Best Practices in Research Compliance: Update on Policies and Regulations and Implementation at Inst

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Best Practices in Research Compliance Update on
Policies and Regulations and Implementation at
Institutions

• Broadcast September 13, 2005

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Faculty

• Moderator
• Marianne Woods, Associate Vice President for
  Research, The University of Alabama
• Presenters
• Michael Carome, Associate Director for
  Regulatory Affairs, Office for Human Research
  Protections, DHHS
• Linda Triemer, Director of Regulatory Affairs
  Operations, Office of the Vice President for
  Research and Graduate Studies, Michigan State
  University

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Faculty Continued

• Benjamin Fontes, Biosafety Officer and Manager,
  Safety Advisor Program, Office of Environmental
  Health Safety, Yale University
• Daniel Vasgird, Director, Office of Research
  Integrity and Compliance, University of Nebraska,
  Lincoln
• Todd Guttman, Associate Vice President for
  Research Compliance, Ohio State University

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Overview

• Constitution Day and Citizenship Day
• Compliance Oversight Review
• Human Subject Accreditation
• Biosafety Issues Changes affecting Central
  Administration and Departmental Administration
• Responsible Conduct of Research Initiatives and
  Training
• Conflicts-of-Interest

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A Definition of Compliance

• The act or process of complying to a desire,
  demand, or proposal or to coercion
• Conformity in fulfilling official requirements
• -Websters Dictionary

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Compliance

• Compliance is the cost of doing business with the
  government
• Its required, its regulated, its tough, it
  costs money.
• Suspension of federal funds can harm research and
  the university credibility
• A faculty member can go to jail!
• The University can be fined!

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Constitution Day and Citizenship Day

• Effective May 24, 2005
• Congressional Mandate
• Agency Office of Innovation and Improvement,
  U.S. Department of Education

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Constitution Day and Citizenship Day continued

• Requirement All educational institutions
  receiving federal funds must hold an educational
  program pertaining the U.S. Constitution on Sept.
  17th of each year.
• Unfunded

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The Office for Human Research Protections A
Regulatory and Compliance Update
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OHRP Update Overview

• Recent and pending regulatory changes
• New assurances Federalwide Assurances (FWA)
• New guidance from OHRP
• Recent OHRP answers to questions
• Compliance oversight activities

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Title 45 Code of Federal Regulations Part 46

• Protection of Human Subjects (Last revised June
  23, 2005)

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The Belmont Report

• Respect for Persons
• Beneficence
• Justice

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Regulatory Changes (1)

• Final Rule issued on 6/23/05 making technical
  amendments to the Federal Policy for the
  Protection of Human Subjects (70 FR
  36325-36328)

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Regulatory Changes (1) cont.

• Changed OPRR references to OHRP
• Updated footnote related to exemptions
• Updated OMB control number

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Regulatory Changes (2)

• Revised subpart B (Additional Protections for
  Pregnant Women, Human Fetuses and Neonates
  Involved in Research (66 FR 56778, 11/13/01)
• removed provisions related to research
  involving human in vitro fertilization

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Regulatory Changes (3)

• Revised subpart B (cont)
• exemptions under 45 CFR 46.101(b) apply
• altered requirements for when informed consent
  of father of fetus is required
• requirements for neonates of uncertain
  viability and nonviable neonates

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Regulatory Changes (4)

• Revised subpart B (cont)
• Research not otherwise approvable which
  presents an opportunity to understand, prevent,
  or alleviate a serious problem affecting the
  health or welfare of pregnant women, fetuses, or
  neonates. Requires approval of Secretary after
  consultation with panel of experts and public
  review/comment.

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Regulatory Changes (5)

• Revised subpart B (cont)
• One problematic area, 45 CFR 46.204 For
  research involving pregnant women or fetuses,
  if there is no prospect of benefit for the woman
  or fetus, the risk to the fetus is not greater
  than minimal and

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Regulatory Changes (5) cont.

• the purpose of the research is the development
  of important biomedical knowledge which cannot be
  obtained by other means.

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Regulatory Changes (6)

• Notice of Proposed Rulemaking (NPRM) for IRB
  Registration (69 FR 40584-40590, 7/6/04)
• Would require submission of additional
  information beyond that required under assurance
  provisions of 45 CFR part 46, subpart A.
• contact information of chair, organization
  running the IRB, and primary point of contact

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Regulatory Changes (7)

• NPRM for IRB Registration (cont)
• Number FTEs supporting the IRB
• Total number of active protocols, number of HHS
  supported protocols, and number of FDA-regulated
  protocols
• Accreditation status

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Regulatory Changes (8)

• HHS Unified Agenda Advanced NPRM (ANPRM),
  Additional Protections for Adult Individuals with
  Impaired Decision making Capacity
• Jointly with FDA

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Regulatory Changes (8) cont.

• Will seek comment on whether it is necessary to
  develop additional safeguards to protect adult
  individuals with impaired decision making
  capacity and if so, suggestions for safeguards

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Assurances (1)

• 4 types of assurances currently in effect
  Single Project Assurances (SPA), Cooperative
  Project Assurances (CPA), Multiple Project
  Assurances (MPA), and Federalwide Assurances
  (FWA)
• FWA introduced in 2000 a revised FWA was
  approved by OMB in January 2005

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Assurances (2)

• Effective 12/31/05, all MPAs and CPAs will be
  deactivated, must be replaced by FWA.
• Implications for institutions holding an
  approved MPA or CPA
• Implications for institutions holding an
  approved FWA

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Assurances (2) continued

• SPAs remain effective for all non-competitive
  renewals of existing HHS awards

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New OHRP Guidance (1)

• Guidance on Research Involving Coded Private
  Information or Biological Specimens (August 10,
  2004)
• Guidance on Extension of an FWA to Cover
  Collaborating Individual Investigators and
  Introduction of the Individual Investigator
  Agreement (January 31, 2005)

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New OHRP Guidance (2)

• Children Involved as Subjects in Research
  Guidance on the HHS 45 CFR 46.407 Process (May
  26, 2005)
• Guidance on Reporting Incidents to OHRP (May 27,
  2005)
• FAQs on Assurances and IRB Registration (June
  2005)

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Recent OHRP Answers to Questions

• Please see supplemental handout 1, entitled,
  Recent OHRP Answers 1-9.

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Compliance Activities (1)

• For-cause compliance oversight activities
• Not-for-cause compliance oversight activities

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Compliance Activities (2)New For-Cause Cases
1990-2005
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Compliance Activities (3)Site Visits 1990-2005
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Compliance Activities (4)

• For-cause compliance oversight site visits
• 46 since 1990
• Not-for-cause compliance oversight site visits
• 3 in 1990-2001
• Average of 3 per year since 2002
• 13 of last 17 OHRP site visits

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Compliance Activities (5)Suspend/Restrict
Assurance
1990-2005
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Compliance Activities (6)Common Findings

• OHRP Compliance Activities Common Findings and
  Guidance 7/10/02 http//www.hhs.gov/ohrp/compli
  ance/findings.pdf
• http//www.hhs.gov/ohrp/compliance/letters/index.h
  tml

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Compliance Activities (7)Common Findings

• Compliance oversight letters issued between
  10/01/98 and 6/30/02
• 269 determination letters to 155 institutions
• 18 institutions site-visited
• 1,120 citations of noncompliance or deficiencies
• 142 institutions (92) had at least one finding
  (range 0-53, median 4)

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Compliance Activities (8) Data on 155 institutions

• 10/98-6/02
• Deficient IRB initial review - 55
• Deficient IRB continuing review - 45
• Deficiency in IRB-approved informed consent
  document/process 51

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Compliance Activities (9)Data on 155 institutions

• 10/98-6/02
• Deficient IRB written procedures 55
• Deficient IRB records/minutes 37
• Research conducted without IRB review 17
• More data at Borror, K, et al. A review of
  OHRP compliance oversight letters. IRBEthics
  Human Research. 25(2003) 1-4.

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Underlying Causes of Noncompliance

• Inadequate education and training of IRB
  members, IRB staff, and investigators
• Inadequate staff and resources for the IRB
• Overburdened IRBs

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Compliance Hot Spots

• The boundary between research and other
  activities (QI/QA, public health, innovative
  medical practice, program evaluation)
• IRB approval of research contingent upon
  substantive questions/clarifications

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Compliance Hot Spots cont.

• Minimizing the possibility of coercion or undue
  influence when obtaining informed consent
• Additional safeguards for vulnerable subjects

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Implementing Regulations for Human Subject
Research through Accreditation
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Accrediting Organizations for Human Subject
Research

• Association for Accreditation of Human Research
  Protection Programs, Inc.
• www.aahrpp.org
• 24 accredited organizations, 11 universities
• Partnership for Human Research Protection, Inc.
• www.phrp.org
• 9 accredited organizations, 1 university

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AAHRPP Accredited Universities

• Indiana U Purdue U, Indiana (IUPUI)
• U of Arkansas for Medical Science
• U of New Mexico Health Science Center
• U of Minnesota
• U of Iowa
• U of Louisville
• Vanderbilt
• Washington U in St. Louis
• Baylor Research Institute
• Dana-Farber / Harvard Cancer Center
• Johns Hopkins Medical Institution

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AAHRPP Domains

• I - Organization
• II - Research Review Unit (IRB)
• III - Investigator
• IV - Sponsored Research
• V - Participant Outreach

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Accreditation is a Process

• Prescribed Self Assessment
• Criteria or Standards
• DOCUMENTATION
• External Review and Evaluation
• Education
• Continuous Quality Improvement

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Example AAHRPP Standard

• STANDARD I -1The organization has a systematic
  and comprehensive human research protection
  program with appropriate leadership.
• ELEMENTS
• I.1.A. The Organization has a written plan for
  its Human Research Protection Program appropriate
  for the volume and nature of the research
  involving human participants conducted under its
  auspices.

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Example AAHRPP Standard

• I.1.B. The Organization has and follows written
  policies and procedures for reviewing the
  scientific or scholarly validity of a proposed
  research study. Such procedures are coordinated
  with the ethics review process.
• I.1.C. The Organization delegates responsibility
  for the Human Research Protection Program to an
  official with sufficient standing,

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Example AAHRPP Standard

• Authority, and independence to ensure
  implementation and maintenance of the program.
• I.1.D. The Organization has and follows written
  policies and procedures for working with
  sponsors, investigators, research participants,
  and the Research Review Unit to uphold ethical
  standards and practices in research.

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Challenges of Accreditation

• Commit resources
• Change organizational structures
• Share responsibility
• Invest in new IT solutions
• Garner support
• IRB, Administration, Faculty
• Educate community

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Planning for Accreditation

• Resources
• Director and staff
• Advisory teams
• Administrators
• Budget
• Application Fees
• Annual Fees
• Tasks and Timeline

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Hidden Costs of Accreditation

• Time commitments
• Document current policies and procedures
• Develop new policies and procedures
• Educate IRB members and faculty

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Hidden Costs of Accreditation

• Unexpected problems
• Gaps (gaping holes) in policies
• Compliance issues
• Culture shift

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Tough Policies

• Non-compliance
• Unanticipated problems / adverse events
• Reporting
• Changing organizational policies

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Tough Procedures

• Minutes of IRB meetings
• Documentation of review
• Coordination with Contracts Grants

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Plan for the Site Visit

• Need logistics team
• Expect the unexpected
• Transportation train delays
• Angry investigators inviting themselves

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If we had to do it over again

• Increase resources
• Involve IRB as much as possible
• Go through preliminary application
• Test out new policies procedures
• Educate research community
• Double our time estimate

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Results of Accreditation Process

• More transparent operation
• Improved communication
• Restructured administration
• Increased resources
• Reduced noncompliance

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Biosafety
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Current and Pending Biosafety Issues

• Patriot Act Select Agent compliance
• Review of dual-use research
• IBC site visits
• Increase in Biosafety Level 3 research

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Select Biological Agents/Toxins

• USA PATRIOT Act (Public Law 107-56)
• Public Health Security and Bioterrorism
  Preparedness Response Act of 2004
• Possession, Use and Transfer of Select Agents and
  Toxins Final Rule (3/18/05)

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Select Agent Registration

• Identify Owner/Controller
• Appoint Responsible Official(s)
• Background Clearance
• Responsible Officials
• Principal Investigators
• Researchers/others with access

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Sustaining your SA program

• Remain in compliance
• Evaluate new threats, risks, vulnerabilities
• Inspection readiness
• Continuous improvement

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Sustaining your SA program

• Actively seek out problems/issues
• Immediately document/address non-compliance
• Benchmark with relevant groups

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Sustaining your SA program

• Periodically update
• Biohazard registration(s)
• Signed PI declarations of possession
• Written Biosecurity Plan
• Training
• Drills

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Sustaining your SA program

• Update personnel
• Background check/clearances
• Security challenges
• Physical, operations, ITS
• Change locks, combinations

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Inventory

• Transfer records
• Periodic inventory
• Access records
• Quantities used and destroyed

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Retraining

• Review key requirements
• Loss, theft, or release
• SA destruction
• Emergency Drills
• Suspicious people, packages, activities
• Security/facility alarms, breaches

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Test Security/Facility Systems

• Alarm function
• Facility tests
• Condition of security features
• Access logs (written/electronic)

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Mock Audit

• CDC/USDA Checklists
• Include
• Records
• Tour of labs/storage areas
• Interview authorized personnel

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Mock Audit

• Documentation
• Plans
• Inspections
• Incident reports
• Transfers
• Amendments
• Training

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National Science Advisory Board on Biosecurity
(NSABB)

• Biosecurity for dual-use research
• Oversight of federally funded or supported
  research
• Training
• Educate on dual-use experiments
• Existing IBCs as local review body

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Dual Use

• Dual use means technical data and commodities
  that have both civilian and military use
• Related to U.S. Export Control Regulations
• Used in relation to technical data and commodities

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Dual-Use Research

• Legitimate research that could impact public
  health or security
• Examples
• New pathogens
• Increased pathogenicity/virulence
• Altered host range
• Weaponization

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Dual-Use Research

• Increase/develop drug resistance
• Synthesis of pathogen genome

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Dual-Use Equipment

• Isolators, anaerobic chambers, glove boxes
• Fermentation Vessels (gt 100 liters)
• Centrifugal separators, decantors (gt100 L per
  hour)
• Steam sterilizable freeze drying equipment

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Dual-Use Equipment

• BSL-3/BSL-4 containment equipment or housing
• Full or ½ protective ventilated suits
• Class III Biosafety Cabinets or similar devices

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Dual-Use Research

• Implications for IBCs (upcoming?)
• Train lab staff
• Identify research that could threaten public
  health
• Seek advice of NSABB
• Monitor research if approved

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IBC Site Visits

• Monitor IBC Compliance
• On-site education and advice
• Improve IBC function

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Evaluation of IBC Function

• Registration
• Membership
• Expertise
• Training
• Records
• Reporting
• Public Access

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IBC Review

• rDNA protocols (new, updates)
• Inspections
• Facility Evaluation
• Emergency plans
• Evaluation of other Biohazards
• Select Agents
• Human, animal, plant pathogens
• Toxins

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Suggested IBC Subcommittees

• Biosafety Level 3
• Human Gene Transfer
• Dual Use?

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Requirements for BSL-3 Research

• Registration
• Risk Assessment
• Training
• Medical Surveillance
• Researcher Authorization
• Protocol Approval

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BSL-3 Facilities

• Pertinent standards/guidelines
• CDC
• USDA
• NIH
• Health Canada
• World Health Organization

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BSL-3 Facilities

• Design team
• IBC approval
• Pre-qualify contractor(s)
• Facility commissioning/certification
• Written facility maintenance plan

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Addressing Increased Biosafety Program Needs

• Increased regulations
• Growth in biomedical research funding
• Safety Advisor Program
• Retrain existing professionals
• Support for all EHS Programs

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Biosafety Profession

• Resources
• American Biological Safety Association
  www.absa.org
• Centers for Disease Control Prevention
  www.cdc.gov
• National Institutes of Health Office of
  Biotechnology Activities http//www4.od.nih.gov/o
  ba/

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The Responsible Conduct of Research
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The Fundamental Proposition

• Rules are just a small part of the picture.
  The alpha and the omega has to be integrity from
  which all else will follow, including compliance.

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RCR Core Areas

• Human Research Protections
• Research Protections for Animals
• Research Misconduct
• Conflict of Interest and Commitment
• Mentor/trainee Relationships
• Responsible Authorship
• Peer Review
• Data Management, Sharing and Ownership
• Collaborative Science

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Martin Arrowsmiths struggle to be a scientist
is a matter of freeing himself from a universe of
Babbitts. - E. L. Doctorow
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Consequences of Ambition

• Perseverance and success, but increased
• Risk for unintentional bias
• Willingness to cut corners
• Willingness to commit serious misconduct

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"For a scientist, integrity embodies above all
the individual's commitment to intellectual
honesty and personal responsibility For an
institution, integrity is a commitment to
creating an environment that promotes responsible
conduct by embracing standards of excellence,
trustworthiness, and lawfulness" - Integrity in
Scientific Research, The National Academy of
Sciences
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The first step in the evolution of of ethics is
a sense of solidarity with other human beings.
- Albert Schweitzer
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Individual ethical behavior is likelier to
flourish within a just society. So in order to
lead an ethical life one should work for a just
society. That is, if most of us will behave about
as well as our neighbors, it is incumbent on us
to create a decent neighborhood. - Randy Cohen
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Consequences of Ambition

• Perseverance and success, but increased
• Risk for unintentional bias
• Willingness to cut corners
• Willingness to commit serious misconduct

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Robert K. Merton

• Stated that the disinterested pursuit of truth is
  the norm of science, expressed as
• Universalism
• Communalism
• Disinterestedness
• Organized skepticism

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Milton Friedman

• Stated that the limits of the social
  responsibility of industrial corporations are to
  make as much money for their stockholders as
  possible.
• What does this mean for academia considering the
  scale of private research funding these days?

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National Academy of Sciences Report Primary
Recommendations

• Funding agencies should establish research
  grants to determine factors that influence
  integrity in research Done and accessible from
  ORI.
• Research institutions should promote integrity in
  research through top-down commitment to RCR
  through strong supervision, communication,
  socialization, etc.

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NAS Report Primary Recommendations cont.

• Research institutions should offer effective
  educational programs that enhance RCR.
• Research institutions should perform
  self-assessments to determine areas of need.

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Federal Sentencing Guidelines for Organizations
Compliance Elements (HHS NSF)

• Implementing written policies and procedures
• Designating a compliance officer and compliance
  committee
• Conducting effective training and education
• Developing effective lines of communication

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FSGO Compliance Elements (HHS NSF) cont.

• Conducting internal monitoring and auditing
• Enforcing standards through well-publicized
  disciplinary guidelines and
• Responding promptly to detected problems.

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Jesse Gelsinger
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Penns Analysis of Problems

• Uncertainty over what is standard care versus
  research
• Uncertainty over whether IND / IDE required
• Poorly written protocols
• Protocol amendments poorly documented
• Informed Consent Form inadequacies

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Penns Analysis of Problems

• Study Files incomplete - absent or insufficient
  documentation
• Case Report Forms did not capture required
  information
• Study did not have a Research Coordinator
• Study was not monitored

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Samuel Waksal, PhD

• Founder of ImClone Systems in 1985
• Insider trading, perjury, obstruction of justice,
  bank fraud (Martha Stewart)
• Research career, 1974-1985

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Samuel Waksal, PhD cont.

• 4 labs (Stanford, National Cancer Institute,
  Tufts University, Mt. Sinai School of Medicine)
  ousted Waksal, WSJ, Sept. 27, 2002
• Research misconduct false claims (antibodies),
  claimed results of experiments not done,
  published data different from lab books

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Fakery at a Top Research Lab

• NY Times, 10/1/02
• J. Hendrik Schön of Bell Labs
• Published in Science and Nature (peer review)
• Falsified Data
• Bell Labs no Research Misconduct policy (Cant
  happen here)
• PhD at U. of Konstanz revoked

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National Academy of Sciences

• To maintain (public) confidence and trust in this
  (the scientific) enterprise, researchers must
  protect the empirical objectivity of research,
  the unbiased reporting of results and the open
  sharing of that information for the good of
  society.

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The OSTP Definition of Misconduct

• Research misconduct is defined as fabrication,
  falsification, or plagiarism in proposing,
  performing, or reviewing research, or in
  reporting research resultsResearch misconduct
  does not include honest error or differences of
  opinion.

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HHS Research Misconduct Final Rule (June, 2005)

• Universities must
• Have research misconduct PPs
• Foster an environment that promotes RCR
• Deal with allegations or possible evidence of
  research misconduct promptly

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New HHS Appeals Process

• New rules call for an Administrative Law Judge
  (ALJ) to handle all appeals.
• Replaces the Departmental Appeals Board (DAB)
  panel reduces role of scientists in appeal
  process.
• ALJ has option to ask for scientific advice but
  not required unless either party requests it.

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Research and/or Ethics Does it matter? Yes

• Of all the traits which qualify a scientist for
  citizenship in the republic of science, I would
  put a sense of responsibility as a scientist at
  the very top. A scientist can be brilliant,
  imaginative, clever with his hands, profound,
  broad, narrow-but he is not much as a scientist
  unless he is responsible." - Alvin Weinberg, The
  Obligations of Citizenship in the Republic of
  Science

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Update on Conflict of Interest Regulatory
Requirements and Management
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Current Regulatory Requirements

• Public Health Service 42 CFR Part 50
• Disclosure by investigators of significant
  financial interests.
• Institutional determination and management,
  reduction or elimination of the conflict.
• Institutional disclosure to sponsor.

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Current Regulatory Requirements

• National Science Foundation
• NSF generally obligates awardees to comply with
  PHS regulations for objectivity in research at 42
  CFR Part 50
• NSF Investigator Financial Disclosure Policy (59
  Fed Reg. 33308 (June 28, 1994)).

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Current Regulatory Requirements

• Food and Drug Administration
• FDA regulations at 21 CFR Part 54 apply to
  entities sponsoring a covered clinical study.
• Sponsors are required to meet the FDAs conflict
  of interest disclosure and reporting obligations.

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Current Regulatory Requirements

• FDA has provided specific guidance for when an
  academic institution is a sponsor for conflict
  of interest disclosure purposes.

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Recent Regulatory Guidance

• National Institutes of Health Financial
  Relationships and Interests in Research Involving
  Human Subjects Guidance for Human Subject
  Protection, May 12, 2004, recommended
• Establishing conflict of interest committees or
  identifying other bodies or persons and
  procedures to address financial interests in
  research.

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Recent Regulatory Guidance

• Determining whether current methods for managing
  conflicts of interest are adequate for protecting
  the rights and welfare of human subjects and
  whether other actions are needed to minimize
  risks to subjects.
• Using special measures to modify the informed
  consent process when a potential or actual
  financial conflict exists.

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Association Guidelines and Policies

• Association of American Universities (AAU) 2001
  Report on Individual and Institutional Financial
  Conflict of Interest.
• American Medical Association (AMA) Ethics Opinion
  Managing Conflicts of Interest in the Conduct of
  Clinical Trials.

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Association Guidelines and Policies cont.

• The Association of American Medical Colleges
  (AAMC) 2002 report Protecting Subjects,
  Preserving Trust, Promoting Progress II
  Principles and Recommendations for Oversight of
  an Institutions Financial Interests in Human
  Subjects Research.

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Association Guidelines and Policies cont.

• American Society of Gene Therapy 2000 Policy.

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Current Best Practice for Inst. Conflict
Management

• Faculty involvement in the conflict assessment
  and management process
• Annual faculty disclosures
• Written management plans for significant
  financial interests.
• Updating management plans
• Institutional consistency

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Current Management Issues

• Individual Financial Interest
• What is magic about 10,000?
• Allow investigators with significant financial
  interest in a company to be PI on clinical trial
  funded by a company?
• Does it matter if the sponsor is a university
  start-up company?

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Current Management Issues

• Institutional Conflicts of Interest
• Most current policies appear to focus on the
  potential conflicts of institutional officials
  and those associated with equity ownership in the
  institutions start-up companies

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Current Management Issues

• What about
• Development and large unrestricted gifts
• Master sponsored research agreements
• Device Testing

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Conflict of Commitment

• Consulting extremes and the Ruths Chris
  Steakhouse circuit
• Faculty and research staff start-up companies
• Entrepreneurial leaves of absence

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Additional materials from this program can be
downloaded from http//research.unc.edu/osr/train
ing/index.phpcompliance