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General Principles for Meeting Regulatory
Responsibilities
Terry VandenBosch, RN, PhD, CIP, CCRP
Senior Research Compliance Associate
Office of Human Research Compliance Review
University of Michigan
June 1, 2010
Today’s Discussion
Describe Best Research Practices (BRP) and Good Clinical Practices (GCP)
Compare GCP requirements for FDA regulated studies and regulatory requirements for non-FDA regulated studies
Identify common sense principles for implementing best practices and GCP in clinical studies
What is “Best Practice”
Experience-basedEvidence-based?Effective and efficient practices to meet
1) ethical principles 2) federal regulations & guidance 4) state laws & practice acts5) university policies and procedures6) any applicable study SOPs
Best Practices = Responsible Research Practices
Ultimate Goal:Responsible Research Practices
“The University of Michigan is committed to the highest standards of ethical behavior by faculty, staff, and students engaged in the conduct and administration of research and other scholarly activity.”
UM Provost Policy Statement on Academic and Research Integrity
Ethical Principles & Best Practices Ethical principles inform decision-making and basis for
federal regulations and guidancePast abuses stimulate use of Best Practices
Nuremburg Tuskegee syphilis study Willowbrook retarded children hepatitis study
Are these ethical lapses and abuses all in the past? Nicole Wan (healthy volunteer- died), 1996 Jesse Gelsinger (ineligible-died), 1999 Ellen Roche (healthy volunteer-died), 2001 Inadequate monitoring with overdose of pediatric subjects-
Pfizer FDA warning letter, April 9, 2010
Ethical Principles-Belmont
• Belmont Report – 1979• Summarized ethical principals identified by National
Commission for the Protection of Human Subjects • Prompted by the Tuskegee Syphilis Experiment and
the Willowbrook hepatitis study• 3 basic ethical principles:
• (1) Respect for persons • (2) Beneficence• (3) Justice
Peter Buxtun, PHS venereal disease investigator, the Tuskegee “whistle-blower”
The Tuskegee Study Group were invited to receive "special treatment", which was actually a diagnostic lumbar puncture
Respect for Persons
Ethical convictionsAcknowledge autonomy of the individualProtect those with diminished autonomy
Applying the principleInformed consent
The elements of informed consentInformation, comprehension, voluntary
Vulnerable populations
Beneficence
Ethical convictions Do no harm Maximize possible benefits Minimize possible harms
Applying the principle Investigator & IRB
Minimize risks Weigh risks and benefits When appropriate, a plan to monitor and
ensure safety
Justice
Ethical ConvictionsFairness in distribution of burdens and benefits
of research participation
Applying the principle Investigator-subject selection IRB asks “Is the selection of subjects equitable?”
RegulationsRegulations developed in response to egregious, harmful
research conductDeveloped on ethical principlesCongressional legislation signed into law by President Laws interpreted in CFR (Code of Federal Regulations)
by responsible federal agencyCFR regulations detail how law is implementedNoncompliance with CFR may result in criminal
prosecution, fines, sanctions or debarment from research
Regulations (cont’d)
Regulations are not specificRegulations don’t address everything that is
important in the protection of human subjects No regulations address decision-making capacity
of possible subjects
Regulations MUST be met
Federal Guidance and Information SheetsPublished by federal agencies to provide more
information or to recommend best practicesInterprets application of regulationsCurrent thinkingNOT legally bindingFDA “… An alternative approach may be used
if such approach satisfies the requirements of the applicable statue, regulations, or both…”
Guidance “should” be met
University of Michigan Policies and ProceduresStandard Practice Guide
Approved by RegentsSection 303, http://spg.umich.edu/section/303
Human Research Protection Program (HRPP) Operations Manualhttp://www.hrpp.umich.edu/om/
IRB Guidance & SOPsSee IRB websites
What is “GCP”A type of “Best Practice” term coined by the
International Conference on Harmonization (ICH) and used by FDA
Refers to FDA regulations, guidance and notices for Drugs, Devices & BiologicsFDA assures …the safety and efficacy of pharmaceuticals,
biologics, and medical devices on the market in the U.S.A.
What entities covered by FDA GCP? IRB InvestigatorResearch Sponsor
NIH- “Scientific and ethical standards of human subject research”
ICH E6– International Conference on Harmonization
Multi-national body, USA, EU & Japan, est. 1989Meets periodically to resolve different technical
requirements for drug registrationGoal: Create guidelines and standards for conducting
clinical trials allowing sponsors to generate a single set of data to meet submission requirements of the three regions
Originally based on ethical principles from the Declaration of Helsinki-1964 with revisions
Adopted as guidance for drugs/biologics by FDA in 1997
Also used by FDA in reference to devices
ICH-E6 “GCP” DefinitionA standard for the design, conduct,
performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that:
the Data and Reported Results are Credible, and Accurate, and that
the Rights, Integrity, and Confidentiality of Trial Subjects are Protected
Adopted as guidance by FDA in 1997
= Quality Data
= Ethics
FDA Regulations and ICH Guidelines Companies that wish to have study data accepted
by the regulatory agencies in the US, EU, and/or Japan need to follow the ICH guideline.
Differences between FDA Regulations and ICH GCP Guidelines: ICH Guideline states general principles is more
prescriptive than regulationse.g., 21 CFR 50 requires signature and date of subject
while ICH E6 says one should also have the signature of the investigator.
Why GCP?Failures
Ethical Atrocities Preventable Research Deaths/Injury Scientific Fraud
Subject safetyPublic trust and support of research missionAssure valid data for evidence-based Health CareDrug development trajectory long, arduous, expensive
(GCP assures safety and quality data)Useful products brought to market with known safety
profile and effectivenessThe better the GCP-the sooner the product is available
for patients
Best Practices, GCP & Types of Studies
Investigator Initiated May or may not be FDA regulated
NIH (HHS) supported 45 CFR 46
17 Federal agencies and the “common rule” Part A of 45 CFR 46 e.g., Dept. of Energy, Dept. of Education
FDA Regulated 21 CFR 312 Drugs & Biologics 21 CFR 812 Devices 21 CFR 50 Protection of Human Subjects 21 CFR 56 Institutional Review Boards
Research Clinical Trials “Best Practices” and ICH E6 GCP
Both can be viewed as a series of key activities or “practices”Order of activities may vary and may be simultaneousMultiple parties participate but PI remains accountable
Study scientific and ethical quality achieved by defining key study “best practices” and assuring oversight to implement them
“Best Practices” Key Activities Obtain Informed consent Provide for Subject Safety & Medical Care Follow the IRB approved protocol or submit amendment to IRB Maintain Confidentiality Record keeping-Maintain accurate, current, organized records and submit
reports Maintain communication with IRB Provide appropriate oversight of qualified staff FDA-Investigational Product Accountability FDA-Essential Documents Binder Additional areas
Conflict of interest Communication with sponsor (FDA) Shipping regulations
“People and Paper” Skills
NegotiationCommunication Time managementRecord keepingComputerOrganizationOversight of other research staffDetail-oriented Knowledge of regulations and their applicationIntimate knowledge of protocol
Informed Consent
Obtain Informed Consent
Informed Consent as a Process Interpersonal communication skills assess subject understanding
and motivation to participate Informed consent is freely given and is obtained from each subject
prior to study participation The consent discussion is in language understandable to the
participant or the representative and is done by a qualified person The consent process provides sufficient opportunity for the
participant or the participant’s legally authorized representative to consider whether to participate
The consent process minimizes the possibility of coercion or undue influence (Research is not the same as therapeutic txmt)
The consent discussion is free of exculpatory language The IRB approved document without any changes and with the
elements of informed consent is used Children’s “assent” & “Parental Permission” Adapted from AAHRPP, 2009
Informed Consent MonitoringPrivacy respectedVoluntaryConducted as a process by PIProcess follows the IRB approved protocol
Waiver of consent possible
Copy of consent given to subjectConsent signed prior to any study proceduresRe-consent completed and documented as
appropriate100% of consents used correct IRB approved
version and were appropriately signed and dated
What does the public think?
29%
9% 10%
40%
13%
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
0.45
A person who gives blood
A person who volunteers to take part in a clinical trail
A person who raises money for
charity by running in a race
A person who donates an
organ
Not sure/Refused
Pe
rce
nt
N=900
Which one of the following do you think makes a greater contribution to mankind?
CISCRP/ODC Survey, 12/2006
“It is a confusing time to be a subject-or to be thinking about
becoming one…”
Moreno, 2001
Subject Safety
Provide for Subject Safety
and Clinical Care
Adverse Events & Harms.
Adverse event (AE) definedPrevent, monitor for, identify, provide immediate care for, track,
analyze cause, report to IRB, may submit protocol amendment or changes to consent document & notify Sponsor (FDA)
IRBMED Guidance and timetable for reporting AEs at http://med.umich.edu/irbmed/ae_orio/ae_report.htm
HarmsPhysicalPsychosocialSocialEconomicLegalDignitary
What Can Result in Harms? The protocol/treatment
Side effects of drugs/biologics or adverse device effects NOT following the protocol NOT maintaining up-to-date records NOT maintaining communication with investigator and/or study
sponsor Prevent harm
Qualified person monitors overall study Monitor laboratory results and tests and treat as appropriate May withdraw subject from study Know emergency procedures for breaking a study blind Keep primary care provider in communication as appropriate
AEs are graded by Seriousness Relatedness to the study Expected/Unexpected
The Protocol
Follow the Protocol or Amend it
The Tension in Research
“The principal duty of a physician is to the well-being of the individual.”
“The principal duty of society (social ethics) is to the greatest good for the greatest number of people.”
Research is protocol drivenClinicians often want to adapt the protocol for
an individual
Know and Follow the Protocol Changes to the protocol, “…may not be initiated without IRB review
and approval except when necessary to eliminate apparent immediate hazards to the subject.”
Read it FDA-each person on study team signs it
Protocol Readily Available No mix ups-Clearly label current version
Follow it Prevent and track any protocol deviations
Notes to file-circumstances, CAPA Report to IRB and sponsor as applicable Amend protocol with IRB as needed
Follow randomization procedures If applicable, procedures follow data safety and monitoring plan
(DSMP) submitted to IRB and funding agencies
Confidentiality
Maintain Confidentiality
Data Confidentiality & Security: Outcomes
Data maintained according to IRB approved protocolAccess to confidential data is restrictedSafe & secure storage
Don’t share passwords!Mobile device security for researchers at
http://www.safecomputing.umich.edu/MDSUM Electronic data security Questions to Guide
Research Protections at OHRCR website http://www.ohrcr.umich.edu/news/electronicdata.pdf
Implications for Confidentiality
Being notified only, with no re-consent or opt out process, before their information goes to a national database47% completely unacceptable20% somewhat unacceptable
No notification or re-consent at all, before their information is sent to a national database54% completely unacceptable16% somewhat unacceptable
How much do current and potential subjects want to be informed, give consent and maintain confidentiality of their data?
Record Keeping & Reports
Maintain Accurate, Current, Organized Records and Submit Reports
Study Files
Organized, accurate, up-to-dateDirect/Indirect subject identifiers
Direct-subject identifiers stored with data Indirect-subject identifiers in key & not stored with data
Informed consent-stored with files?FDA-Complete, sign and submit FDA Form 1572Work efficiently
Study schema of subject progress for complex procedures Checklist of forms completed
Maintain records for: FDA- two years after FDA approves NDA NIH- three years after study terminated HIPAA- six years after study terminated
ALCOA (FDA)
FDA Documentation Guidance
A Attributable (who, when)
L Legible (readable, pen, no white out, single line)
C Contemporaneous (up-to-date)
O Original (source document)
A Accurate (verifiable with source)
Source Data and Documents (FDA)
All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification
Source Document Definition Original documents, data, and records, (e.g., ALL study records such
as visits, CRF/Data Collection Forms, and, Subjective self-report instruments, hospital, clinical and office charts,
laboratory notes, notes to file, subject diaries, checklists, pharmacy dispensing records, recorded data from automated instruments, X-Rays, digital records…
Source Data Generate and Keep source documents in original records May be using Electronic Data Capture (EDC)
The IRB
Maintain Communication
with the IRB
IRB Communications and SubmissionsInteract with IRB
Ask questions Get to know UM IRB contacts
Initial IRB submission and approvalOngoing oversight
AEs, protocol deviations, unanticipated problems, DSMC reports or safety officer reports, UM OHRCR report, new information that changes risk/benefit of study participation
Continuing review
Terminate a study Don’t let it expire!
Study Oversight & Qualifications
Overall PI/Investigator Responsibilities
Ensure a study is conducted according to the protocol or study plan and applicable regulationsFDA Form 1572
Protect the rights, safety, and welfare of subjects under the investigator’s care
FDA-Control drugs, biological products, and devices under investigation
FDA Guidance for Industry: Investigator Responsibilities, Oct 2009
Study Oversight by the PI/InvestigatorAre individuals who are delegated study
tasks qualified to perform them?Have individuals received training to the
protocol and to the tasks?Oversight and involvement in ongoing
conduct of the studyWhere reasonably possible, oversight of 3rd
parties
Guidance for Industry: Investigator Responsibilities, Oct. 2009
Adequate Resources
Appropriate facilitiesAppropriate equipment
Correct equipment availableCalibratedPreventive maintenanceStudy staff training
Proper laboratory facilities (FDA=CLIA certified)Reference ranges for laboratory testsDetails of analytical methodsQuality assurance information
Delegating Tasks
The investigator should ensure that any individual to whom a task is delegated is qualified by education, training, and experience (and state licensure where relevant) to perform the delegated task
The level of supervision should be appropriate to the staff, the nature of the trial, and the subject population.
Study logs & Oversight
Delegation log with study roles, tasks and dates worked on study
Signature log with initials logTrain to protocolTraining logStay up-to-date on subject and overall study
progressRegular staff meetings (FDA-take minutes)
Investigational Product (FDA)
Accountability for the Investigational Product
Investigational ProductProcess investigational product
Receipt (shipping) and DispensingLabelingAccountability to reconcile records for each tablet,
compounded drugSecure storage of device & device returnReturn/Destroy drug as determined by sponsor Interface with Investigational Drug Services /
Biomedical Engineering staff, as neededInvestigational products should be
manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP)
Essential Documents(FDA)
Maintain Study Binder
Binder Index
1. Contents2. Subject Logs and Lists3. Contact Logs and Monitoring4. Communications: General5. Protocol and Amendments6. Case Report Forms7. Investigator Information8. IRBMED Documents9. Laboratory Information
Binder Index (cont’d)
10. Equipment11. Investigational Product Information12. Investigational Product Accountability
Records13. Adverse Events/Effects14. Investigator Meeting Documents15. Regulatory Information16. Study Reports17. References18. Contracts and Grants19. Patient Data
Additional Best Practices Conflict of Interest Disclosure
Applies to all members of the study team Includes spouses and dependents May have a management plan FDA forms for financial disclosure from sponsor
Communication with sponsor (FDA) Annual reports to sponsor Maintain ALL sponsor communications
Letters, reports, emails, phone log, faxes Report AEs and unanticipated problems Report protocol deviations Monitoring log/visits
Shipping Regulations for Biologics
University personnel who ship infectious substances including patient (clinical) specimens, human-derived research materials, infectious micro-organisms, certain genetically-modified organisms, etc. must complete a training program prior to shipping infectious or biological substances.
The Department of Occupational Safety and Environmental Health (OSEH) offers the IATA/DOT Shipping Infectious Substances Class on a monthly basis. More information and schedule can be found on the OSEH website www.oseh.umich.edu.
Those who complete training receive a training certificate which is valid for two years.
Overall
Legal or regulatory is not always adequateA personal commitment to integrity needs to
be coupled with a firm understanding of “Best Practices”
The public support of research rests on its trust of scientists, scholars and the institutions
Individual actions can bolster trust and confidence or, unfortunately, undermine it as well
FDA GCP BIMO ProgramClinical Investigator InspectionSponsor/Monitor/CRO Inspection Inspection programs allow the agency to
determine:Adherence to applicable regulationsValidity of studies in support of pending marketing
applicationsWhether the rights and safety of subjects have
been protected
FDA Common Investigator “Deficiencies”
Failure to follow the investigational plan & Protocol deviations (38%)
Inadequate recordkeeping, source documentation, case hx, record retention (27%)
Inadequate accountability for investigational product, shipping, handling, storage, labeling (10%)
Inadequate subject protection-including informed consent (11%) and adverse event (8%) issues
Toth-Allen, J. APEC GCP Inspection Workshop, 2008
Most Common FDA Sponsor “Deficiencies”
Inadequate monitoringFailure to bring investigators into
complianceInadequate accountability for the
investigational product
Selected Recent OHRP Noncompliance Determinations
Informed Consent Failure to obtain the legally effective informed consent of subjects or
of the IRB to appropriately waive the requirements to obtain informed consent
Failure to document informed consent or of the IRB to appropriately waive the requirements to document informed consent
Failure to provide a copy of the informed consent document (ICD) to the subject or the subject's legally authorized representative
Inadequate ICD for specific research/lack of basic elements Inadequate ICD for specific research/lack of additional elements ICD language too complex Exculpatory language in ICDs Enrollment procedures did not minimize possibility of coercion or
undue influence
Selected Recent OHRP Noncompliance Determinations
Initial and continuing review Research conducted without IRB review and/or approval IRB lacks sufficient information to make determinations required for
approval of research Inadequate IRB review at convened meetings
IRB review of protocol changes Changes to research initiated without IRB review and approval Inadequate IRB review and/or approval of protocol changes
IRB membership, expertise, staff support and workload IRB documentation, findings and procedures
OHRP, http://www.dhhs.gov/ohrp/compliance/findings.html#D20
Questions?
Resources UM IRBMED & HBHS Workshops Join MICHR research coordinator email network Clinical Trials Network (Duke U)
Forms, education, etc. at https://www.ctnbestpractices.org FDA Device Advice & training
http://www.fda.gov/medicaldevices/deviceregulationandguidance/default.htm Virtual Regulatory Binder
http://www.partners.org/phsqi/vrb/files/index.htm NIH-Office of Human Subject Research
http://ohsr.od.nih.gov/ OHRP Guidance documents
http://www.dhhs.gov/ohrp/policy/ ICH E6
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073122.pdf
ICH E6 Principles Clinical Trials should be conducted in accordance with the
ethical principles that have their origin in the Declaration of Helsinki and that are consistent with applicable regulatory requirements.
Foreseeable risks should be weighed against anticipated benefits for the individual and for society as a whole; a trial should only be initiated if anticipated benefits justify the risks.
The rights, safety and well being of the trial subjects are the most important considerations and should prevail over interests of science and society.
The non-clinical and clinical information on an investigational product should be adequate to support the proposed clinical trial.
ICH E6 Principles
Clinical trials should be scientifically sound, and described in a clear, detailed protocol.
A trial should be conducted in compliance with the protocol and amendments that have received prior IRB approval.
The medical care given to, and medical decisions made for subjects should always be the responsibility of a qualified physician.
Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s).
Freely given informed consent should be obtained from every subject prior to clinical trial participation.
ICH E6 Principles
All clinical trial information should be recorded, handled, and
stored in a way that allows its accurate reporting, interpretation,
and verification. The confidentiality of records that could identify subjects should be
protected, respecting the privacy and confidentiality rules in
accordance with the applicable regulatory requirements. Investigational products should be manufactured, handled, and
stored in accordance with applicable good manufacturing practice
(GMP). They should be used in accordance with the approved
protocol Systems with procedures that assure the quality of every aspect of
the trial should be implemented.
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