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
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King Nebuchadnezzar (562 BC) – The Bible (1st “clinical trial”)
Avicenna (1025) – Canon of Medicine (rules for testing drugs)
Ambroise Pare (1537) – 1st trial of a new therapy (an accident!)
1747: James Lind and the Scurvy Trial
1800: “placebo” defined
1863: Austin Flint – 1st study comparing placebo to active tx
1943: 1st 2x blind controlled trial (patulin for Common Cold)
1946: 1st randomized controlled trial (streptomycin for TB)
Brief History of Clinical Research
Ethical and Regulatory Framework
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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
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Human Subjects Research Protections / IRB
HIPAA / Privacy
Good Clinical Practice (GCP)
Conflict of Interests
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CMS Open Payments (“Sunshine Act” reporting)
• Research Misconduct
• Clinical Trials Billing
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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 3
Stage 2
Stage 1
Stage 0
Informal Clinical
Research
Management
Process is informal, not
well-defined, or based
mainly on individual
experience.
Functional Clinical
Research Management
Excellence
Process is defined within
one or more functional
disciplines but is not
well integrated across
the hospital.
Operations
Management Excellence
Process is integrated
across functional
disciplines and provides
a clear road map across
the hospital.
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
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Clinical Research Management
Integration and Planning
Project Management
Financial Management
Create Demand with
Study Actiivities
Matching Cost and Revenue
With Study Activities
Resource Management
Matches Demand With
Resource Capacity
Integrated
Operations
and
Business
Planning
Portfolio Management
Defines Strategic Positions and Defines
Priorities Among Studies
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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:
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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.
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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
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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:
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Gather essential documentation.
Determine whether the study is a qualifying clinical trial.
Identify all items and services that are part of the clinical trial.
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.
Identify all non-billable items and services.
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.
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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
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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:
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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:
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Human subject protections (privacy and safety)
Subject injury
Indemnification
Publication rights
Payment
Intellectual property rights and ownership
• Common ground:
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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.
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Monitoring should be commensurate with the risks associated
with the experimental therapy.
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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.
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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:
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Must document a plan to ensure data and safety monitoring as
a provision of becoming a grant awardee
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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:
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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:
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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.
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Questions?
Nick Repucci
Director, Clinical Trials Business Office
Boston Children’s Hospital
[email protected]
Eric Tomasini
Director, Research Enterprise Solutions
Huron Consulting Group
[email protected]