengthen clinical trial offices, offices of research administration, research compliance programs, as well as large scale high performance computing environments supporting omics research platforms. He also has experience with governance planning, research cores and cost take out projects. He specializes in clinical research strategic planning, business process assessment, design, and implementation of people process and technology systems.
Brief History of Clinical Research
Brief History of Clinical Research Landmark Studies 562 BC - 1537: pre-james Lind King Nebuchadnezzar (562 BC) The Bible (1 st clinical trial ) Avicenna (1025) Canon of Medicine (rules for testing drugs) Ambroise Pare (1537) 1 st trial of a new therapy (an accident!) 1747: James Lind and the Scurvy Trial 1800: placebo defined 1863: Austin Flint 1 st study comparing placebo to active tx 1943: 1 st 2x blind controlled trial (patulin for Common Cold) 1946: 1 st randomized controlled trial (streptomycin for TB)
Brief History of Clinical Research Ethical and Regulatory Framework ANTIQUITY: the ancient Hippocratic Oath 1906/1938: U.S. Food and Drugs Act (drug safety) 1947: the Nuremberg Code (informed consent requirement) 1949: WMA International Code of Medical Ethics 1962: Kefauver-Harris amendments (informed consent law) 1964: Helsinki Declaration 1974: National Research Act and 45 CFR 46 (IRB regs) 1979: Belmont Report (Respect, Beneficence, and Justice) 1991: Common Rule 1996: ICH Guideline E6: Good Clinical Practice
Clinical Research in Context
Clinical Research in Context Along the Spectrum Research can be thought of as a spectrum, where bench activity and insight build over time and translate into bedside improvements for the improved health of patients. Clinical Research is an area of patient-oriented research conducted in human subjects related to mechanisms of disease, therapeutic intervention, clinical trials, epidemiology and outcomes based research.
Clinical Research in Context Along the Spectrum
Clinical Research in Context Academic Medical Centers
Clinical Research in Context Academic Medical Centers Tripartite Mission is Complicated Defined Grant Funded Career Translational Research Focus NIH Funded Culture and Competency Clinical Trials may be seen as other in the portfolio
Clinical Research in Context Academic Medical Centers AMCs have three missions: 1) Teaching, 2) Research, and 3) Patient Care. These missions enhance the complexity of a health care environment: in transition. Decrease in funding sources Competing needs for investment Decrease in medical care reimbursement Increasing demands for external reporting information Highly regulated environment Clinical Enterprise
Clinical Research Compliance
Clinical Research Compliance Human Subjects Research Protections / IRB HIPAA / Privacy Good Clinical Practice (GCP) Conflict of Interests CMS Open Payments ( Sunshine Act reporting) Research Misconduct Clinical Trials Billing Medicare National Coverage Determination 310.1 Routine Costs in Clinical Trials Affordable Care Act, Section 2709
Clinical Research Management
Clinical Research Management Operational Structure Guiding principles: Streamline operations Improve compliance Educate and mentor research faculty and staff Provide infrastructure and tools Support translational research activities Develop, implement, and report internal and external metrics Stage 0 Informal Clinical Research Management Process is informal, not well-defined, or based mainly on individual experience. Stage 1 Functional Clinical Research Management Excellence Process is defined within one or more functional disciplines but is not well integrated across the hospital. Stage 2 Operations Management Excellence Process is integrated across functional disciplines and provides a clear road map across the hospital. Stage 3 Portfolio Management Excellence Methodology is fully integrated with processes such as research strategy and life-cycle management and can be integrated across the hospital. AMC Clinical Trial infrastructure varies in maturity, from informal processes to fully integrated service level management operations 16
Clinical Research Management Integration and Planning Project Management Financial Management Create Demand with Study Actiivities Resource Management Integrated Operations and Business Planning Matching Cost and Revenue With Study Activities Portfolio Management Matches Demand With Resource Capacity Defines Strategic Positions and Defines Priorities Among Studies 17
Clinical Research Management Framework
Clinical Research Management Stages
Selected Study Start-up Activities
Selected Study Start-up Activities Medicare Coverage Analysis An MCA is a detailed examination of the items and services provided in a clinical trial to determine whether they are conventionally or routinely provided to patients in a particular disease state, or if they are to be provided to the patients for study purposes only. Benefits: Help institutions ensure clinical trials billing compliance, avoid government scrutiny, and improve the coordination and management of clinical trials. Help researchers develop and negotiate better clinical trial budgets and agreements, maximize recovery of research-related costs, and minimize financial burden on research participants.
Selected Study Start-up Activities Medicare Coverage Analysis There are three Medicare coverage rules that provide guidance and restrictions on reimbursement for care provided during clinical trials: 1. 42 C.F.R. 413.90 a regulation that has been in place since 1966 specifying that costs incurred for research purposes, over and above usual patient care, are not includable as allowable costs; 2. Medicare s Clinical Trial Policy [National Coverage Determination for Routine Costs in Clinical Trials (NCD 310.1)] a Medicare coverage rule that was introduced in 2000, last revised in 2007, and outlines coverage rules for routine costs in qualifying clinical trials; and 3. regulations on category B investigational device exemptions (IDE) found in 42 C.F.R. 405.201-405.215, 411.15, and 411.406.
Selected Study Start-up Activities Medicare Coverage Analysis Medicare coverage analysis relies on the use of Medicare coverage rules and routine care guidelines as the basis for making billing decisions. Can be used as a proxy for making billing determinations for most payors Institutions should not solely rely on Medicare regulations to make billing determinations Affordable Care Act, Section 2709 State Laws Payor Policies Institutions should specify in P&P which laws/regs to use.
Selected Study Start-up Activities Medicare Coverage Analysis Step-by-Step Instructions for Conducting Medicare Coverage Analysis: 1. Gather essential documentation. 2. Determine whether the study is a qualifying clinical trial. 3. Identify all items and services that are part of the clinical trial. 4. Identify all items and services that are reimbursed by the sponsor or provided by the sponsor at no cost to the research site or study subjects. 5. Identify all non-billable items and services. 6. Determine whether or not any remaining non-routine care items and services are covered by Medicare.
Selected Study Start-up Activities Budgeting The MCA for a protocol becomes the template for the development of the budget. Non-billable administrative activities should be covered by the sponsor Routine care should be covered by insurance, or sponsors may agree to cover it Non-routine care should be covered by the sponsor If the study doesn t qualify for coverage, the sponsor must pay for everything.
Selected Study Start-up Activities Budgeting Budget for start-up costs (much more than an IRB fee) and close-out costs If it takes time or resources to prepare to conduct the study or wind down a study, you should budget (and bill) for it. Determining the cost of non-billable study activities: Define the time requirements and responsible personnel for all non-billable activities Estimate the costs based on the time requirements and average salaries of the personnel performing the tasks. For billable AND non-billable patient care expenses, use the CDM to budget. Start with the highest $ (unless it s federal).
Selected Study Start-up Activities Agreements Confidentiality Disclosure Agreement (CDA): governs the scope, use, and ownership of confidential information shared between and developed by the parties; can be oneway or mutual, depending on the purpose of the exchange Clinical Trial Agreement (CTA): governs the legal and administrative terms and provisions under which a clinical trial is to be conducted; incorporates the study protocol and payment terms (w/budget) Data Use Agreement (DUA): governs the transfer of data between the Institution and another party; for incoming and outgoing data.
Selected Study Start-up Activities Agreements Competing Interests and Common Ground Issues/Competing Interests: Human subject protections (privacy and safety) Subject injury Indemnification Publication rights Payment Intellectual property rights and ownership Common ground: Conduct a successful, well-managed trial Create new therapies and improve patient care Protect their rights
Monitoring Clinical Research
Monitoring Clinical Research Data and Safety Monitoring Data and safety monitoring is required for all types of clinical trials. There are two main principles that guide the monitoring of data and safety of clinical trials. Monitoring should be commensurate with the risks associated with the experimental therapy. The method and degree of monitoring needed should be tied to the amount of risk involved. Monitoring should be commensurate with size and complexity of the clinical trial. Various individuals or groups may be involved in the monitoring of a trial, and this oversight may be conducted in different ways depending on the magnitude of the research effort.
Monitoring Clinical Research Data and Safety Monitoring NIH-sponsored investigative sites: Must document a plan to ensure data and safety monitoring as a provision of becoming a grant awardee Who shall perform the monitoring activities? How frequently should monitoring take place? Should meetings be open or closed, public or private? What content should be contained within meeting reports and should be asked when developing a monitoring plan? All NIH-sponsored multi-site interventional clinical trials require the establishment of Data Safety and Monitoring Boards ( DSMBs )
Monitoring Clinical Research Data and Safety Monitoring DSMBs: Regularly reviews accumulated data from one or more ongoing clinical trials to ensure the safety of participants in the trials and the validity and integrity of the scientific data generated. DSMBs are primarily in place to ensure the safety of human subjects in situations in which safety concerns may be excessive. DSMBs are often not needed for trials of drugs or devices in the early stages of product development, or when the study population is not high risk of encountering serious adverse events.
Monitoring Clinical Research Data and Safety Monitoring Activities of the DSMB: Review the research protocol Evaluate data and safety monitoring plan Evaluate the progress of the trial Analyze the quality of the data Address subject enrollment issues Assess the risks and benefits Examine any other factors that may affect the study results Conducting interim analyses of the accumulating data Make recommendations to the investigator(s), the sponsor, and the IRB as to whether the trial should continue or be concluded
Monitoring Clinical Research Industry / Sponsor Monitoring When conducting industry-sponsored and initiated clinical trials, the majority of the monitoring and oversight of the research is conducted by the company, itself, or by a contract research organization (CRO). Industry sponsors of clinical trials evaluating new drugs, biologics, and devices are required to monitor these studies. Generally adhere to the Food and Drug Administration s (FDA) industry guideline for the monitoring of clinical investigations
Monitoring Clinical Research FDA Guidelines for the Monitoring of Clinical Investigations FDA Guidelines for Sponsors: Monitor should know the study data, protocol and regulations. Number of monitors and the expertise required should be a function of the number of investigators, the number and location of the performance sites, the complexity of the study, the specific test article, and the disease characteristics. Written monitoring policy or procedure Should conduct an initial site visit and make certain that the investigator clearly understands and accepts the protocol requirements prior to the initiation of the study. Visits should help ensure proper handling of the test article and investigator oversight
Monitoring Clinical Research FDA Bioresearch Monitoring (BIMO) Program FDA developed BIMO to ensure: The protection of the rights, safety, and welfare of human research subjects The quality and integrity of data submitted to the Agency BIMO Program involves site visits to clinical investigators, IRBs, nonclinical (animal) laboratories, and bioequivalence analytical laboratories
Monitoring Clinical Research Types of BIMO Inspections FDA conducts inspections of clinical investigators: Routinely to verify data that has been submitted to the Agency As a result of a complaint to the Agency about the conduct of the study at the site In response to sponsor concerns or termination of the clinical site At the request of an FDA review division
Monitoring Clinical Research Types of BIMO Inspections Routine Inspection VS For-cause Inspection
Monitoring Clinical Research Types of BIMO Inspections Routine Inspections: Triggered by a New Drug Application (NDA) or Pre- Market Application (PMA) submission Routine inspections account for over 80% of the inspections performed each year Clinical Investigators who enroll the most subjects in the NDA s pivotal trial are the most likely to be inspected
Monitoring Clinical Research Types of BIMO Inspections For-cause Inspections: Conducting a large volume of clinical trials Conducting clinical studies outside of one s field of specialization Reporting significantly better efficacy, fewer adverse effects, or different laboratory results than other investigators studying the same drug Having apparent access to too many patients with a specific disease state for the locale or practice setting Complaints from a patient or sponsor of an alleged violation of the regulations, protocol, or human rights Evidence that an investigator has significant financial interest
Monitoring Clinical Research Most Common FDA Findings Failure to follow the investigational plan Failure to ensure that informed consent was obtained in accordance with 21 CFR 50 Failure to maintain accurate, complete, and current records Inadequate device/drug accountability Failure to obtain IRB approval
Summary
Summary Clinical research has existed in some form or fashion for thousands of years, but the ethical and regulatory framework for conducting clinical research has evolved only over the past century. and it is still evolving. Clinical research is just one part of the research continuum. It is one step in the process of translating scientific discoveries into long-term improvements in public health. Clinical trials are an essential but smaller (and often undervalued) part of the research portfolios of many academic medical centers.
Summary The clinical research legal and regulatory environment is immensely complex and challenging to navigate. To be highly effective, clinical trials management must be thought of as a fully integrated system one that enables multiple offices, processes, technologies, and researchers to work together across the institution. Clinical Research Management needs to be scalable, efficient and tailored to the needs of the institution and the research community
Summary Routinely monitoring data and safety in clinical trials is also critically important to properly manage clinical trials. Data and safety monitoring should be commensurate with the safety risks involved but some degree of study monitoring and reporting is required of all clinical trials. Sites and sponsors want the same things: compliance, successful trials, adequate study oversight, ownership and protection of intellectual property, and among others, better treatment options for patients. This is one small snapshot of clinical research. There are courses entirely focused on each topic we discussed today. 45
Questions? Nick Repucci Director, Clinical Trials Business Office Boston Children s Hospital nicholas.repucci@childrens.harvard.edu Eric Tomasini Director, Research Enterprise Solutions Huron Consulting Group etomasini@huronconsultinggroup.com