Transcript Conflict of Interest - Drexel University College of Medicine

care
community
Overview of Good
Clinical Practice
Donna W. Dorozinsky, RN, MSN, CCRC
research
teach
Welcome
• Please silence cell phones
• Please limit exits and entrances
2
Course Objectives
• Discuss the purpose and various sponsors of
clinical research
• Discuss the evolution of Good Clinical Practice
and the importance of it in today’s research
environment.
• Discuss the general principles of Good Clinical
Practice including ICH Guidelines, Title 45 and
21 CFR, Parts 11, 50, 54, 56, 312 and 314
• Identify the sponsor, investigator and monitor
responsibilities in conduct of FDA regulated
studies.
The Clinical Research Process
• Clinical trials are a principled partnership
between the clinical investigator and industry
– Provide an avenue for providing cutting edge health
care to your patients.
– Provide a scientific and ethical pathway
for new product development.
– Create public awareness of the clinical research
process.
The Clinical Research Process
• Industry, in collaboration with clinical investigators,
develops diagnostic, therapeutic, and preventative
products to better serve the health care community.
– The clinical investigator plays an important role by
conducting
• Clinical trials to further profile the new product by
testing the safety and efficacy in a diversified patient
population
• Safety and efficacy testing involving patients
• Conducting translational research
Clinical trial: What does it mean?
Trials to evaluate the effectiveness and
safety of medications or medical devices
by monitoring their effects on large groups
of people.
Who are the players?
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Sponsor
NIH
CRO
SMO
Clinical Investigator
Institutional Review Board
The Sponsor
• Individual, group or company that takes responsibility for
the design, management and financing of the study.
– Investigator-sponsored research
– Commercial organization
• Biotech company
• Pharmaceutical company
– Federally funded (NIH)
• The responsibilities of the sponsor can be retained by
the original party or transferred to another organization
such as a Clinical Research Organization (CRO).
National Institutes of Health
• Department of Health and Human Services
• Funds research, conducts studies, and funds multicenter
national studies
• Composed of 27 Institutes and Centers
• NIH annually invests over $28 billion in medical research
through competitive grants
• 10% research is conducted at NIH in Bethesda,
Maryland
• Examples
– National Cancer Institute
NIH Impacting Health Care
• Death rates from heart disease and stroke fell by 40% and 51%,
respectively, between 1975 and 2000.
• The overall five-year survival rate for childhood cancers rose to
nearly 80% during the 1990s from under 60% in the 1970s.
• The number of AIDS-related deaths fell by about 70% between 1995
and 2001.
• Sudden infant death syndrome rates fell by more than 50% between
1994 and 2000.
• Infectious diseases—such as rubella, whooping cough, and
pneumococcal pneumonia—that once killed and disabled millions of
people are now prevented by vaccines.
• Quality of life for 19 million Americans suffering with depression has
improved as a result of more effective medication and
psychotherapy.
NIH Medical Discoveries
• The sequencing of the human genome
• Bioterrorism research
• Aggressively pursue ways to make effective vaccines for deadly
diseases like HIV/AIDS, tuberculosis, malaria, and potential agents
of bioterrorism.
• Progress in understanding the immune system may lead to new
ways to treat and cure diabetes, arthritis, asthma and allergies.
• New, more precise ways to treat cancer are emerging, such as
drugs that zero in on abnormal proteins in cancer cells.
• Novel research methods are being developed that can identify the
causes of outbreaks, such as Severe Acute Respiratory Syndrome
(SARS), in weeks rather than months or years.
CRO
• Sponsor delegates specific responsibilities to the
CRO
• Accountability remains with the original sponsor.
• A CRO that assumes a sponsor obligation is
required to comply with the local regulatory
requirements
• Examples
Site Management Organization
(SMO)
• Individual, a network of individuals or an organization
that sub-contracts clinical trial responsibilities from a
CRO.
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Contract negotiations with the trial institution
IRB approval
Patient recruitment
Patient follow-up
Informed consent form (ICF) translation into vernacular
languages
– Site initiation and trial close-out operations
– Trial-related documents archival and maintenance
– Reporting Serious Adverse Events to the CRO and the IRB/IEC
Clinical Investigator
• Ensures that an investigation is conducted
according to:
– the signed investigator statement,
– the investigational protocol
– applicable regulations;
• Protects the rights, safety, and welfare of
subjects under the investigator's care
• Responsible for the control of drugs under
investigation.
IRB
• A group of scientists, doctors, clergy, and
consumers
• Designed to protect study participants.
• Review and must approve the consent, protocol
and any other information that is given or seen
by the subject.
• Confirm that the trial is well designed, does not
involve undue risks, and includes safeguards for
subjects
What regulates this entire process?
• The Federal Food, Drug and Cosmetic
Act (505(a))
– “…evidence consisting of adequate and
well-controlled clinical investigations, by
experts (education, training, and
experience) to show the drug has the
effect it claims.”
• 21 CFR 314.126
Good Clinical Practice
• What is it?
• A collection of regulations, guidelines, and
accepted quality research practices which
define the standards and procedures for
the design, conduct, performance,
monitoring, auditing, recording, analysis,
and reporting of clinical trials.
GCP Applicability
• All phases of clinical research
• All aspects of clinical research
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Ethical conduct
Study conduct
SOPs
Processing of data
Archiving of records
Quality assurance
Staff training
History of GCP
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1902 Biologics Act
1906 Food and Drug Act
1937 Elixir of Sulfanilamide Tragedy
1938 Food, Drug, and Cosmetics Act
1962 Thalidomide Tragedy
1962 Kefauver-Harris Amendments
1965 Declaration of Helsinki
1977 FDA Bioresearch Monitoring Program
History of GCP
• 1981 Informed Consent and IRB Regulations
• 1987 Regulations covering clinical investigator and
sponsor obligations
• 1997 ICH GCP guidelines
• Computerized Systems Used in Clinical Investigations,
May 2007
• Protecting the Rights, Safety and Welfare of Study
Subjects-Supervisory Responsibilities of Investigators,
May 2007
• FDAA, 2008
Common Elements of GCP
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Human subject protection
Informed Consent
Investigator obligations
Sponsor obligations
Monitor obligations
Documentation/data handling/statistics
Record keeping/archival
Quality Assurance
Good Clinical Practice
Sponsor
Regulatory
Agency
Clinical
Investigator
IRB/IEC
Subject
Mission of FDA Good Clinical
Practice Program
• Focal point within FDA for Good Clinical Practice issues
• Coordinates FDA policies
• Contributes to leadership and direction through participation in
FDA's Human Subject Protection/Bioresearch Monitoring Council
• Coordinates FDA's Bioresearch Monitoring program with respect to
clinical trials, working together with FDA's Office of Regulatory
Affairs (ORA)
• Contributes to international Good Clinical Practice harmonization
activities
• Plans and conducts training and outreach programs
• Serves as a liaison with the HHS Office for Human Research
Protection (OHRP) and other stakeholders of GCP
Office for Good Clinical Practice
(OGCP)
• Established to be watchdog for GCP in clinical
trials
• Committed to Quality Assurance in clinical trials
• “Quality assurance and quality improvement
should become the prevailing themes in clinical
research.”
Office for Good Clinical Practice
(OGCP)
• In Clinical trials, you should strive for
– Building quality upfront
– Assuring Quality throughout
– Developing the capacity for continuous quality
improvement now and in the future
• Quality Assurance is the cornerstone of
success in GCP
Office for Good Clinical Practice
(OGCP)
• Why do we need QA in Clinical Trials?
– More studies, more sites, and more volunteers at
each site
– Expansion and fluidity of the clinical investigators pool
– New players in new roles (CROs, SMOs)
– New technologies (Electronic record keeping)
– More participation by vulnerable subjects
– Global expansion
What Defines U.S. GCPs?
• Food & Drug Administration’s Code of Federal
regulations
• FDA Guidelines
• Other sources
• International Conference on Harmonisation
Good Clinical Practice: Guideline (ICH/GCP)
• Hippocratic oath/Nurse Practice Act, etc.
FDA Regulations
• Electronic Records
– 21 CFR, part 11
• Protection of Human Subjects
– 21 CFR, part 50
• Financial Disclosure
– 21 CFR, part 54
• Institutional Review Boards
– 21 CFR, part 56
• Investigational New Drug Applications
– 21 CFR, part 312
• Application for FDA Approval to Market a New Drug or
an Antibiotic Drug
– 21 CFR, part 314
21 CFR, Part 11
21 CFR, Part 11
• Went into effect August 1997
• Establishes the FDA’s requirements for
electronic records and electronic signatures
• Applies to records in electronic format that are
created, modified, maintained, archived,
retrieved, or transmitted under any records
requirements in FDA regulations.
21 CFR, Part 11
• The regulation applies to source
documents which are
– Created in hard copy then entered into a
computerized system
– Created by direct entry by a person into a
computerized system
– Created automatically by a computerized
system.
21 CFR, Part 50
• Applies to all clinical investigations regulated by
the FDA
• No investigator may involve a human being as a
subject in research unless the investigator has
obtained informed consent
• Details exceptions to informed consent
• Details 8 elements of informed consent
• IC must be documented using a written
document of IC.
• Subpart D details the additional safeguards for
children.
21 CFR, Part 54
Financial Disclosure
• Purpose: To ensure that financial interests and
arrangements of the clinical investigators are
identified and disclosed.
• Applies to drugs, biologics and devices
• Intent is to make the agency aware of payment
arrangements between commercial sponsors
and investigators that could lead to inadvertent
bias
• FDA will give closer scrutiny to studies where
investigators have reportable financial interests
or arrangements
21 CFR, Part 54
Financial Disclosure
• Applicant must completely and accurately
disclose or certify information concerning the
financial interests of a clinical investigator who is
not a full-time or part-time employee of the
sponsor for each covered clinical study.
• Reporting Requirements
– Compensation affected by the outcome of clinical
studies
– Significant equity interest in the sponsor of a covered
study
– Proprietary interest in the tested product
21 CFR, Part 56
Investigational Review Boards
• Composition, operation, and responsibility of an
Institutional Review Board (IRB) that reviews clinical
investigations regulated by the Food and Drug
Administration
• Clinical investigation which must meet the requirements
for submission to the FDA can not be initiated unless
that investigation has been reviewed and approved by,
and remains subject to continuing review by, an IRB
• Membership must have at least 5 members
– Diversity in race, gender
– One individual who is Scientist
– One individual who is a non-scientist
– One member not affiliated with the institution
21 CFR, Part 56
Investigational Review Boards
• Requires that IRB follows detailed written
procedures
• Requires review of documents at
convened meetings
• Allows for expedited review for situations
with minimal risk
21 CFR, Part 312 Investigational
New Drug Application
• Details procedures and requirements for the use of
investigational new drugs
• Allows you to ship drugs that have not been approved by
the FDA for the purposes of conducting a clinical trial.
• Drug must be labeled with "Caution: New Drug--Limited
by Federal (or United States) law to investigational use."
• FDA's primary objectives in reviewing an IND are,
– To assure the safety and rights of subjects,
– In Phase 2 and 3, to help assure that the quality of the scientific
evaluation of drugs is adequate to permit an evaluation of the
drug's effectiveness and safety.
21 CFR, Part 312 Investigational
New Drug Application
• Sponsor submits IND when conducting a study with a
drug that is regulated by part 312
• Focus of the initial IND submission is on the general
investigational plan and the protocols for specific human
studies
• Amendments contain new or revised protocols build
logically on previous submissions and include additional
information
• Annual reports to the IND report the status of studies
being conducted under the IND and update the general
investigational plan for the coming year.
21 CFR, Part 314
Application to Market a New Drug
• Applications to the FDA to review and
approve a new drug to market.
• Establishes an efficient and thorough drug
review process in order to:
– (a) Facilitate the approval of drugs shown to
be safe and effective; and
– (b) ensure the disapproval of drugs not shown
to be safe and effective.
FDA Guidelines
• FDA Information Sheets
• FDA Guidelines for Monitoring of Clinical
Investigations
• Guidance for IRBs, Investigators, and Sponsors
• FDA compliance Program Guidance Manuals
• FDA Compliance Policy Guidelines
• FDA Guidelines for the Preparation of IND
Products
• www.fda.gov
ICH/Good Clinical Practice
• What is it?
An international, ethical, and scientific
quality standard for designing, conducting,
recording, and reporting trials that involve
the participation of human subjects.
ICH/Good Clinical Practice
• Goals:
– Identify and reduce differences in technical
requirements for drug development among
regulatory agencies
– Ensure worldwide acceptability of data
– Improve the quality of research
– Protection of research subjects
ICH/Good Clinical Practice
• History:
– Initiated in 1990 with focus on Safety, Quality and Efficacy.
– Agreement between US, Europe and Japan to take action on
harmonization
– Primarily concerned with studies conducted in United States,
Japan, and the European Union
• As a result of the need for better quality in clinical trials the ICH GCP
guideline was developed.
– 1997 Publication of Document E6 providing guidelines that
describe the responsibilities and expectations of all participants
in the conduct of clinical trials,
– Adopted by FDA as guidance document
International Conference on
Harmonization (ICH)
• E2D Post-Approval Safety Data
Management: Definitions and Standards
for Expedited Reporting
• E9 Statistical Principals for Clinical Trials
• E11 Clinical Investigation of Medicinal
Products in Pediatric Population
• E14 The Clinical Evaluation of QT/QTc
Interval Prolongation and Pro-arrhythmia
Potential for Non-Anti-arrhythmic Drugs
ICH/Good Clinical Practice
• General Points of Document E6
– Protocol development
– Institutional Review Board (IRB)/Independent Ethics
Committee (IEC) review and approval
– Informed consent processes
– Study conducted according to protocol
– Data recording, handling, storage
– Investigational drug accountability/control
– Adverse experience reporting
– Procedures to ensure quality of trial and data
ICH/Good Clinical Practice
• ICH Guidelines cover the following topics:
– Institutional Review Board (IRB)/Independent
Ethics Committee (IEC)
– Investigator
– Sponsor
– Protocol
ICH/Good Clinical Practice
– Investigator’s Brochure (IB)
– Essential documents for the conduct of a
clinical trial
Institutional Review Board
(IRB)/Independent Ethics
Committee (IEC)
• Primary function is to safeguard the rights,
safety, and well-being of all trial subjects,
especially vulnerable subjects
• Local IRB vs Central IRB
Investigator Responsibilities –
Ethical Principles
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Medical management of study subjects
Qualifications
Adequate Resources
Medical Care of Trial Subjects
Communication with IRB/IEC
Compliance with Protocol
Investigational Product
Informed Consent
Patient records/case report forms
Investigator Responsibilities
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Records and Reports
Progress Reports
Safety Reporting
Premature termination/suspension of trial
Final Report
Sponsor Responsibilities
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Medical expertise – Investigator’s Brochure
Study design
Trial management,
Data management
– Data Handling, Recordkeeping, and
Independent Data Monitoring Committee
– Supervise conduct of study
– Data handling and verification
Sponsor Responsibilities
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Investigator selection
Confirmation of review by IRB/IEC
Safety reporting
Record management
Sponsor Responsibilities
• Audit
– Evaluate trial conduct is in compliance with
protocol, GCP and SOP
• Monitoring
– Purpose: insure rights of subjects are
protected, data are accurate, complete and
verifiable, trial conducted to GCP
– Selection/Qualifications of Monitor
Sponsor Responsibilities
• Quality Assurance/Quality Control
– SOPs regarding trial conduct
• Registration of clinical trials
• Contract Research Organization
– Sponsor may transfer all trial responsibilities
to a CRO
– CRO must implement QA/QC
– All sponsor responsibilities transfer to CRO
Monitoring Responsibilities
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Main line of communication
Verify investigator qualifications
Monitor handling of investigational product
Verify adherence to protocol
Informed consent
Manage study regulatory documents on behalf of the
sponsor
• Ensure site training is provided
• Provide Monitoring Report
Protocol and Amendments
• Should include
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General Information
Background Information
Trial Objectives and Purpose
Trial Design
Selection/Withdrawal of subjects
Treatment of Subjects
Assessment of Efficacy
Assessment of Safety
Statistics
Investigator’s Brochure
• Compilation of the clinical and nonclinical data on the
investigational drug.
• Needs to reviewed at least annually and revised as
necessary
• As per GCP, relevant new information may be so
important that it should be communicated to the
investigators before it is included in a revised IB
– IND safety updates
• Copy provided to IRB.
KEYS to GCP
• Follow
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The regulations
The protocol
The SOPs
Guidelines
• If it’s not documented, it didn’t happen!
• Must be able to recreate CRF data from source
documents
Links
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E6 Consolidated Guidance for Good Clinical Practice
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FDA 21 CFR, Part 50
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http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=312
FDA 21 CFR, part 314
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http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=56
FDA 21 CFR, part 312
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http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=54
FDA 21 CFR, part 56
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http://www.access.gpo.gov/nara/cfr/waisidx_00/21cfr50_00.html
FDA 21 CFR, part 54
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http://www.fda.gov/cder/guidance/959fnl.pdf#search='fda%20E6‘
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=314
NIH
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http://www.nih.gov/about/NIHoverview.html
care
community
Role of the Principal
Investigator
Donna W. Dorozinsky, RN, MSN, CCRC
research
teach
Objectives
• Describe the Investigator responsibilities as
defined by the FDA and ICH
• Discuss the practical elements necessary to
remain in regulatory and ethical compliance with
all aspects of the clinical trial process
• Discuss the additional responsibilities of the
Investigator in Investigator initiated research.
GCP and the
and the Investigator
• To ensure the integrity of clinical research
data
• To provide adequate safeguards to ensure the
protection of human subjects
• To ensure that the highest standard of ethical
conduct is preserved
• To address all applicable regulatory
requirements
Expectations
• What does the FDA expect of you?
– Manage the clinical trial
– Conduct the protocol
– Collect quality data
– Investigational article
accountability
Expectations
• What does the FDA expect of you?
– Manage the clinical trial
• Responsibility, authority, accountability, delegation,
and documentation
– Conduct the protocol
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Who did what?
Who obtained informed consent?
Who determined participant eligibility?
Who corresponded with the IRB?
Who identified, reported and followed-up on AEs?
Expectations
• What does the FDA expect of you?
– Quality data
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Who maintained study files?
Who collected the data?
Who completed the case report forms?
What source documents are used to validate and support
data submitted to FDA?
– Investigational article accountability
• Where was the investigational drug stored?
• Who dispensed the drug?
• Who can account for the investigational drug?
Statement of Investigator
Your commitments
Form FDA 1572
DEPARTMENT OF HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
FOOD AND DRUG ADMINISTRATION
STATEMENT OF INVESTIGATOR
(TITLE 21, CODE OF FEDERAL REGULATIONS (CFR) PART 312)
(See instructions on reverse side.)
Form Approved: OMB No. 0910-0014.
Expiration Date: January 31, 2006.
See OMB Statement on Reverse.
NOTE: No investigator may participate in an
investigation until he/she provides the sponsor with
a completed, signed Statement of Investigator,
Form FDA 1572 (21 CFR 312.53(c)).
1. NAME AND ADDRESS OF INVESTIGATOR
2. EDUCATION, TRAINING, AND EXPERIENCE THAT QUALIFIES THE INVESTIGATOR AS AN EXPERT IN THE CLINICAL INVESTIGATION OF THE
DRUG FOR THE USE UNDER INVESTIGATION. ONE OF THE FOLLOWING IS ATTACHED.
CURRICULUM VITAE
OTHER STATEMENT OF QUALIFICATIONS
3. NAME AND ADDRESS OF ANY MEDICAL SCHOOL, HOSPITAL OR OTHER RESEARCH FACILITY WHERE THE CLINICAL INVESTIGATION(S) WILL
BE CONDUCTED.
4. NAME AND ADDRESS OF ANY CLINICAL LABORATORY FACILITIES TO BE USED IN THE STUDY.
5. NAME AND ADDRESS OF THE INSTITUTIONAL REVIEW BOARD (IRB) THAT IS RESPONSIBLE FOR REVIEW AND APPROVAL OF THE STUDY(IES).
6. NAMES OF THE SUBINVESTIGATORS (e.g., research fellows, residents, associates) WHO WILL BE ASSISTING THE INVESTIGATOR IN THE
CONDUCT OF THE INVESTIGATION(S).
7. NAME AND CODE NUMBER, IF ANY, OF THE PROTOCOL(S) IN THE IND FOR THE STUDY(IES) TO BE CONDUCTED BY THE INVESTIGATOR.
8.
ATTACH THE FOLLOWING CLINICAL PROTOCOL INFORMATION:
FOR PHASE 1 INVESTIGATIONS, A GENERAL OUTLINE OF THE PLANNED INVESTIGATION INCLUDING THE ESTIMATED DURATION OF
THE STUDY AND THE MAXIMUM NUMBER OF SUBJECTS THAT WILL BE INVOLVED.
FOR PHASE 2 OR 3 INVESTIGATIONS, AN OUTLINE OF THE STUDY PROTOCOL INCLUDING AN APPROXIMATION OF THE NUMBER OF
SUBJECTS TO BE TREATED WITH THE
DRUG AND THE NUMBER TO BE EMPLOYED AS CONTROLS, IF ANY; THE CLINICAL USES TO BE
INVESTIGATED; CHARACTERISTICS OF SUBJECTS BY AGE, SEX, AND
CONDITION; THE KIND OF CLINICAL OBSERVATIONS AND
LABORATORY TESTS TO BE CONDUCTED; THE ESTIMATED DURATION OF THE STUDY; AND COPIES
OR A DESCRIPTION OF CASE
REPORT FORMS TO BE USED.
9.
COMMITMENTS:
I agree to conduct the study(ies) in accordance with the relevant, current protocol(s) and will only make changes in a protocol after notifying
the sponsor, except when necessary to protect the safety, rights, or welfare of subjects.
I agree to personally conduct or supervise the described investigation(s).
I agree to inform any patients, or any persons used as controls, that the drugs are being used for investigational purposes and I will ensure
that the requirements relating to obtaining informed consent in 21 CFR Part 50 and institutional review board (IRB) review and approval in 21 CFR Part 56 are met.
I agree to report to the sponsor adverse experiences that occur in the course of the investigation(s) in accordance with 21 CFR 312.64.
I have read and understand the information in the investigator’s brochure, including the potential risks and side effects of the drug.
I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the study(ies) are informed about their obligations
in meeting the above commitments.
I agree to maintain adequate and accurate records in accordance with 21 CFR 312.62 and to make those records available for inspection in accordance with 21 CFR 312.68.
I will ensure that an IRB that complies with the requirements of 21 CFR Part 56 will be responsible for the initial and continuing review and approval of the clinical investigation. I also agree to
promptly report to the IRB all changes in the research activity and all unanticipated
problems involving risks to human subjects or others. Additionally, I will not make any changes in the research without IRB approval, except where necessary to eliminate apparent immediate
hazards to human subjects.
I agree to comply with all other requirements regarding the obligations of clinical investigators and all other pertinent requirements in 21 CFR
Part 312.
INSTRUCTIONS FOR COMPLETING FORM FDA 1572
STATEMENT OF INVESTIGATOR:
1. Complete all sections. Attach a separate page if additional space is needed.
2. Attach curriculum vitae or other statement of qualifications as described in Section 2.
3. Attach protocol outline as described in Section 8.
4. Sign and date below.
5. FORWARD THE COMPLETED FORM AND ATTACHMENTS TO THE SPONSOR. The sponsor will incorporate
into an Investigational New Drug Application (IND).
10.
SIGNATURE OF INVESTIGATOR
this information along with other technical data
11.
DATE
(WARNING: A willfully false statement is a criminal offense. U.S.C. Title 18, Sec. 1001.)
Public reporting burden for this collection of information is estimated to average 100 hours per response, including the time for reviewing instructions,
searching existing data sources, gathering and maintaining the data needed, and completing reviewing the collection of information. Send comments
regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to:
Food and Drug Administration
CBER (HFM-99)
1401 Rockville Pike
Food and Drug Administration
CDER (HFD-94)
12229 Wilkins Avenue
"An agency may not conduct or sponsor, and a
person is not required to respond to, a
collection of information unless it displays a
Investigator Responsibilities
FDA Form 1572
• Protocol compliance. Agree to…
– conduct of the trial according to the Protocol.
– Personally supervise the study
– Inform subjects of drugs that are being used for investigational
purposes
– Ensure all clinic staff fully understand and follow the protocol
– Implement changes to the protocol only after written consent of
sponsor, IRB and regulatory agencies.
– Report AEs
– Read and understand the IB
– Maintain records
– Comply with 21 CFR Parts 56 and 312
I.
Investigator Responsibilities
• Medical management of trial participants
• To provide information to the participant regarding
nature of the investigation
• To provide adequate medical care for the
participant during the trial
• To ensure welfare and safety of the participant
during the trial
• To provide appropriate medical care and follow-up
procedures at the conclusion of the trial
The
se
are
not
ordi
Translation Into Practice
• Answer subject questions
• Medical care takes priority over the
protocol
• Safety comes first
• Follow events to resolution
• Communication with PCP
• Subject access to PI
Investigator Responsibilities
• Staff and Facilities
• To ensure that there is adequate staff to support
the study, that they are familiar with the trial
protocol and the standards of Good Clinical
Practices
• To ensure adequate facilities and equipment
• To use certified laboratories with validated assay
methodology
Translation Into Practice
• Study Coordinator
• Facilities and Equipment
– Secured storage of IP and study files
– Evidence of equipment maintenance
• Validated assays
Investigator Responsibilities
• Adequate Resources
– Potential for recruiting adequate number of
qualified subjects.
– Sufficient time to properly conduct study
– Adequate staff and resources
– Ensure all staff involved in conduct of study
have been properly trained
Translation Into Practice
• Available qualifying patients
• Research is time consuming
• Are your coordinators carrying too many
studies?
• If your subjects need eye examinations do
you have arrangements with an
ophthalmologist?
Investigator Responsibilities
• Compliance with local regulations and
institutional requirements
• To obtain the review/approval of the IRB
• To provide periodic study status reports to the IRB
(at least annually)
• To promptly inform the IRB / DSMB of significant
safety issues (SAEs from site, IND Safety Reports
for program)
• Informed Consent
Translation Into Practice
• Communication with a duly constituted
IRB
– Local vs. Commercial
– Annual update
– Communicating IND safety updates to the IRB
• Evaluating IND safety updates to
determine need for adjustments to ICF
• Process for identifying and reporting SAEs
• Process for obtaining informed consent
Investigator Responsibilities
• Control of investigational drugs, vaccines, or devices
(article)
– To provide accountability system to address receipt, distribution,
and return of all investigational supplies
– To ensure that supplies are properly stored and accessible only
to designated study staff
– To ensure that investigational materials are used only according
to protocol
– To ensure that randomization procedures exist along with
process for breaking the blind
– May be delegated to a qualified individual
– Explain correct use to the subject
• Procedures for randomization and blinding
Translation Into Practice
• Process for receipt storage and return
• Secure IP storage area that is monitored
for temperature
• Drug Accountability performed each time
drug is dispensed
• Establish procedure for maintaining
randomization and breaking the blind
Investigator Responsibilities
D
•
O
C
U
M
E
N
T
A
T
I
O
N
Patient records/case report forms
• To provide complete and accurate data to the sponsor
• To maintain patient records to include history, prescribed
medication and investigational product(s), measurements,
exams, evaluations and adverse events
• To apply corrections to clinical research data according to
principles of good research practice (i.e., single-line delete,
date and initial)
• Correlation between the CRF and the source document
Translation Into Practice
• Patient records/case report forms
D
O
C
U
M
E
N
T
A
T
I
O
N
• Complete and accurate data to the sponsor
• Patient records that include history,
measurements, exams, evaluations and adverse
events
• Access to in-patient records
• QC of CRFs to source documents
Translation Into Practice
• Regulatory Binder
–
–
–
–
–
–
–
–
–
–
–
–
–
IRB Communications
Protocol, ICF, Amendments
IB
FDA Form 1572
Financial Disclosure
CVs
Site Signature Log
Delegation of Authority Log
Study Communications
Screening Log
Laboratory Reference Ranges
Site Visit Log
IP Accountability
Translation Into Practice
• Archive Essential Study Documents at end
of study
• Should be easy to retrieve documents
• If you move your location, notify the
sponsor
Investigator Responsibilities
• Safety Reporting
– SAEs reported immediately to the sponsor
– AE or laboratory abnormalities reported to the
sponsor within the agreed timeline.
– Report deaths and all associated
documentation to sponsor and IRB.
Translation Into Practice
• Assess for AEs at each visit
• IB is the driver for determining SAEs
– Key is “unexpected”
• Report all adverse events – you never know!
• All clinically significant laboratory or diagnostic
results are AEs
• Functioning under an assurance
– Unexpected events
– Unexpected problems
Investigator Responsibilities
• Compliance with the Protocol
– Conduct the study as described in the
protocol
– No deviations without agreement from
sponsor and IRB
– Documentation of any unintentional deviations
– Deviation for immediate hazard
Translation Into Practice
• Follow the protocol as it is written
– Recipe versus Contract
• Defined process for training staff involved
in conduct of the trial
• Do not implement a change in the protocol
until you have received written IRB
approval.
• Revision to ICF
Investigator Responsibilities
• Informed consent
– Comply with all regulatory requirements and adhere
to GCP
– Revise ICF when new information becomes available
– There should be no coercion of the subject to
participate
– Use non-technical language
– Provide ample time for consenting
– Copy of the signed and dated ICF
High Risk to Delegate
• Approval for study participation
• Assignment of causality for adverse
events (AE)
• Physical examinations
• Final review of CRFs
Protecting the Rights, Safety, and Welfare of Study
Subjects – Supervisory Responsibilities of
Investigators
• Draft FDA Guidance, May 2007
• Responsibilities related to human subject
protection and data integrity.
• Clarification of FDA expectations:
– To supervise a clinical study where some
study tasks are delegated
– To protect rights, safety and welfare of study
subjects.
Clinical Trials of Drugs
• Clarification of Investigator
Responsibilities
– Supervision of Conduct of the Study
– Protecting the Rights, Safety and Welfare of
Study Subjects
Supervision of Conduct of Study
• Appropriate delegation of tasks
– Ensure that individuals to whom a task is
delegated is qualified to perform the task.
– Generally related to tasks that are clinical or
medical in nature.
– Historically in appropriate delegation of tasks.
Supervision of Conduct of Study
• Define adequate training
– General familiarity with the protocol
– Specific understanding of the details related
to the tasks they will be performing
– Awareness of regulatory requirements and
acceptable standards
– Competency
– Informed of changes to protocol
Supervision of Conduct of Study
• Adequate Supervision
– Routine meetings with staff to review trial progress and update
staff
– Routine meetings with the sponsor’s monitors
– Procedure for
• correcting problems identified by study personnel.
• documenting the performance of delegated tasks in a satisfactory
manner.
• ensuring study is conducted in accordance with 21 CFR, Part 50.
• Ensuring that information in source documentation matches CRFs.
• dealing with data queries and discrepancies identified by the study
monitor.
• Ensuring staff comply with protocol, AE assessment and reporting
and other medical issues.
Supervision of Conduct of Study
• Oversight of other parties involved in the
conduct of the study.
– Study staff not in direct employ of the
investigator.
– Parties other than study staff (clinical
laboratories
Protecting the Rights, Safety and
Welfare of Study Subjects
• Provide a reasonable standard of medical
care.
• Reasonable access to medical care by
being available to subjects during the
conduct of the trial at their site.
• Seek to minimize protocol violations which
may be considered a failure to protect the
rights, safety and welfare of subjects
Investigator Initiated Research
• Reasons Investigators choose to act as a
sponsor
– Scientific interest in a drug or product
– An opportunity to contribute to clinical
knowledge
– A potential for publication of study results
Investigator Initiated Research
• Responsibilities
– Writing the protocol and designing the Case Report
Form
– Monitoring the study and reviewing the source
documents
– Drug accountability
– Submitting safety reports to the FDA
– Complying with all applicable FDA regulations
– IND submission
Questions
• ???
care
community
Human Subject
Protection
Donna W. Dorozinsky, RN, MSN, CCRC
research
teach
Course Objectives
• Discuss the history of human subject protection and the
historical events impacting today’s current regulations.
• Identify the 8 elements of informed consent.
• Discuss the general requirements in obtaining informed
consent.
• Discuss the IRB requirements and the contents of 21
CFR, Part 56.
• Discuss the HIPAA requirements as they relate to
privacy in clinical research.
Human Subject Protection
•
•
•
•
•
History of Human Subject Protection
Declaration of Helsinki
Belmont Report
Informed Consent
Institutional Review Boards
Historical Abuse of Subjects
• 1932: Tuskegee syphilis study
– Designed to determine the natural history of untreated
syphilis
– 400 black men with syphilis were recruited without
informed consent
– Syphilis left untreated to determine course of disease
– 100 men died, 40 wives infected, 19 children
contracted disease at birth
• World War II
– Appalling experiments conducted on imprisoned
ethnic groups by physicians
Human Subject Protection
•
•
•
•
1947: Nuremberg Code
1962: Kefauver-Harris Amendment
1964: Declaration of Helsinki
1967: FDA required informed consent to be
obtained in writing
• 1974: National Research Act
• 1979: Belmont report
• 1981: Congress enacted 3 statutes that govern
human subject protection
Declaration of Helsinki
• Research must conform to generally accepted scientific
principles and should be based on adequately performed
laboratory and animal experiments.
• Follow a protocol which is reviewed by a “specially
appointed independent committee for consideration,
comment, and guidance” e.g. IRB
• Conducted only by scientifically qualified persons;
supervised by clinically competent medical person
• Importance of the objective is in proportion to the risk to
the subject
• Predictable risks outweigh foreseeable benefits
• Respect the privacy of the subject and safeguard his/her
integrity
Declaration of Helsinki
• Each subject must give informed consent
indicating they he/she is adequately informed of
the study, benefits, hazards; they must be
informed that he/she can decide not to
participate or to withdraw from the study
• If subject is incompetent, then informed consent
must be obtained from the legal guardian.
• If the subject is a minor who can give consent,
this should be obtained in addition to the legal
guardian’s.
Belmont Report
• Objective is to provide an analytical
framework that will guide the
resolution of ethical problems arising
from research involving human
subjects.
Belmont Report
• Covers 3 topics
– Boundaries between practice and research
– Basic ethical principles
– Applications
Belmont Report
• Boundaries between practice and research
– Practice: interventions to enhance the well-being of a
patient with a reasonable expectation of success. To
provide diagnosis and preventive treatment or therapy.
– Research: Activity designed to test a hypothesis,
draw conclusions, and contribute to general
knowledge. Formal protocol with an objective and set
of procedures. Benefits are not always known.
– May be carried on together when the research is to
evaluate the safety/efficacy of a new therapy.
– If there is any element of research, it needs to undergo
review for the protection of human subjects, i.e. IRB
review.
Belmont Report Basic Ethical
Principles
Respect for Persons:
 Individuals should be treated as autonomous agents
 Persons with diminished autonomy are entitled to protection
 Subjects must enter into the research voluntarily and with
adequate information.
Beneficence
 An obligation to improve a persons’ well being.
 Do not harm
 Maximize possible benefits
 Minimize possible risks
Belmont Report Applications
Informed consent:





People should have the opportunity to choose what shall or
shall not happen to them.
Contains 3 elements: information, comprehension,
voluntariness
Information: subject must understand that research is neo
necessary for their well being nor are the effects of the
research fully known.
Comprehension: The information provided to the subject
must be in a language and at a level that he/she can
understand. Investigators are responsible for making sure that
a subject understands the information.
Voluntariness: A consent is valid only if it is voluntarily given
which means it is free of coercion and undue influence.
Belmont Report Applications
Assessment of Risks and Benefits:
– Risk: the possibility that harm may occur
– Benefit: something positive related to well being.
– Risks to the subject should be outweighed by the sum of
anticipated benefits to the subject and society
Selection of Subjects:
– Two levels of justice: individual and societal
– Individual justice: Investigator must demonstrate fair
procedures in selecting the subjects.
– Societal justice: fair and equitable selection of subjects across
economic, ethnic, and gender classes.
Informed Consent
Informed Consent
• Governing documents:
– FDA 21 CFR 50: Protection of Human
subjects
– HHS 45 CFR 46: Protection of Human
Subjects
– FDA Information Sheet: Informed Consent
Regulations
– FDA Information Sheet: A Guide To Informed
Consent Documents
Informed Consent
• “Informed consent is more than just a
signature on a form, it is a process of
information exchange that includes,
recruitment materials, written materials,
verbal instructions, question/answer
sessions, and measure of subject
understanding.”
Informed Consent
• “The consent document should be the
basis for a meaningful exchange between
the investigator and the subject.”
Ethical Standards of Informed
Consent
• One of the biggest obligations facing
everyone involved in developing new
medicines and medical devices that use
the human research subject is the
consistent requirement of
– Respect, compassion, understanding
JAMA, 5/24/00, Vol 283, No. 20 “What makes Clinical Research Ethical?
Informed Consent
• Informed Consent Definition
– A process by which a subject voluntarily
confirms his or her willingness to participate in
a particular trial, after having been informed of
all aspects of the trial that are relevant to the
subject’s decision to participate. Informed
consent is documented by means of a written,
signed, and dated informed consent form.
Informed Consent
• Informed consent documents must meet
the requirements of 21 CRF 50.20 and
contain the information required by 21
CRF 50.25.
• IRBs have the ultimate authority for
ensuring the adequacy of the information
in the informed consent document.
Informed Consent
• General Requirements for Informed
Consent:
– No investigator may involve a human being as
a subject in research unless informed consent
is obtained.
– Sufficient opportunity must be give to the
subject to decide whether or not to participate
Informed Consent
• General Requirements for Informed
Consent:
– Must minimize the possibility of coercion or
undue influence
– No informed consent may include any
exculpatory language (release of
responsibility).
Informed Consent
• Informed consent must be understandable
– Technical and scientific terms must be
adequately explained or simpler terms
substituted.
– More understandable if the subject is referred
to as “you” and the investigator as “I/we”
– Subjects should not be asked to certify that
they “fully understand” the study.
Informed Consent
• Informed consent must be understandable
– Consent must not imply or state that the study
is approved by the FDA
– If subject population includes non-English
specking subjects, a translated consent
document should be prepared
Informed Consent
• Informed consent must be understandable
– A person who understands English, but does
not read and write can be consented by their
“making their mark” on the document.
– When consenting older children, it is
recommended that there be two forms: an
informed consent for the parent/guardian to
sign as well as an assent document for the
child to sign.
Can they read the consent form?
• 48%
• Of American adults
• Have low literacy
• skills
Who are we protecting?
•Job applicants tested in 1998 - >33% lacked
reading and mathematics skills for employment!
•Question?
•Do we expect these people to read and
understand the consent form?
Elements of Informed Consent
1. Statement that the study involves
research, explanation of the purposes
of the research, expected duration of
the subject’s participation, description
of the procedures to be followed,
identification of any procedures which
are experimental.
Elements of Informed Consent
2. Description of any reasonably foreseeable
risks or discomforts to the subject.
3. Description of any benefits to the subject or to
others which may reasonably be expected
from the research.
4. Disclosure of appropriate alternative
procedures or courses of treatment, if any, that
might be advantageous to the subject.
Elements of Informed Consent
5. Statement describing the extent, if any, to
which confidentiality of records identifying the
subject will be maintained and that notes the
possibility that the FDA may inspect the
records.
6. For research involving more than minimal risk,
an explanations to whether any compensation
and an explanation as to whether any medical
treatments are available if injury occurs.
Elements of Informed Consent
7. Explanation of whom to contact for answers to
pertinent questions about the research and
research subjects’ rights and whom to contact
in the event of a research-related injury.
8. Statement that participation is voluntary, that
refusal to participate will involve no penalty or
loss of benefits, that the subject may
discontinue participation at any time without
penalty.
Elements of Informed Consent
The following elements should be included if
appropriate:
 Statement that the particular treatment or
procedure may involve risks to the subject (or to
the embryo or fetus, if the subject is or may
become pregnant) which are currently
unforeseeable.
 Anticipated circumstances under which the
subject’s participation may be terminated by the
investigator without regard to the subject’s
consent.
Elements of Informed Consent
 Any additional costs to the subject that my
result from participation in the study.
 The consequences of a subjects’ decision
to withdraw from the research and
procedures for orderly termination of
participation by the subject.
Elements of Informed Consent
 A statement that significant new findings
developed during the course of the
research which may relate to the subject’s
willingness to continue participation will be
provided to the subject.
 The approximate number of subjects
involved in the study.
The Consent Process
• The clinical investigator is responsible for
ensuring that informed consent is obtained from
each subject prior to their participating in the
study.
• FDA does not require that the investigator
actually obtain the informed consent. May
delegate it to appropriate individual who is
knowledgeable about the research.
• The investigator retains ultimate accountability.
The Consent Process
• The subject should date & sign the document.
– Time of consent should be recorded.
• A copy of the consent form must be provided to
the subject.
• A note is written in the progress notes confirming
the consenting process.
• The signed consent form must be retained in the
study records.
Informed Consent
• 2 types of forms
– Written consent document that includes all the
elements of informed consent required by 21
CFR 50.25.
– Short form written consent stating that the
required elements of informed consent have
been presented orally.
Informed Consent Exceptions
•
Both the investigator and a physician not participating in
the investigation must certify in writing that the following
conditions have been met.
– Subject is in a life threatening situation
– Consent cannot be obtained from the subject
– Insufficient time to obtain consent from the subject’s
legal representative
– No alternative treatment that would have an equal
or greater chance of saving the patient is available
– The test article is required to save the life of the
subject.
Informed Consent Exceptions
• Documentation of both the investigator and independent
physician must be submitted to the IRB within 5 working
days.
■
Planned study that must be done in the
emergency room in order to evaluate use of the
test article in that setting.
 Limited to situations where intervention is lifesaving and there is not time to obtain consent.
 Required FDA approval, IRB approval, and public
disclosure.
Informed Consent Issues
• Disclosing information to subjects requires
common sense.
– Too much information can be as bad as too
little.
– Too much can interfere with the subject’s
ability to understand what is truly important.
– Need to provide enough information to make
an educated decision.
Informed Consent Issues
• Poor comprehension of consent documents is
usually a result of low readability and excessive
length.
– General population reads at a 6th or 7th grade level.
– Retention of information can be improved with
repetition.
– Using a variety of methods such as individualized
discussion and visual aids may increase retention and
understanding.
– Improve readability by using short sentences and
short words.
Informed Consent Issues
• To demonstrate comprehension a subject
must understand:
– Their condition
– The nature of the proposed treatment
– Alternatives to treatment
– Consequences of accepting or rejecting
proposed treatment
– Risks and benefits of various options
Informed Consent Issues
• Sufficient time must be given for the
consent process.
– Sufficient time to read and digest the consent.
– Sufficient time to ask questions of staff.
– Sufficient time to consult with a friend or
relative if appropriate.
– Sufficient time to reflect on his/her decision.
Informed Consent Issues
• Informed consent must be obtained prior to participation
in the study.
– Prior to any specific exams or screening procedures
specific to the study to determine eligibility.
– Prior to discontinuing any existing medications the
subject is taking to meet inclusion/exclusion criteria.
(wash-out period)
– Procedures that are performed as part of the practice
of medicine and which would be done regardless of
the study, may be performed and the results used to
determine eligibility.
Study Payment
• Payment for subjects is viewed as a recruitment
incentive not a benefit.
• Financial incentives are generally used when
benefits to the subject are remote or non-existent.
• Amount and schedule of payment should be
presented to the IRB at the time on initial review.
• IRB should review the amount of payment and
timing of payment to assure that they are not
coercive or do not present undue influence.
Study Payment
• Payment should accrue as the study progresses.
• Payment may not be contingent upon the subject
completing the entire study.
• Payment to subjects who withdraw may be made at
the time they would have completed the study (or
completed a phase of the study).
• Payment of a small proportion as an incentive for
completion of the study is acceptable as long as it is
not coercive.
• Payment details must be included in the informed
consent.
Informed consent must be approached as
a process rather than a distinct event in
time.
Assess Competence to Consent
• Ability to Express a choice
• Ability to Understand information about a
trial
• Ability to Reason with relevant information
to understand a logical process of
weighing options
What Can We Do?
• When obtaining consent ask yourself…..
• “Is the subject adequately informed to
understand and comprehend the
information in order to make a conscious
decision to participate in a clinical
research trial?”
What Can We Do?
•
•
•
•
•
Reduce boilerplate language
Extended discussion about the trial
Multimedial presentations
Enhanced forms
“Test” of knowledge
The Ability to Understand the
Informed Consent
• It is a function of:
–
–
–
–
Intelligence
Rationality
Maturity
Language
• Ethically it is the investigator’s responsibility to
ensure that the research subject has
comprehended the information.
What Can We Do?
• Use less text and more graphics.
• Simplify language – use action verbs and direct
statements
• Read the FDA information sheets
• Substitute long wordy sentences with tables or
lists.
• Develop a list of lay terms
• Make the form “EYE” friendly
Sample Phrases
All blood samples will be drawn from a forearm
vein via an intravenous catheter contra lateral to
the one used for drug administration in the case of
the continuous infusion regimens.
We will need to take some blood from your arm for
this study. We will insert a needle attached to a
plastic tube in your forearm. A second needle with
a plastic tube will be placed in your opposite arm
What Can We Do?
• How the document is laid out is just as
important to readability and
comprehension as the information it
contains
• Use a written or verbal post-consent
evaluation to determine if the critical points
were understood (must be IRB approved)
Informed Consent Questions??
Is getting the subject to sign a consent
document all that is required by the
regulations??
No!! The consent document is just a written
summary of the information that should be
provided to the subject.
Informed Consent Questions??
May informed consent be obtained by
telephone from a legal representative?
No. This does not satisfy the regulations. A
document can be faxed to the representative.
The discussion can be conducted by
telephone and then the signed form can be
faxed back.
Informed Consent Questions??
Does the copy of the consent form given to
the subject have to be a signed copy?
No! This is encouraged but not mandatory.
The purpose of this is to allow the subject to
review the information with others as well as
to serve as a continuing reference for them.
Informed Consent Questions??
Who should be present when the informed consent
interview is conducted.
FDA does not require a third person or witness.
The person who conducts the consent interview
should be knowledgeable about the study and able
to answer questions. Investigator may delegate
responsibility to a person who has received
appropriate training to perform this activity.
Informed Consent Questions??
When should study subjects be informed of
changes in the study?
Those subjects who are enrolled and actively
participating in the study should be informed of any
changes if it may affect to their willingness to
continue their participation in the study. FDA does
not require reconsenting subjects that have
completed their active participation or who are still
actively participating but the change will not affect
their participation.
IRBs
Sound Clinical Research
Depends on Compliance with …
Good Clinical Science
(Industry and Investigator)
+
Good Statistical Design
(Industry and IRB)
+
Sound Ethical Conduct
(IRB, Investigator, Industry)
What is an IRB?
• Knowledge and application of
commitments, regulations, guidelines,
state and local laws and standards of
professional conduct
• Knowledgeable about the care and
protection of vulnerable population
• An appreciation for doing the right thing
What is an IRB?
• Under FDA Regulations (21 CFR 56 Subpart C) and (45 CFR 46 - Subpart A)
• An IRB is an appropriately constituted
group that has been formally designated to
review and monitor biomedical and
behavioral research involving human
subjects.
What is an IRB?
• An IRB has the authority to approve,
require modifications (in order to secure
approval), or disapprove search.
• An IRB is responsible for ensuring, in
advance and by periodic review, that steps
are taken to adequately protect the rights
and welfare of human subjects.
Why an IRB?
• Knowledge and application of
commitments, regulations, guidelines,
state and local laws and standards of
professional conduct
• Knowledgeable about the care and
protection of vulnerable population
• An appreciation for doing the right thing.
Institutional Review Boards
• Membership
–
–
–
–
At least five members with varying backgrounds.
Must consist of both men and women.
May not be entirely of members of one profession.
At least one member whose primary concerns are in
a scientific area and one member in a non-scientific
area.
– At least one member who is not otherwise affiliated
with the institution.
Institutional Review Boards
• IRBs must:
– Follow written procedures
– Review research at convened meetings at
which a majority of the members (quorum) is
present including at least one member whose
primary concerns are in nonscientific areas.
What is the Role of the IRB?
• Protect the rights and welfare of human
research subjects.
• Answer three basic questions:
1. Should the study be done at all?
2. Do the benefits outweigh the probable risks
and is this information adequately conveyed
in the consent form?
3. How will the research subject be protected on
an ongoing basis?
Institutional Review Boards
• Data submitted to IRB for review:
– Protocol, protocol amendments
– Informed consent form
– Advertising and recruitment process
– Information on the drug e.g. Investigator’s
brochure
– Information on the investigator e.g. CV
What is the Role of the IRB?
Criteria for IRB Approval
• Risks v Benefits
• Risks minimized
• Equitable selection
• Documentation of
informed consent
• Monitoring of data
• Informed consent
• Privacy and
confidentiality
• Investigator training
relative to
responsibilities
• Additional safeguards
of all vulnerable
populations
IRB Decisions
• Authority to make three possible decisions
regarding studies:
– Approved
– Disapproved
– Requires modifications to be approved
• Notification of decisions must be made in writing
to investigator.
• Continuing review of research must be done at a
minimum of once per year.
The IRB
“A collegial and cooperative relationship”
• Judge
• Protector
• Facilitator
• Enforcer
• Educator
• Colleague
• Partner
Institutional Review Boards
• The purpose of IRB review is to assure that
appropriate steps are taken to protect the rights
and welfare of humans participating as subjects
in the research.
• Risks to subjects are minimized
• Risks to subjects are reasonable in relation to
anticipated benefits
• Selection of subjects is equitable
• Informed consent will be sought
• Research plan makes adequate provisions for
monitoring the data collected to ensure the safety
of subjects
• Adequate provision to protect the privacy of
subjects
Focusing on Continuing Review:
Why?
• Has any significant and/or new information been
made available since the study received last
approval?
• Do the research subjects need different
information with which to reconsider their
continued participation
• Is the study being conducted as approved?
• Did the IRB use the same review and approval
process that it used to conduct the initial review?
Information required by the IRB for
Continuing Review
• Enrollment and study start and stop
• Adverse event information and follow-up where
indicated
• Study progress reports
• Review of consent process and document
changes.
• Any new findings important to the subject’s
safety
• Unanticipated problems that pose a risk to the
subject
Institutional Review Boards
• Expedited review:
– Procedure to review and approve research without
convening a meeting of the IRB.
– Used for minor changes in previously approved
research.
– Review is done by the IRB chairperson or by one of
the experienced members of the IRB
– May not be disapproved by expedited review—only
be full review.
HIPAA Requirements
What is HIPAA
• Health Insurance Portability and
Accountability Act
• Signed August, 1996
• Congress mandated that the Secretary of
HHS adopt standards to facilitate the
electronic exchange of health information
• http://aspe.hhs.gov/admnsimp/
Who Must Comply with HIPAA?
• Health Plans, health care clearinghouses, and health care providers
that transmit health information electronically in connection with
defined HIPAA statute
• Transmissions related to …
– Health care claims
– Health care payment or remittance advice
– Coordination of benefits
– Health clam status
– Enrollment and disenrollment in a health plan,
– Eligibility for health plan
– Health plan premium payments
– Referral certification and authorization
– First report of injury
– Health claims attachments
– Other transactions
What is a Covered Entity
• Employees of a covered entity (hospital,
etc), then they must comply with
regulation.
• Function independent of a covered entity
(i.e. physician who is not employee of the
hospital), they must meet all of the
requirements independent of the
institution.
What about Researchers
• Research is not a covered function, however….
• If the research involves either
– the provision of health care by a covered
entity
– Retention of medical records or biological
samples by a covered entity
• ….then disclosure of information or clinical trial
data for research purposes must comply with the
Privacy Rule
Penalty for Non-Compliance
• Civil monetary penalty of $100 per
occurrence ($25K max)
• Federal Criminal penalties for persons
who knowingly obtain or disclose health
information in violation of Privacy Rule.
What is Protected Health
Information?
• Either oral or recorded information in any
form or medium
– Is created or received by a health care
provider, health plan, etc.
– Provision of health care to an individual
What is De-Identification?
•
•
De-Identification information is no longer covered by the HIPAA
requirements.
All identifying information has been removed including
– Names
– Geographic subdivisions smaller than a state (i.e., no city, no
zip code), except for the initial three digits of the zip code if,
according to the current publicly available data from the Bureau
of the Census, the geographic unit contains more than 20,000
people
– Any date (except year; i.e., no month or day of month)
– For subjects older than 89 years of age, specific age may not be
mentioned
– Telephone number
– Fax number
– E-mail address
What is De-Identification?
– Social security number
– Medical record number
– Health plan beneficiary number
– Any other account numbers
– Certificate or license numbers
 Vehicle identification number
 Medical device identification or serial number
 Personal website URL
 Internet protocol (IP) address
 Fingerprint, voiceprint, or other biometric identifiers
 Full-face photographic images
 Any other unique identifying number, characteristic, or code
Impact of Reviewing Records for
Research Participation
• Allows covered entities to permit researchers to
review PHI held in medial records or elsewhere
for “review Preparatory to research” for the
purpose of assessing the pool of potentially
eligible subjects.
• Contact of these subjects is related to whether
the individual is a member of the covered
entities workforce
Other Issues
• Adverse events may be reported to
research sponsors, public health agencies
and health oversight agencies without
obtaining authorization
• IRBs, DSMBs, or other investigators
should be identified in the original
authorization form.
Authorization Core Elements
• A description of the PHI to be used or disclosed,
• The names or other specific identification of the person or persons
(or class of persons) authorized to make the requested use or
disclosure
• The names or other specific identification of the person or persons
(or class of persons) to whom the covered entity may make the
requested use or disclosure
• A description of each purpose of the requested use or disclosure
• Authorization expiration date or expiration event that relates to the
individual or to the purpose of the use or disclosure ("end of the
research study" or "none" are permissible for research, including for
the creation and maintenance of a research database or repository)
• Signature of the individual and date.
What does this mean practically
speaking?
• In the clinic use first names only
• Sign-in sheets should have cover over
previous names
• Limit access to the clinic to essential
personnel only
• Name tags should only have first name
• Screen saver on clinic computers, if first
and last names are displayed
In Summary
•
•
•
•
•
Historical misuse and abuse
Key Investigator responsibility
Informed consent is critical component
IRB oversight
Patient Privacy
Questions!!!!!!
care
community
Drug Development
Process
Donna W. Dorozinsky, RN, MSN, CCRC
research
teach
Course Objectives
• Discuss the differences in Phase I, II and
III of the drug development process.
• Identify the key requirements of a New
Drug Application.
• Discuss the different types of studies done
at the CPU
©
192
Introduction:
• Only 5 in 5,000 compounds that go into
pre-clinical make it to human testing.
• It takes 10-12 years from conception of a
new drug to its approval
• Time is money
©
193
• $1B/year in sales
• $2.7m/day
• 2 week delay = $38m
©
194
Drug Development Costs
• Triangle Pharmaceuticals
Cumulative Drug Development
Expenses
©
195
Drug Development Costs
• 2003 as reported by University
• $897M
• 2006 as reported by CEO at Lilly
• $1.2B
• 2010 forecast by CEO at Lilly
• $2B
©
196
Contributions to Rising Costs
•
•
•
•
Soaring R&D costs
Lowered drug approvals
Increased development times
The loss of patent protection on several
blockbuster
• Safety issues
• Pricing pressures.
©
197
Drug development difficulties:
• Drugs usually do not cure diseases.
• Diseases don’t follow a predictable path
• Sometimes measurements of a disease
are subjective
©
198
Drug Development Steps
• Pre-clinical (animal) testing
• Filing Investigational New Drug Application (IND) with
the FDA
• Phase 1 studies
• Phase 2 studies
• Phase 3 studies
• New Drug Application (NDA)
• Drug approval by FDA
©
199
Drug Development Steps
• Pre-clinical (animal) testing
• Filing Investigational New Drug Application (IND) with
the FDA
• Phase I studies
• Phase II studies
• Phase III studies
• New Drug Application (NDA)
• Drug approval by FDA
©
200
©
201
www.fda.gov/cder/handbook/develop.htm
Pre-Clinical Testing
• Pre-clinical studies are studies that test a
drug on animals and other non-human test
systems
• Start with initial chemical development of a
compound
©
202
Pre-Clinical Testing
• Studies are done with cell tissues, isolated
tissues, and animals to determine:
– Pharmacologic effects
– Toxic effects
– LD-50 (lethal dose)
– ADME
©
203
Pre-Clinical Testing
• ADME
– Absorption: how it goes from being a pill or liquid to a biologically
available form. (a form the body can actually use)
– Distribution: getting the drug to the tissue
– Metabolism: (biotransformation) getting the drug from the biologically
available form to a more water soluble form
– Excretion: moving metabolites from tissue to circulation to organs of
excretion
• Kidneys
• Liver
• bowel
©
204
Pre-Clinical Testing
• Must think about marketing considerations before going
to Phase I
– What is the intended population and what is the incidence in
that population?
– Do competitors have similar compounds in their pipeline?
– What are current therapy options for this disease and are they
effective and safe?
– Are there any unique or disqualifying toxicology results for
this specific compound?
– What will be the likely route of administration?
– What will be the dosing frequency?
©
205
The IND When…
• Filed prior to human dosing
• If no response from the FDA, the clinical
trial may start 30 days after it is received.
• Annual IND update.
©
206
The IND Why….
• FDA to ensure the safety and rights of
subjects
• In Phase 2 and 3, help assure that the
quality of scientific evaluation is adequate
to evaluate safety and efficacy.
• Allow for shipping of drugs across state
lines.
©
207
Investigational New Drug Application (IND)
• An IND is
– Submitted to the FDA demonstrating there is
reasonable justification for studying the drug
in humans
– Includes results of pre-clinical testing
– Shows plan for human testing
– Must be obtained before the first dose in
humans
©
208
Investigational New Drug Application (IND)
• Includes
–
–
–
–
–
–
–
–
–
–
Table of contents
Introductory statement
General investigational plan
Investigators Brochure
Protocols including study protocols, investigator data,
facilities data, IRB data
Chemistry, manufacturing and controls (CMC)
Pharmacology and Toxicology information
Previous human experience, if any
Additional information including drug dependence and
abuse potential
Any other relevant data
©
209
Investigational New Drug Application (IND)
• Becomes effective 30 days after it is
received by the FDA
• Updated annually and amended to reflect
protocol changes, additional protocols,
and information about serious adverse
events
• FDA decides if it is safe to move on to
testing in humans
©
210
Clinical Trials
• Human studies designed to distinguish a drug’s effect
from other influences.
• Necessary to determine if a drug is safe and effective,
establish dose efficacy, and identify side effects
• Best way science has come up with to determine what a
new drug really does
• It is important to test drugs in the population of people
that they are meant to help
• Need to design clinical studies that ask and answer the
right questions
©
211
Clinical Trials
# of
Patients
Length
Purpose
% of Drugs
Successf
ully
Tested
Phase
1
20-100
Several
months
Mainly safety
70%
Phase
2
Up to several
hundred
Several
months
to 2
years
Some shortterm
safety but
mainly
efficacy
33%
Phase
3
Several
1-4 years
hundred to
several
thousand
Safety,
efficacy,
dosage
25-30%
©
212
Study Design Terminology
• Blinding
– Unblinded or open-label
– Single Blind
– Double-blind
©
213
Study Design Terminology
• Subject Assignment
– Randomization – assigned by chance
– Stratification – assigning someone to a treatment
group based on their sex, weight, age, disease state
• Cross-over design – Each patient receives both
treatments
• Parallel Design – Patients are randomized to one of two
treatment groups and usually receive the same
treatment through-out the entire study
©
214
Phase I
• Primarily intended to determine the
tolerability of the drug
• Conducted in healthy volunteers
• Establishes a dosing range
• Establishes the route of administration
• Determines the most frequent adverse
events
©
215
Phase I
• Determination of pharmacokinetics and
pharmacodynamics
– Pharmacokinetics (PK)
• What the body does to the drug
• ADME
• Usually measured in blood or urine
– Pharmacodynamics (P-dyne)
• What the drug does to the body
• E.g. heart rate, ECG, blood pressure
©
216
ADME
©
217
©
218
©
219
Phase I
• Usually start with single dose study
• Dose escalation to maximum tolerated
dose
• Multiple ascending repeat dose studies
• Kinetic profile is established
• Drug interactions
• QTC intervals
©
220
Phase I
• Future is in establishing early signaling of
drug efficacy.
• Proof of Concept often conducted in
Phase I then move to phase II while
completing drug interactions, food
interactions, etc.
©
221
Phase II
• Primary objective
– To examine safety and therapeutic
effectiveness in patients
– Proof of concept--To find out whether the drug
works in people who have the targeted
disease or condition.
©
222
Phase II
• Goals
– Determine dose and regimen
– Evaluate potential study endpoints
– Evaluate therapeutic regimens including concomitant
medications
– Evaluate target population including disease severity
Determine all of above for further study in phase 2 or 3
©
223
Phase II
• May be divided into two phases
– Phase 2A: proof of concept pilot studies
– Phase 2B:
• Demonstrate efficacy
• Assess short term safety
• Dose finding/dose ranging
• Uses a few dozen to 300 subjects
• Duration: short to medium length lasting up to a few
months
©
224
Phase II
• Information defined in Phase 2
–
–
–
–
–
–
–
–
–
Safety in patients
Efficacy
Pharmacodynamics
Pharmacokinetics
Bioavailability
Drug/disease interactions
Drug/drug interactions
Efficacy at different doses
Pediatric information
©
225
Phase III
• Primary objective
– To confirm therapeutic effectiveness and
safety in a less restricted patient group
• Consists of well-controlled trials to support
marketing approval by confirming
preliminary data collected in phase 2 on
safety and efficacy in intended patient
population
©
226
Phase III
• Uses several hundred to 3000 subjects
• Duration:
– parallels anticipated treatment
– May be several years for chronic conditions
• Takes place at multiple centers including hospitals and
doctors offices
• Study design has broader patient eligibility and may
have 2-3 treatment groups
• Tests final formulation of drug
©
227
Phase III
• Information typically defined:
– Efficacy and safety in population subgroups including different
disease stages
– Dosing interval
– Dose response relationship
– Efficacy with another drug (drug combination therapy)
– Drug/drug interactions
– Drug/disease interactions
– Risk/benefit information
©
228
Pravachol Approval
•
•
•
•
•
•
Pravachol Primary Prevention Study, also known as the West of Scotland
study, was pivotal phase III study used to file NDA
The Pravachol Primary Prevention Study, evaluated the use of Pravachol in
6,595 subjects over a five-year period, demonstrated that Pravachol
reduced the risk of first heart attack by 31%.
Death from cardiovascular disease was reduced by 32%, and there was no
increase in death from non-cardiovascular causes.
The study showed that Pravachol reduced the need for coronary
procedures such as balloon angioplasty and bypass surgery by 37%.
Another major finding from the Pravachol Primary Prevention Study was
that Pravachol benefit, in terms of reduction in first heart attacks, begins at
about six months after the initiation of therapy.
http://www.centerwatch.com/patient/drugs/dru142.html
©
229
The NDA What….
• Formal step a drug sponsor takes to
receive FDA approval to market a new
drug in the USA
• Application to market a new drug under
Section 505 of FDA.
• Establishes an efficient and thorough drug
review process
©
230
When?
• Once all pre-clinical and clinical reports
are available to support the file.
©
231
New Drug Application (NDA)
• Includes:
– Index
– Overall summary of drug and study results
– Technical sections
•
•
•
•
•
•
Chemistry, manufacturing, and controls (CMC)
Non-clinical pharmacology and toxicology
Human PK and availability
Clinical microbiology if applicable
Clinical data
Statistics
©
232
New Drug Application (NDA)
• Includes
–
–
–
–
–
–
Case Report Tabulations
Case Report Forms
Patient information and certification
Establishment description
Environmental assessment or exemption
Includes samples of the drug
• Typically consists of over 100,000 pages and may contain data
on more than 3000 patients
©
233
New Drug Application (NDA)
• Once the NDA is filed, the FDA has 60
days to decide whether to file it for review
• FDA’s Center for Drug Evaluation and
Research (CDER) will then review the
drug for approval
©
234
New Drug Application (NDA)
• Review team consists of:
– Chemists
– Pharmacologists
– Physicians
– Pharmacokineticists
– Statisticians
– Microbiologists
©
235
New Drug Application (NDA)
• Team evaluates the drug to see if it is “safe” and
effective for proposed use
– “Safe” means the benefits of the drug
outweigh the risks
– They analyze the results and look for any
weaknesses of study design or analyses
– They determine if they agree with the
sponsors or need additional information
©
236
New Drug Application (NDA)
• Prescription Drug User Fee Act passed in 1992 to
provide funding in an effort to reduce FDA approval
time and bring drugs to market faster.
• CDER’s goal is to review and act on at least 90% of
NDAs for standard drugs no later than 10 months
after the NDA is received and no later than 6 months
for priority drugs
– Standard drug: Drugs that offer only a minor improvement or
no improvement over drugs currently on the market
– Priority drug: a drug believed to represent potential major
advances in healthcare
©
237
New Drug Application (NDA)
• FDA has worked to shorten time devoted
to clinical trials by
– Having meetings with drug companies to
streamline studies and eliminate duplicate
studies
– Expediting approval of innovative agents
• As part of the review process, on-site
inspections are made of some of the
clinical sites
©
238
New Drug Approval Time by Year
Median of Total Approval Times (in months)
35
30
32.9
29.9
Months to Approval
25
29.3
27.2
24.3
20
22.1
22.6
23.0
17.5
15
15.9
15.6
14.3
13.4
10
12.0
11.6
5
n = 20
n = 21
n = 20
n = 23
n = 23
n = 30
n = 26
n = 25
n = 22
n = 28
n = 53
n = 39
n = 30
n = 35
n = 27
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
Calendar
Year
©
239
©
240
New Drug Application (NDA)
• Advisory committee
– Panel of outside experts
– Review the safety and efficacy results
– CDER is does not have to take the
committees recommendations but they
usually do
©
241
New Drug Application (NDA)
• Three possible results
– Approved
– Approvable: drug can probably be approved
after resolution of certain issues
– Not approvable
©
242
©
I
N
D
&
243
New Drug Approval Time by
Year
Median of Total Approval Times (in months)
35
30
32.9
29.9
Months to Approval
25
29.3
27.2
24.3
20
22.1
22.6
23.0
17.5
15
15.9
15.6
14.3
13.4
10
12.0
11.6
n = 30
n = 35
n = 27
1998
1999
2000
5
n = 20
n = 21
1986
1987
n = 20
1988
n = 23
n = 23
n = 30
n = 26
n = 25
n = 22
n = 28
n = 53
1989
1990
1991
1992
1993
1994
1995
1996
n = 39
1997
Calendar Year
©
244
Label
• When the FDA approves a drug, it
approves the label for the drug
• The label is what appears on the package
insert for the drug. This information also
appears in the PDR.
©
245
Label
• Label includes:
– Description of the drug
• Chemical class and structure
• Pharmaceutical action
• Product presentation
– Clinical Pharmacology
• Mechanism of action
• Pharmacodynamics
• Pharmacokinetics and metabolism
©
246
Label
• Label includes
– Indications and usage
– Contraindications
– Warnings, WARNINGS
– Precautions
• Drug interactions
• Carcinogenesis
• Mutagenesis
• Fertility Effect
• Nursing Mothers
• Pregnancy
• Children
• Elderly
©
247
Label
• Label includes
– Adverse Reactions
• By organ or body system
• Stratification by % incidence
– Drug abuse and dependency potential
– Overdosage
– Dosage and Administration
– How supplies
©
248
Label
• May include a Black Box warning
– This is a separate warning that is highlighted
for the drug
– May be mandated by the FDA as terms of
approval
– Not desirable
©
249
Phase IV
• These are studies that occur after a drug has been
approved
• May explore long term effects
• May explore how participants respond to different
dosages
• May compare with competitors products to support
marketing claims
• May look at the incidence of adverse reactions
©
250
Questions
• ??????
©
251
care
community
Legal Issues
in
Research
Priya Sankar, Esq.
Assistant General Counsel
Associate Director, Contracts and Budgets
research
teach
Red Flag
25
3
ROAD MAP
25
4
I
General
II
Contracts
A. Why have a Research Agreement?
B. Confidentiality Agreements
C. Clinical Trial Agreements
D. Government Grants/Cooperative Grants
III
Fraud & Abuse Regulations
A. Conflict of Interest Regulations
B. Federal Anti-Kickback Statute
C. Federal False Claims Act
IV
Other Legal Issues
Type of Clinical Research
25
5
1.
Internal
2.
Industry Sponsored
3.
Government-Funded (e.g. NIH)
Public Health Service (PHS )
Department of Health & Human
Services (HHS)
National Institute of Health
(NIH)
Center for Medicare & Medicaid Services
(CMS)
Agency for Healthcare Research & Quality
(AHRQ)
Health Resources &
Services Administration
(HRSA)
25
6
Food and Drug Administration
(FDA)
Center for Disease Control
(CDC)
Agency for Toxic Substances and Disease
Registry
(ATSDR)
Substance Abuse and Mental Health
Services
(SAMHSA)
What do they do?
HHS
 Department of Health & Human Services
 Protecting the health of all Americans and
providing essential human services
PHS
 Primary division of HHS
 Component of HHS that makes up the key
agencies (e.g. NIH, FDA, etc.)
OHRP
 Office of Human Research Protections
 Oversees national system of protecting human
subjects in research (i.e. Institutional Review
Boards) through regulations, oversight, guidance
25
7
What do they do?
NIH
 NIH is the government’s research organization.
 It supports 38,000 research projects nationwide in
diseases including cancer, Alzheimer's, diabetes, arthritis,
heart ailments and AIDS.
 Includes 27 separate health institutes and centers.
FDA
 FDA assures the safety of foods and cosmetics, and the
safety and efficacy of pharmaceuticals, biological
products, and medical devices
OIG
 Office of Inspector General
 Protect the integrity of Department of Health and Human
Services (HHS) programs, as well as the health and
welfare of the beneficiaries of those programs
25
8
Key Players in Clinical Research
Study Subject
St. Peter’s
University Hospital
PHS
(HHS OHRP)
NIH
FDA
Industry Sponsor
25
9
Researcher
IRB
ROAD MAP
I
26
0
General
II
Contracts
A. Why have a Research Agreement?
B. Confidentiality Agreements
C. Clinical Trial Agreements
D. Government Grants/Cooperative Grants
III
Fraud & Abuse Regulations
A. Conflict of Interest Regulations
B. Federal Anti-Kickback Statute
C. Federal False Claims Act
IV
Protection of Human Subject (HIPAA)
Why Have A Contract?

Anti-Kickback Safe Harbor

Ensure Compliance

Protect Existing Rights
• Intellectual Property
• Confidential Information

Allocate Rights and Obligation
• Publication Rights
• Intellectual Property (Inventions)
• Liabilities (Indemnification & Insurance)
• Cost
26
1
Confidentiality Agreements
The Contract before the Research Contract



26
2
What is it?
Usually required by Industry
Synonyms:
• CDAs
• NDA
• Nondisclosure Agreements
• Secrecy Agreements
Key Terms
Confidentiality Agreements
Defines what is “Confidential Information”

Study Drug/Device

Study

Never undefined
2.
Defines what is not “Confidential Information:

Public Information

Already Know

Already Given by Third Party

Required to Disclose by Law

Independently Developed
1.
26
3
Key Terms
Confidentiality Agreements
3.
4.
5.
26
4
Defines how it will be disclosed
Defines who it may be disclosed to
Defines how long it shall be held confidential
Confidentiality Agreements
Protect Yourself! Protect your Colleagues!





Know your institution’s policy
Be careful what you sign
Be careful what you open
Make sure you are aware of your obligations.
When in doubt, seek legal counsel
You may be personally liable!
26
5
Clinical Trial Agreements
5 Key Provisions





26
6
Intellectual Property
Confidential Information
Publication
Indemnification
Patient Injury Compensation (if clinical)
Government Funded
(e.g. PHS Funded Research)
Grants
 Funds transferred to awardee
 Work independently
 Report results at end
Cooperative Agreements
 Substantial involvement
 Gov’t involved in planning and implementation
Subcontracts to Grants/Cooperative Agreements
26
7
ROAD MAP
I
26
8
General
II
Contracts
A. Why have a Research Agreement?
B. Confidentiality Agreements
C. Clinical Trial Agreements
D. Government Grants/Cooperative Grants
III
Fraud & Abuse Regulations
A. Conflict of Interest Regulations
B. Federal Anti-Kickback Statute
C. Federal False Claims Act
IV
Protection of Human Subject (HIPAA)
What is Conflict of Interest?
Conflict of interest exists if it actually or
potentially may have influence over the
outcome of the research
26
9
Laws & Regulations
Each agency has developed differing
definitions of conflict of interest and how and
to whom conflict disclosures should be
made.
27
0
Laws & Regulations
Neither the PHS or FDA regulations:
1.
Identify specific conflicts of interest or financial interests that
are prohibited.
2.
Define the role of the IRB in dealing with conflict of interest.
27
1
PHS FUNDED RESEARCH
27
2
PHS Regulations
(42 CFR § 50 )
(45 CFR § 94)
Applies to:
PHS grants or cooperative agreements
27
3
How does PHS regulate conflict?
Regulations Require:
Institution to act as “Enforcer” and “Reporter”
Investigator to disclose “significant financial interests”
27
4
Institution as “Enforcer”
1.
Must establish and enforce a written process that identifies, and
manages , reduces, or eliminates any significant financial
interests of an Investigator.
2.
Inform Investigator of process and reporting responsibilities.
42 CFR § 50.604
45 CFR § 94.4
27
5
Institution as “Reporter”
1.
Must certify to PHS agency that written enforced COI process is in
effect.
2.
Must report any COI (including Significant Financial Interest) to
PHS agency and assure that the COI has been managed,
reduced, or eliminated on an annual basis or as new reportable
Significant Financial Interests are identified
3.
Must report to PHS agency any failure of an Investigator to
comply with Institution’s COI process
4.
Must make COI information available to HHS
42 CFR § 50.604, 50.606
45 CFR § 94.4, 94.6
27
6
Who must disclose a Significant
Financial Interest?

Principal Investigator

Any other person who is responsible for the design, conduct,
or reporting of the PHS grant (e.g. Co-investigators).

Their spouse and dependent children
42 CFR § 50.603
45 CFR § 94.3
27
7
What is a
Significant Financial Interest?
Anything of monetary value
42 CFR § 50.603
45 CFR § 94.3
27
8
Examples
Significant Financial Interest?

Salary other payments of services
(consulting fees, honoraria)

Equity interests
(stocks, stock options, any ownership interests)

Intellectual Property Rights
(patents, copyrights, and royalties)
42 CFR § 50.603
45 CFR § 94.3
27
9
Examples
Not Significant Financial Interest?

Salaries, royalties or other remuneration from the Institution

Income from seminars, lectures, teaching engagements
sponsored by public or non- profit entities

Equity Interest that does not exceed $10,000 in value and does
not represent more than 5% ownership interest in any single entity

Salaries, royalties, or other payments that do not exceed $10,000
over a 12 month period
42 CFR § 50.603
45 CFR § 94.3
28
0
How does an Institution manage,
reduce or eliminate COI?






Public Disclosure of SFI
Monitoring of PHS research by independent reviewers
Modification of the research plan
Disqualification from participation in all or part of the PHS
research
Divestiture of significant financial interests
Severance of relationships that create actual or potential conflicts
42 CFR § 50.605
45 CFR § 94.5
28
1
FDA Regulations
(Clinical Trials)
28
2
Who is a Clinical Investigator?

Investigators or Sub-Investigators who are directly involved in
the treatment or evaluation of research subjects

Their spouse and dependent children
21 CFR § 54.2
28
3
What financial relationships and interests
must be disclosed?

Compensation to the investigator for conducting the Study is based
on the outcome of the Study

Any significant payments of other sorts from Sponsor of monetary
value of more than $25,000 (i.e. grant to fund other research,
equipment, consulting fees, honoraria)
Any proprietary interest in the Drug/Device


Any significant equity interest in the Sponsor.
- Publicly-held entity: Exceeds $50,000
- Privately-held entity: Cannot be readily determined

Any steps taken to minimize the potential for bias
resulting
from any of the above arrangements, interests, or payments
21 CFR § 54.4
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4
FDA Review
After the Study is completed, Sponsor will submit its IND/IDE
application to the FDA which will contain Form 3454 (Certification) or
Form 3455 (Disclosure) for each Clinical Investigator.
If FDA determines that the disclosed financial interests raise a serious
question about the integrity of the data, it may take any action
necessary to ensure reliability of the data.
21 CFR § 54.5
42 CFR § 50.606
45 CFR § 94.6
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5
FDA Actions

Audit of the data

Requesting further analysis of data

Requesting further independent studies to confirm results

Reject results
21 CFR § 54.5
28
6
ROAD MAP
I
28
7
General
II
Contracts
A. Why have a Research Agreement?
B. Confidentiality Agreements
C. Clinical Trial Agreements
D. Government Grants/Cooperative Grants
III
Fraud & Abuse Regulations
A. Conflict of Interest Regulations
B. Federal Anti-Kickback Statute
C. Federal False Claims Act
IV
Protection of Human Subject (HIPAA)
Federal Anti-Kickback Statute
 Arrangement between vendor and healthcare professional
 Induces or influences the purchase, order, or referral of drugs,
devices, products, services, or other items
 Reimbursable under a federal healthcare program
28
8
Federal Anti-Kickback Statute

Criminal Offense

Penalties up to $25K or imprisonment up to 5 years, or both

Exclusion from Federal healthcare programs
(i.e. Medicare, Medicaid)

HHS may seek civil penalty $50K for each act that violates the
AKS
28
9
Personal Services Safe Harbor
(Application to Research Agreements)
 Contract in writing and signed by parties
 Specify all services
 Term of contract over 1 year
 Compensation
• Set in advance
• FMV
• Not determined by volume, referrals, etc.
29
0
Relevance in Research?
Research arrangement is suspect when:

Initiated/directed by Sponsor’s marketing dept

Study results not shared with Sponsor’s science dept

Duplicate research/ serves no legitimate purpose
 Product promotional activity masked as postmarket
research

29
1
Payments for services above FMV
ROAD MAP
I
29
2
General
II
Contracts
A. Why have a Research Agreement?
B. Confidentiality Agreements
C. Clinical Trial Agreements
D. Government Grants/Cooperative Grants
III
Fraud & Abuse Regulations
A. Conflict of Interest Regulations
B. Federal Anti-Kickback Statute
C. Federal False Claims Act
IV
Protection of Human Subject (HIPAA)
Federal False Claims Act
Organization knowingly submits a false claim for payment/approval to
an agency of the federal government.
“Knowingly” includes
 actual knowledge
 deliberate ignorance
 reckless disregard of the truth
29
3
Relates to Research?
Certification Theory
Gov’t requires certifications:
 Apply for a grant
 Submit an application to the FDA
 Submit a claim for reimbursement for research-related care
Whenever a false certification is made, FCA is violated.
29
4
Examples in Research
•
•
•
•
•
•
•
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5
False certification in grant applications
False statements in use of grant funds
Failure to make financial disclosures (FDA Form 3454)
Failure to make complete financial disclosures (FDA Form 3455)
Allocations of costs in funded research
Medicare/Medicaid billing
Double-billing
Federal False Claims Act




Civil action
May include criminal penalties
Damages plus $11K penalty for each false claim
If brought by whistleblower, s/he may receive as much as 30%
reward if government does not intervene
 Potential exclusion from federal healthcare programs
29
6
AKS and FCA Cases
Warner-Lambert (FCA)
• $430 million
• $83.6million for FCA Violation
• $106.4 million for State Settlement
• $240 million Federal Criminal Fine
• Whistleblower’s share = $24.64 million
• Corporate Integrity Agreement
29
7
AKS and FCA Cases
TAP Pharmaceuticals (AKS & FCA)
• $875 million
• $559.5 million for FCA Violations
• $25.5 million for State Settlement
• $290 million federal criminal fine (DOJ’s Crime Victims
Fund )
• Whistleblower share 1 = $78 million (TAP VP of Sales)
• Whistleblower share 2 = $17.1million (Tufts Health Plan &
Physician)
• Corporate Integrity Agreement
29
8
AKS and FCA Cases
Arizona Heart Institute (FCA)
• $6.7 Million
• $5.8Million Arizona Heart Institute
• $900K Medical Practice Groups
• Corporate Integrity Agreement (5 years)
• Violated FCA by submitting Medicare claims for
experimental procedures
29
9
ROAD MAP
I
30
0
General
II
Contracts
A. Why have a Research Agreement?
B. Confidentiality Agreements
C. Clinical Trial Agreements
D. Government Grants/Cooperative Grants
III
Fraud & Abuse Regulations
A. Conflict of Interest Regulations
B. Federal Anti-Kickback Statute
C. Federal False Claims Act
IV
Other Issues
Double-Billing
Seeking multiple reimbursement for same services
Seeking Medicare/Medicaid reimbursement for services reimbursed by
sponsors/grant funds
30
1
HIPAA
Informed Consent – Authorization
Limited Data Set Agreements
30
2
Insider Trading
Providing results to a third party for the purpose of assessing corporate
stock violates insider trading laws
Violates Confidentiality Agreements
30
3