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.