The Office of Human Subjects Researchs Compliance Monitoring Program Educational Seminars:

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The Office of Human Subjects ResearchsCompliance
Monitoring Program Educational Seminars

• Projects that Do Not Involve FDA Regulated
  Products Investigator Responsibilities and
  Compliance

Barbara Starklauf, MAS, CIP Jenna Schulcz, BA,
CCRP Lea Olverson, MS, CIM Frederick W. Luthardt,
MA, CCRP
September 26, 2006 October 5, 2006
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Presentation Topics

• Federal Requirements of the Department of Health
  and Human Services (DHHS) and our Institutions
  Federal Wide Assurance (FWA) responsibilities
• Institutional Compliance mechanisms Monitoring
  and Auditing
• Organizational strategies for regulatory and
  applicable subject documentation

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The Power of the FDAWhat we already know

• The FDA regulations are often considered the
  gold-standard for study organization, conduct,
  and oversight.
• Researchers and Institutions are aware of what
  the FDA can do if the regulations are not
  followed.
• Weve seen the painful outcomes of bad FDA
  audits fines, debarment, prison

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Rhetorical Question

• Should a study not subject to FDA authority be
  organized and conducted less rigorously or with
  diminished attention to research integrity and
  subject safety?
• Answer No. The DHHS and Institutional
  authorities are also authorized to regulate,
  oversee, and enforce requirements for research.

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Does my study fall under FDA or HHS authority?

• OHRP recommends that the process for determining
  whether the HHS regulations apply should address
  the following three questions in order
• (1) Does the activity involve research under 45
  CFR 46.102(d)? (If yes, proceed to the second
  question.)
• (2) Does the activity involve human subjects
  under 45 CFR 46.102(f)? (If yes, proceed to the
  third question.)
• (3) Is the activity exempt under 45 CFR
  46.101(b)?
• If the answer to the first two questions is
  "yes", and the answer to the third question is
  "no", then the HHS regulations apply otherwise,
  the HHS regulations do not apply. To view a chart
  regarding this decision-making process, see
  OHRP's "Human Subject Regulations Decision
  Charts" at http//www.hhs.gov/ohrp/humansubjects/
  guidance/decisioncharts.htm.

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DHHS Definitions

• Research a systematic investigation, including
  research development, testing and evaluation,
  designed to develop or contribute to
  generalizable knowledge.
• Human Subject means a living individual about
  whom an investigator conducting research obtains
  (1) Data through intervention or interaction with
  the individual, or (2) Identifiable private
  information.
• Research Subject to Regulation those research
  activities for which a federal department or
  agency has specific responsibility for regulating
  as a research activity, (for example,
  Investigational New Drug requirements
  administered by the Food and Drug
  Administration).
• Institution Any public or private entity or
  agency that is engaged in research.

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FDA vs. DHHS

• Not all studies are subject to FDA Regulations,
  e.g. non-IND studies.
• Department of Health and Human Services requires
  institutions to assure compliance with
  regulations (FWA).
• Research that is neither conducted nor supported
  by a federal department or agency but is subject
  to regulation as defined in 46.102(e) must be
  reviewed and approved, in compliance with
  46.101, 46.102, and 46.107 through 46.117 of
  this policy, by an institutional review board
  (IRB) that operates in accordance with the
  pertinent requirements of this policy.
• Non-FDA studies must comply with 45 CFR 46 The
  Common Rule.

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45 CFR 46 The Common Rule

• Subpart A Basic HHS Policy for the protection of
  Human Research Subjects
• Requirement for assuring compliance with Federal
  Regulations for research
• Obtaining Informed Consent
• Oversight of research by Institutional Review
  Board
• Research institutions will assure the federal
  government that it will provide and enforce
  protections for human subjects of research.
• Subpart B-D Provide additional protections for
  Pregnant Women, Human Fetuses and Neonates (Part
  B), prisoners (Part C), and Children (Part D) who
  are involved in research

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DHHS Scope at Johns Hopkins

• 45 CFR 46.101 All research involving human
  subjects conducted or supported by HHS or
  conducted in an institution that agrees to assume
  responsibility for the research in accordance
  with 45 CFR 46 regardless of the source of
  funding.
• The Institution maintains several Federal Wide
  Assurances (FWA), which indicate the above
  agreement that the Institution will oversee
  research and assure Human Subject Protection.

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Federal Wide Assurance (FWA)

• Highlights of the terms of the Agreement?
• Human Subjects Research Must be Guided by Ethical
  Principles
• Compliance with the Federal Policy for the
  Protection of Human Subjects and Other Applicable
  Federal, State, Local, or Institutional Laws,
  Regulations, and Policies
• Written Procedures
• Scope of IRB(s)s Responsibilities
• Informed Consent Requirements
• Compliance with the Terms of Assurance
• Assurance Training
• Education Training

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FWAs across the Institution
The Institutions had been operating under
Multiple Project Assurance M-1011 for the
period of 11/01/98 to 10/31/03. The MPA was
replaced by Federal-Wide Assurances associated
with each of the organizations linked to the JHM
IRBs. The specific Federal-Wide Assurance
numbers and expiration dates are as follows
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Examples of Studies that must comply with HHS
regulations

• Studies that receive Federal funding in whole or
  in part from any Federal entity
• Studies receiving NIH Award
• Studies funded by specified Federal agencies,
  e.g. DOE, DOD, etc.
• Studies supported by the VA
• Studies that receive no Federal funding
• Investigator initiated protocols
• Studies funded by private organizations
• Studies receiving internal fellowships/grants

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Specific types of studies that fall under HHS and
Institutional (IRB) authority

• Non-IND/IDE e.g., comparison of approved
  treatment modalities
• Pilot Studies e.g., proof of concept
• Observational/non-interventional e.g., biomarker
  assays on stored samples
• Quality Improvement e.g., surveys of inpatients

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Institutional Compliance

• The HHS advises that institutions implement
• Internal audit procedures to assure the
  institution's administration that its policies
  and procedures are being adhered to and that they
  are proper in scope and content and that
  reporting of noncompliance is accomplished and
  that appropriate follow-up measures are taken
• internal audit or self-assessment procedures
  and practices designed to assure proper protocol
  and consent document preparation, protocol
  submission, review and approval by the IRB, and
  timely monitoring of protocol implementation.
• Monitoring is good policy.
• http//www.hhs.gov/ohrp/irb/irb_chapter1.htm

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Monitoring and Auditing

• IRB approved studies can be audited or monitored
  by
• A sponsor
• A funding agency (NIH, DOE, etc.)
• The IRB via the Compliance Monitoring Program
• Per routine selection
• Directed or for-cause
• The DHHS (in response to a complaint)

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Monitoring Authority of the IRB

• Only consent forms with a valid approval stamp
  may be presented to subjects. All consent forms
  signed by subjects enrolled in the study should
  be retained on file. The Office of Human
  Subjects Research conducts periodic audits of
  protocol
• records, and consent documentation is part
  of such audits.

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What we hear

• Why am I being monitored?
• Implying the following
• Nobody died or
• My study is low-risk or
• Im just collecting samples or
• My study is part of clinical care
• Etc.

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The Bottom Line

• If a study is IRB approved, all regulatory
  documents and subject records must be retained,
  organized, retrievable, and available for
  inspection.

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What do we suggest?

• Develop compliance plans during study design or
  implement plans for corrective action, to include
  the following
• SOPs Standard Operating Procedures are written
  instructions to achieve uniformity of the
  performance of a specific function.
• CRFs Case Report Forms are documents designed
  to record all of the protocol-required
  information
• Source Documentation Maintain all the applicable
  original documents, data and records that
  correspond with the CRFs.
• Checklists A means to verify the completion of
  study related procedures.
• Note-To-File A means of explaining and
  correcting unexpected departures from the
  protocol.
• Consider the following process steps and examples
  for creating a compliance plan
• Source ICH E6 Guideline for Good Clinical
  Practice

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Regulatory Documentation Organization
Recommendations

• The IRB via the Compliance Monitoring Program can
  monitor or audit any study approved by the IRB
• For example, an investigator initiated study
  testing clinical outcomes of two standard
  therapies
• Regulatory Binder contents (what to keep)
• IRB materials (applications, approvals, consent
  forms, problem reports, changes to the protocol,
  correspondence, etc.) to maintain a comprehensive
  audit trail
• Site responsibility delegation table
• The protocol

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Sample Regulatory Binder Table of Contents
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Example Responsibility Matrix
Staff Name/Role Responsibilities
Signature IRB Appr. Date PI
Initials

• RESPONSIBILITY KEY
• Consent Designee
• Evaluates Subject Inclusion/Exclusion criteria
• Maintains Source Documents
• Completes Case Report Forms
• Dispenses Study Drug
• Administrative
• Obtains Laboratory Values (sample collection)
• Interprets Medical Reports and Laboratory Results
  (i.e. ECGs, MRIs, etc.)
• Adverse Event Documenting and Reporting

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Subject Documentation Organization
Recommendations

• Keep and maintain documentation to verify
• Consent process
• Eligibility assessment
• Protocol compliance
• Problem and Deviation reporting to the IRB
• Quality control (error detection and correction)
• Data Collection and a means to verify data

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Informed Consent Process Sample Checklist

• INFORMED CONSENT CHECKLIST
• Subject initials ________________
• Date of Birth ________________
• Subject study identifier _________
• Consent Version /Expiration Date
  _________________
• Consent signed and dated by subject YES
  ? NO ?
• Date ____________
• Was a copy of the consent given to the
  subject YES ? NO ?
• Consent signed and dated by parent YES ?
  NO ? N/A ?
• Date ____________

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Eligibility Assessment Sample Checklist
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Protocol Deviations
Date IRB
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Take Home Points

• Keep everything organized
• There are consequences to non-compliance
• Any IRB approved study can be audited
• Studies in disarray may lead to
• Data rendered not evaluable
• Subject Safety may be compromised
• Study delays
• Call the Compliance Team with questions
• Keep everything organized

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How to Get in Touch with the Compliance
Monitoring Team

• Please contact the JHM IRB office at 410-955-3008
  
  if you have questions
  regarding regulatory guidance.
• For general questions and assistance, the
  monitors may be contacted at the JHM-IRB office.
  Please ask for Compliance.
• The Monitors may also be contacted directly by
  email
• jschulc1_at_jhmi.edu
• lolvers1_at_jhmi.edu
• fluthard_at_jhmi.edu

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References

• DHHS http//www.hhs.gov/
• OHRP http//www.hhs.gov/ohrp/
• FDA http//www.fda.gov/ora/
• FDA comparison with DHHS/OHRP http//irb.jhmi.edu
  /Guidelines/FDAvsOHRP.html
• FWA http//www.hhs.gov/ohrp/humansubjects/assuran
  ce/filasurt.htm
• The Common Rule http//www.hhs.gov/ohrp/humansu
  bjects/guidance/45cfr46.htm
• JHM-IRB Guidance http//irb.jhmi.edu/Guidelines/
• Monitoring http//irb.jhmi.edu/Guidelines/Monitor
  ingVisits.html