FDA - Office of Human Research Compliance Review (OHRCR)

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Oct 25, 2013 (3 years and 10 months ago)

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“Good Clinical Practices”
in Meeting Regulatory
Responsibilities

Terry VandenBosch, RN, PhD, CIP, CCRP

Senior Research Compliance Associate

Office of Human Research Compliance Review

University of Michigan

September 15, 2010


Today’s Discussion


Discuss the growing field of “regulatory science”


Describe responsibilities of FDA sponsor
-
investigators


Contrast ethical principles and ethical conduct in
research with investigator GCP activities


Identify common sense principles for investigators
to implement best practices and GCP in clinical
studies

Evidence
-
based Regulatory
Science


Reactions to Research Participation Questionnaire for
Adults, Children (RRPQ
-
C) and the RRPQ for Parents
(RRPQ
-
P)


Comparison of time to enrollment for emergency brain
-
injured subjects in a study with proxy consent versus
exception from consent

Clinical researchers;

1)
can address human subjects research compliance issues in
conjunction with answering their main research questions

2)
should conduct studies that address regulatory compliance issues

3)
can demonstrate investigator proposed research compliance
procedures are not based on whim or disregard for subject rights
and welfare.

Kassam
-
Adams & Newman, 2002
-
2006

Wright et al, 2008

Maio, 2008, Excerpts Letter to the Editor, Annals of Emergency Medicine

FDA Sponsor
-
Investigator


FDA Sponsor defined:


“…a person who takes responsibility for and
initiates

a clinical investigation (21 CFR 312.3(b)” of a drug,
device or biologic.


A sponsor may be an individual, a company, an
academic institution, a governmental agency or
another organization. (
Not

the same as a financial
sponsor)



FDA Sponsor
-
Investigator:


A sponsor
-
investigator both
initiates and conducts

the
clinical investigation

What are FDA Sponsor
Responsibilities?


Determine if a study needs an IND/IDE or is
exempt (biologics, off
-
label use &
neutraceuticals

most difficult)


Submit an IND or IDE application to the FDA


Follow the IND/IDE application approval process
and administrative actions


Meet ongoing IND/IDE sponsor responsibilities
during study conduct

FDA Sponsor Responsibilities
during Study Conduct


Assure the investigator conducts the study according to the protocol
and meets investigator responsibilities


Maintain an effective IND/IDE with FDA


FDA submissions
-
amendment updates, adverse events, annual reports, any
other FDA communications


Ensure proper monitoring of study data integrity and subject safety


Assure test
-
article control and accountability


Provide for records of disposal of the test
-
article and control of the test article.


Ensure the test article is administered to subjects under the investigator or sub
-
investigator’s personal supervision and by investigators or staff authorized to
administer it


Keep adequate and accurate sponsor records (Maintenance of
sponsor master files/binders)


FDA Monitoring and Ensuring
Quality for SI Studies


FDA recommends sponsors build in quality
monitoring so problems can be detected and
corrected as close to real time as possible


Focus on key parameters of risk to trial
integrity and data quality and to subject safety
and protection which allows sponsors to set
priorities for using resources appropriately

Ethical Principles & GCP


Ethical principles


Inform decision
-
making


Basis for federal regulations and guidance


Past abuses of ethical principles stimulated
development of GCP


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
-
FDA warning letter to Pfizer, April 9, 2010

Ethical Principles

Belmont Report
-
1979


Respect for persons


Acknowledge autonomy of the individual


Protect those with diminished autonomy


Beneficence


Do no harm


Maximize possible benefits


Minimize possible harms


Justice


Fairness in distribution of burdens and benefits of
research participation






Regulations


Regulations developed in response to
egregious, harmful research conduct


Developed on ethical principles


Regulations are not specific


Regulations don’t address everything that is
important in the protection of human subjects



No regulations address decision
-
making
capacity of participants


Regulations MUST be met or sanctions

“GCP” Definition


A series of key activities that assures ethical principles,
regulations, laws, university policies & procedures are met


NIH
-
”Scientific and ethical standards of human subject
research”


FDA
-
”Standard for the design, conduct, performance,
monitoring, auditing, recording, analyses, and reporting of
clinical trials”

Data and reported results are credible, and
accurate

Protects rights, welfare and confidentiality of
subjects

= Quality Data

=
Ethics


Why GCP?


Failures


Ethical Atrocities


Preventable Research Deaths/Injury


Scientific Fraud


Subject safety


Public trust and support of research mission


Assure valid data for evidence
-
based Health
Care


Drug development trajectory long, arduous,
expensive (GCP assures safety and quality
data)


Useful products brought to market with known
safety profile and effectiveness

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 Review


Privacy respected


Voluntary


Conducted as a process by PI


Process follows the IRB approved protocol


Waiver of consent possible


Consent signed prior to any study procedures


Copy of consent given to subject


Re
-
consent completed and documented as
appropriate


100% of consents
used correct IRB approved
version

and were appropriately signed and
dated





What does the public think?

CISCRP/ODC Survey, 12/2006

Subject Safety

Provide for Subject Safety


and Clinical Care

Adverse Events & Harms

.


What is an Adverse event (AE)?


Prevent, monitor for, identify, provide immediate care for,
track, analyze cause, provide follow up treatment, 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


Harms


Physical


Psychosocial


Social


Economic


Legal


Dignitary




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

A 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 driven


Clinicians 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 protocol


Access to confidential data is restricted


Safe & secure storage


Don’t share passwords!


UM ITS Safe Computing Polices
http://www.safecomputing.umich.edu/faculty&staff.p
hp


Mobile device security for researchers at
http://www.safecomputing.umich.edu/MDS


UM Electronic data security Questions to Guide
Research Protections at OHRCR website
http://www.ohrcr.umich.edu/news/electronicdata.pdf




Record Keeping &
Reports

Maintain Accurate, Current,
Organized Records and Submit
Reports

Study Files


Organized, accurate, up
-
to
-
date


Direct/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 1572


Work 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

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


“ALCOA”
-

Attributable, Legible, Contemporaneous, Original, and
Accurate (USE “memo to file”; NEVER use white out or back date)


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
Submissions


Interact with IRB


Ask questions


Get to know UM IRB contacts


Initial IRB submission and approval


Ongoing 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
regulations


FDA 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/Investigator


Are individuals who are delegated study
tasks qualified to perform them?


Have individuals received training to the
protocol and to the tasks?


Is the oversight and involvement in ongoing
conduct of the study appropriate?


Where reasonably possible, is there oversight
of 3
rd

parties?

Guidance for Industry: Investigator Responsibilities, Oct. 2009

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 log


Train to protocol


Training log


Stay up
-
to
-
date on subject and overall study
progress


Regular staff meetings (FDA
-
take minutes)

Adequate Resources


Appropriate facilities


Appropriate equipment


Correct equipment available


Calibrated


Preventive maintenance


Study staff training


Proper laboratory facilities (FDA=CLIA certified)


Reference ranges for laboratory tests


Details of analytical methods


Quality assurance information

Investigational
Product (FDA)

Accountability for the
Investigational Product

Investigational Product


Process investigational product


Receipt (shipping) and Dispensing


Labeling


Accountability to reconcile records for each tablet,
compounded drug


Secure storage of device & device return


Return/Destroy drug as determined by sponsor


Interface with Investigational Drug Services /
Biomedical Engineering staff, as needed


Investigational products should be
manufactured, handled, and stored in
accordance with applicable good current
manufacturing practice (
cGMP
)


Essential Documents

(FDA)

Maintain Study Binder

Binder Index

1.
ALL important study documentation
and correspondence from the study
sponsor & study monitor

2.
Delegation, signature log & monitoring
log

3.
Signed protocol

4.
Laboratory Information w nl. Values

5.
Equipment information

6.
Blank case report forms (CRFs)

7.
CVs



Additional Best Practices


UMHS HIPAA Training


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


Maintain all communication with sponsor (FDA)


Shipping specimens


UM 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.



Summary of “GCP
-
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



ICH
-
GCP has no statements on ethical principles such as risks,
benefits, selection, privacy, vulnerable populations



Overall


Legal or regulatory is not always adequate


A personal commitment to integrity needs to
be coupled with a firm understanding of
“GCP”


The public support of research rests on its
trust of scientists, scholars and the
institutions


Individual actions are important

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

Questions?

University of Michigan

Policies and Procedures


Standard Practice Guide


Approved by Regents


Section 303, http://spg.umich.edu/section/303


Human Research Protection Program
(HRPP) Operations Manual


http://www.hrpp.umich.edu/om/


IRB Guidance & SOPs


See IRB websites



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/GuidanceComplianceRegulatoryInf
ormation/Guidances/ucm073122.pdf