STVHCS Human Research STVHCS Human Research Protection ProgramProtection Program

Kimberly Summers, PharmDKimberly Summers, PharmDAssistant Chief for Clinical ResearchAssistant Chief for Clinical Research

South Texas Veterans Health Care SystemSouth Texas Veterans Health Care SystemResearch & Development ServiceResearch & Development Service

Human Research Protection Human Research Protection Program (HRPP)Program (HRPP)

• The systematic and comprehensive The systematic and comprehensive approach by an organization to ensure approach by an organization to ensure human subject protection in all researchhuman subject protection in all research

• STVHCS HRPP is a focus on STVHCS HRPP is a focus on responsibility and compassion, not only responsibility and compassion, not only compliancecompliance

What are the ethical principles that govern the HRPP?

• Beneficence– Benefits outweigh risks

• Autonomy– Informed consent must be obtained

• Justice– Recruitment is fair and equitable – Study population represents the group that

will benefit from the research

Who is the Institutional Official for Who is the Institutional Official for the STVHCS Research Program?the STVHCS Research Program?

STVHCS Research Program Institutional Official

• RICHARD J. BALTZCenter DirectorSTVHCS

• Responsible for oversight Responsible for oversight of all VA investigators of all VA investigators and IRB activities as they and IRB activities as they related to VA researchrelated to VA research

• Must ensure VA IRB Must ensure VA IRB members and PIs are members and PIs are knowledgeable to knowledgeable to conduct research in conduct research in accordance with ethical accordance with ethical standards and all standards and all applicable regulationsapplicable regulations

When is research human subject research?

• Is the project designed to produce generalizable knowledge?

• Is the research systematic?• Is the information about a living individual?• Is the information about the participants gathered

through any direct or indirect interaction with those participants?

• Is there any intervention via physical procedures or manipulation of a subjects environment?

• Is any private information obtained or used in the research individually identifiable?

Which of the following are defined by Which of the following are defined by the VA as human subjects research?the VA as human subjects research?

• A systematic investigation designed to develop or A systematic investigation designed to develop or contribute to generalizable knowledgecontribute to generalizable knowledge– DHHS definitionDHHS definition

• Experiment that involves a test article and one or Experiment that involves a test article and one or more human subjectsmore human subjects– FDA definitionFDA definition

• Research involving human biological specimensResearch involving human biological specimens– Considered research by VAConsidered research by VA

Which of the following are considered VA research?

• Research sponsored by the VA• Research conducted by or under the direction of

a VA employee– Salaried or WOC– During official tour of duty or in connection with

STVHCS responsibilities

• Research conducted using any property or facility of VA– Includes use of CPRS for recruitment or obtaining PHI

Which of the following is an FDA regulated activity?

• Involves the use of an approved or unapproved drug

• Testing the efficacy or safety of a medical device

• Use of an approved drug in the practice of medicine

• Generating data to be presented to the FDA

What distinguishes QI activities What distinguishes QI activities from research?from research?

• Designed solely for internal program Designed solely for internal program evaluation purposesevaluation purposes

• No external application or generalizationNo external application or generalization

• NOTE: NOTE: – If the intent of the activity changes after it is If the intent of the activity changes after it is

initiated and a desire to generalize and initiated and a desire to generalize and disseminate the results developsdisseminate the results develops

– IRB approval is requiredIRB approval is required

UPIRSOUPIRSOUUnanticipated nanticipated PProblem roblem

IInvolving nvolving RRisk to isk to SSubjects or ubjects or OOthersthers

What are the three elements which What are the three elements which define an UPIRSO? define an UPIRSO?

• UnanticipatedUnanticipated– Not consistent with either the described risks in the research Not consistent with either the described risks in the research

documents or not expected as part of natural progression of documents or not expected as part of natural progression of subjects underlying conditionsubjects underlying condition

– Increases in frequency or severity are considered to be Increases in frequency or severity are considered to be unanticipatedunanticipated

• At Least Possibly Related At Least Possibly Related – More likely than not that the event is at least partially related to More likely than not that the event is at least partially related to

the study intervention or interactionthe study intervention or interaction

• Greater Risk of Harm Greater Risk of Harm – Places subjects or others at greater risk of harm than was Places subjects or others at greater risk of harm than was

previously known or recognizedpreviously known or recognized– Includes physical, psychological, economic, or social harmIncludes physical, psychological, economic, or social harm

What are the reporting requirements for study-What are the reporting requirements for study-related, non-serious adverse events (AEs)?related, non-serious adverse events (AEs)?

• No reporting requirementsNo reporting requirements– Wrong answerWrong answer

• Summary is provided to IRB as part of the progress reportSummary is provided to IRB as part of the progress report– OK answerOK answer

• As part of the DSMP adverse events are monitored regularly As part of the DSMP adverse events are monitored regularly for trends and changes, when incidence or severity changes for trends and changes, when incidence or severity changes as a result of the cumulative events the IRB is notified as a result of the cumulative events the IRB is notified (UPIRSO) and the protocol and or informed consent is (UPIRSO) and the protocol and or informed consent is modified as needed. A summary of cumulative events is modified as needed. A summary of cumulative events is also provided to the IRB as part of the progress report.also provided to the IRB as part of the progress report.– More complete answerMore complete answer

What are the reporting requirements if What are the reporting requirements if an non-serious adverse event occurs an non-serious adverse event occurs

that is not related to the study?that is not related to the study?• No reporting requirementsNo reporting requirements

– Must be at least possibly related to study participationMust be at least possibly related to study participation– Wrong answerWrong answer

• No reporting requirementsNo reporting requirements– Must be seriousMust be serious– Wrong answerWrong answer

• Summary is provided to IRB as part of the progress Summary is provided to IRB as part of the progress reportreport– Correct answerCorrect answer

What are the reporting requirements for What are the reporting requirements for deaths that may be related to study deaths that may be related to study

participation?participation?

• Report to IRB as an UPIRSO– Must be reported by investigator within 48

hours (consider all UPIRSO criteria in order)

• IRB reports UPIRSO to Office of Human Research Protection (OHRP)

• IRB reports UPIRSO to VA R&D office– VA R&D office reports UPIRSO to Office of

Research Oversight (ORO)

What are the reporting requirements for What are the reporting requirements for deaths that are not related to study deaths that are not related to study

participation?participation?

• No reporting requirementsNo reporting requirements– Must be at least possibly related to study participationMust be at least possibly related to study participation– Wrong answerWrong answer

• All deaths are summarized and provided to IRB as part All deaths are summarized and provided to IRB as part of the progress reportof the progress report– Correct answerCorrect answer

Who makes the determination Who makes the determination whether research is exempt from whether research is exempt from

federal regulations?federal regulations?

• Any member of the study teamAny member of the study team

• Principal InvestigatorPrincipal Investigator

• SponsorSponsor

• IRBIRB

• Any of the aboveAny of the above

Who must approve human subject research before it can be conducted at

the VA?

• IRB• ACOS for R&D• Chief of Staff• Director• R&D Committee• Subcommittee for Research Safety

The STVHCS R&D Committee cannot approve a human subject

research protocol that has not been approved by the UTHSCSA IRB

The STVHCS R&D Committee can disapproval a human subject research protocol that has been approved by the

UTHSCSA IRB

What types of research have special restrictions for conduct at the VA?

• Research involving children– Waiver from the Chief Research and Development Officer– Must present no greater than minimal risk– Meets all requirements of the DHHS and FDA regulations– VA Medical Center Director must certify that the facility is able to

respond to pediatric emergencies

• Pregnant women– Adequate provisions to monitor the risks to the participant and the fetus– Adequate consideration is given to the manner in which prospective

participants are going to be selected– Adequate provision is made to monitor the actual consent process

• Prisoners– Waiver from the Chief Research Development Officer

What research populations and situations are NOT conducted at the STVHCS?

• Research in which the subject is a fetus, in-utero or ex-utero (including human fetal tissue)

• Research related to in vitro fertilization

• Planned emergency research

When can non-veterans be enrolled in a VA study?

• Non-veterans may be entered into VA approved research studies only when there are insufficient veterans available to complete the study and accordance with all federal regulations

• All regulations pertaining to veterans as research subjects pertain to non-veteran subjects enrolled in VA approved research

Who can serve as the legally authorized Who can serve as the legally authorized representative if a potential subject is decisionally-representative if a potential subject is decisionally-

impaired?impaired?• Health care agent appointed by the person in a durable power of

attorney for health care• Court appointed guardian of the person• Next of kin in the following order of priority

– Patient’s spouse– An adult child of the patient who has the waiver and consent of all other

qualified adult children of the patient to act as the sole decision-maker or a majority of the patient’s responsibly available adult children

– Patient’s parents– Patient’s adult sibling– Patient's grandparent– Patient’s adult grandchild

• Since VA and Texas state law differ, follow the more restrictive regulation

• Consult with legal counsel in cases of uncertainty

Who can dispense an investigational drug to a research subject?

• Research Pharmacy– All investigational medications must be dispensed through the

VA research pharmacy

• Principal Investigator– Only under exceptional situations when a contractual agreement

is in place with the VA research pharmacy may the PI dispense medication directly to a research subject

• Research Coordinator– Under no circumstances– Study coordinator may receive the dispensed medication from

the research pharmacists (or PI if agreement is in place) and then provide the medication to the research subject

What are the elements of sound What are the elements of sound study design?study design?

• Study problem• Relevance of the project• Literature review• Specific study objectives• Research methods• Selection of subjects and recruitment• Data collection• Intervention• Statistical considerations

Who is ultimately responsible for ensuring a research protocol has sound design and

minimizes risks to subjects?

• IRB

• R&D Committee

• Principal Investigator

• Research Coordinator

• Hospital Director

What educational programs and activities What educational programs and activities are available to investigators and their study are available to investigators and their study

staff?staff?

• On line CITI course in the Protection of Human On line CITI course in the Protection of Human Research SubjectsResearch Subjects

• Monthly research Training SeminarsMonthly research Training Seminars• IRB ForumsIRB Forums• UTHSCSA Course in “Conducting Clinical Research”UTHSCSA Course in “Conducting Clinical Research”• STVHCS Investigator HandbookSTVHCS Investigator Handbook• Individualized TrainingIndividualized Training

• Which of these educational programs and activities are required to conduct research at the VA?

Monitoring of compliance with human Monitoring of compliance with human subjects research regulations is conducted subjects research regulations is conducted

by who at the STVHCS?by who at the STVHCS?

• STVHCS Compliance OfficeSTVHCS Compliance Office• UTHSCSA Compliance OfficeUTHSCSA Compliance Office

– At the request of the IRBAt the request of the IRB

• R&D CommitteeR&D Committee– Through the QI/QA subcommitteeThrough the QI/QA subcommittee

• Sponsor of the studySponsor of the study• STVHCS Compliance Executive BoardSTVHCS Compliance Executive Board

– STVHCS Compliance Office reports to this committeeSTVHCS Compliance Office reports to this committee

To whom should research non-To whom should research non-compliance be reported?compliance be reported?

• UTHSCSA IRB

• STVHCS R&D Office

• Research non-compliance or alleged improprieties may be identified through self-reporting by the PI or by other members of the study team.

How should subject complaints be handled and reported?

• Gather information related to the complaint• Evaluate the complaint on a case-by-case basis

– Make an effort to correct at the administrative level• Forward complaint to R&D office when

– Corrective action can not be implemented at the study staff / PI level

– If an ethical conflict exists with review by study staff/ PI

• If complaint is an alleged impropriety which involves potential harm to subjects or others– R&D Chairman and IRB Director must be notified– Notification may be through the R&D office

What happens when you fail to submit What happens when you fail to submit the continuing review paperwork for an the continuing review paperwork for an

approved protocol by the deadline?approved protocol by the deadline?

• Research protocol expiresResearch protocol expires• All research activity must ceaseAll research activity must cease

– Except for those activities required for patient safety Except for those activities required for patient safety reasonsreasons

– Exception to continue for safety reasons must be Exception to continue for safety reasons must be approved by the IRB Director and the VA Chief of approved by the IRB Director and the VA Chief of StaffStaff

• Research activities may resume when all Research activities may resume when all paperwork for continuing review is received, paperwork for continuing review is received, reviewed, and approvedreviewed, and approved

Who has the authority to suspend Who has the authority to suspend or terminate a research protocol?or terminate a research protocol?

• STVHCS DirectorSTVHCS Director

• R&D CommitteeR&D Committee

• IRBIRB

• ACOS for Research ACOS for Research

What are the requirements for financial What are the requirements for financial disclosure before or during the conduct disclosure before or during the conduct

of human research proposals?of human research proposals?

• COI form must be completed for each study personnelCOI form must be completed for each study personnel• COI form must be updated at the time of any changeCOI form must be updated at the time of any change• As part of the continuing review process, each PI As part of the continuing review process, each PI

must verify for ALL collaborators (all study personnel must verify for ALL collaborators (all study personnel approved for a protocol)approved for a protocol)– Either no COI changes have occurred Either no COI changes have occurred – All changes have been provided to the R&D officeAll changes have been provided to the R&D office

What is the importance of disclosing What is the importance of disclosing financial conflicts of interest in the financial conflicts of interest in the

conduct of human research?conduct of human research?

• Preserves the public trust in the integrity and quality of research carried out by the investigators at the STVHCS

What is the difference between What is the difference between privacy and confidentiality?privacy and confidentiality?

• PrivacyPrivacy– Control over the extent, timing and circumstances of Control over the extent, timing and circumstances of

sharing oneselfsharing oneself (physically, behaviorally, or (physically, behaviorally, or intellectually) with othersintellectually) with others

• ConfidentialityConfidentiality– Pertains to the Pertains to the treatment of informationtreatment of information that an that an

individual has disclosed in a relationship of trust and individual has disclosed in a relationship of trust and with the exception that it will not be divulged to others in with the exception that it will not be divulged to others in ways that are inconsistent with the understanding of the ways that are inconsistent with the understanding of the original disclosure without permissionoriginal disclosure without permission

When can you implement a change When can you implement a change in your study without having IRB in your study without having IRB

approval?approval?

• To eliminate an immediate hazard for enrolled subjects– This includes calling subjects to let them know

about a new risk to determine if they want to continue, halt or not start enrollment until new consent form is approved

How are other providers within the STVHCS notified regarding study related enrollment

and events for a veteran subject ?

• Informed consent and enrollment are documented in CPRS through a “Research Consent/Enrollment Note”

• Informed consent updates and addendums are documented in CPRS through a “Research Consent/Update Note”

• Research procedures, treatments, or interventions that may impact a patient’s clinical care are documented in CPRS through a “Research Progress Note”

• All informed consents and drug information records are scanned into CPRS

• Disenrollment or termination is documented in CPRS through a “Research Disenrollment/ Termination Note”

• Use of the note templates ensures CPRS is flagged to indicate when the participant is either enrolled or disenrolled in a research study

What approaches for subject recruitment may be utilized at the VA?

• IRB-approved mechanisms

– Physician referral

– Posting of IRB-approved advertisements

• “Preparatory to Research” by HIPAA Privacy Rule

– VA guidelines are more restrictive

– In the VA, using individually-identifiable information to contact

potential research subjects as part of recruitment into a research

protocol is NOT considered “preparatory to research” and requires

IRB and R&D approval

What are the requirements for What are the requirements for recruitment ads for research protocols?recruitment ads for research protocols?Advertisements should include:• The name and address of

investigator and/or research facility

• The condition under study and/or

purpose of the study

• A summary of the criteria used to

determine eligibility

• A brief list of participation benefits,

if any

• The amount of time or other

commitment required of subjects

• The location of the research

• A person or office to contact for

further information

Advertisements should not include:• Claims that the test article is safe or

effective for the purpose of the investigation

• Claims that the test article is known to be equivalent or superior to any other drug

• Terms which imply the receipt of newly improved products of proven worth such as “new treatment”, “new medication”, or “new drug”. The advertisement must explain that the drug or device is investigational.

• Promises of free medical treatment when intent is only to state that subjects will not be charged for taking part in the investigation

• Emphasis of payment for participation

What incentives are allowed that assist What incentives are allowed that assist in recruiting patients into studies?in recruiting patients into studies?

• Sponsor provided bonuses for subject recruitment– Prohibited by UTHSCSA and STVHCS

• Finder’s fees

– Prohibited UTHSCSA and STVHCS

What is the difference between a data What is the difference between a data safety and monitoring plan and a data safety and monitoring plan and a data

safety monitoring board?safety monitoring board?

Local PI ResponsibilitiesLocal PI Responsibilities

Local PI ResponsibilityLocal PI Responsibility• DSMBDSMB

– Limited to collecting Limited to collecting information and information and forwarding to DSMB for forwarding to DSMB for analysisanalysis

– Implementing local Implementing local actions based on DSMB actions based on DSMB analysis if neededanalysis if needed

– Studies which include Studies which include an established DSMB by an established DSMB by an external entity an external entity still still require a local DSMPrequire a local DSMP

• DSMPDSMP– Capturing and collecting Capturing and collecting

datadata– Monitoring collected dataMonitoring collected data– Interpretation and Interpretation and

analysis of collected data analysis of collected data – Reporting results of Reporting results of

analysisanalysis– Implementing actions Implementing actions

based on analysis if based on analysis if neededneeded

Studies Which Require a DSMPStudies Which Require a DSMP

• All studies considered to be more than All studies considered to be more than minimal riskminimal risk– Involve high risk populations and/or high risk Involve high risk populations and/or high risk

therapiestherapies

• Multi-site research where UTHSCSA is Multi-site research where UTHSCSA is the coordinating sitethe coordinating site

• Studies where there is an NIH or FDA Studies where there is an NIH or FDA requirement for a planrequirement for a plan

• Studies when requested by the IRBStudies when requested by the IRB

Questions?Questions?

Kimberly Summers, PharmDKimberly Summers, PharmD

Office: (210) 617-5300 ext 15969Office: (210) 617-5300 ext 15969

Email: kimberlyk.Summers@va.govEmail: kimberlyk.Summers@va.gov