Current Topics in Human Subjects Research 2012 Sandra L. Alfano, Pharm.D, CIP Research Scientist, GIM Chair, HIC II and IV December 13, 2012

Current Topics in Human Current Topics in Human Subjects Research 2012Subjects Research 2012

Sandra L. Alfano, Pharm.D, CIPSandra L. Alfano, Pharm.D, CIP

Research Scientist, GIMResearch Scientist, GIM

Chair, HIC II and IVChair, HIC II and IV

December 13, 2012December 13, 2012


ObjectivesObjectives

Understand issues leading to problems with Understand issues leading to problems with compliance, including lapses in protocol approval, and compliance, including lapses in protocol approval, and the need for clinical trials registration at inception of a the need for clinical trials registration at inception of a protocolprotocol

Be cognizant of issues thought of as ‘hot topics’, Be cognizant of issues thought of as ‘hot topics’, including return of results from laboratory work on including return of results from laboratory work on donated tissues, and COI disclosure issues donated tissues, and COI disclosure issues

Be aware of proposed changes to the human subjects Be aware of proposed changes to the human subjects regulations embodied in the recent ‘Advanced Notice regulations embodied in the recent ‘Advanced Notice of Proposed Rule Making (ANPRM)of Proposed Rule Making (ANPRM)


Yale University Human Research Protection Program (HRPP)

Formally implemented in September 2009. Seeks to:Formally implemented in September 2009. Seeks to:• Create a culture of respect for, and awareness of, the rights Create a culture of respect for, and awareness of, the rights

and welfare of human research participants while advancing and welfare of human research participants while advancing scientific knowledge and facilitating the highest quality scientific knowledge and facilitating the highest quality research. research.

• Facilitate compliance of researchers as they conduct research Facilitate compliance of researchers as they conduct research with the federal regulations, and protection of research with the federal regulations, and protection of research participants. participants.

• Develop new approaches that serve the overarching mission, Develop new approaches that serve the overarching mission, such as continuing education and training, ensuring scientific such as continuing education and training, ensuring scientific integrity, tracking and monitoring research activities and integrity, tracking and monitoring research activities and assessing the overall effectiveness of the HRPP. assessing the overall effectiveness of the HRPP.

• Assess the effectiveness and independence of the IRBs.Assess the effectiveness and independence of the IRBs.


Yale University HRPP


Achieved accreditation December, 2010Achieved accreditation December, 2010

Enhanced website, including all policies, Enhanced website, including all policies, procedures, forms and guidance: procedures, forms and guidance: http://www.yale.edu/hrpp/

Implemented every three year training Implemented every three year training requirementsrequirements

Harmonized COI policy with University’sHarmonized COI policy with University’sRestructured HICs into team structureRestructured HICs into team structure

Recent compliance issuesRecent compliance issues

Lapses in IRB approvalLapses in IRB approval It is a violation of federal regulation and University It is a violation of federal regulation and University

policy to continue to conduct research activities policy to continue to conduct research activities once IRB approval for a study has lapsed unless once IRB approval for a study has lapsed unless permission is granted by the Yale IRB to continue permission is granted by the Yale IRB to continue research interventions. Such permission will be research interventions. Such permission will be granted by the IRB when discontinuing the research granted by the IRB when discontinuing the research interventions may jeopardize the health or welfare of interventions may jeopardize the health or welfare of a participant. a participant.


Lapses, cont’dLapses, cont’d

Under no circumstances can federal funds Under no circumstances can federal funds be expended on research and research-be expended on research and research-related activities during a lapse period. If the related activities during a lapse period. If the study is federally funded, you must study is federally funded, you must immediately contact your Grant and Contract immediately contact your Grant and Contract Administration (GCA) and Grants and Administration (GCA) and Grants and Contract Financial Administration (GCFA) Contract Financial Administration (GCFA) representatives for more informationrepresentatives for more information..


Clinical Trial RegistriesClinical Trial Registries

Instituted years ago in an effort to expand Instituted years ago in an effort to expand public knowledge of, and access to, public knowledge of, and access to, clinical trialsclinical trials

Clinicaltrials.gov is an example, run by the Clinicaltrials.gov is an example, run by the NIH/NLMNIH/NLM

Currently over 135,000 studies are Currently over 135,000 studies are registered, with locations in all 50 states registered, with locations in all 50 states and 182 countriesand 182 countries



Clinical Trial RegistriesClinical Trial Registries

Registration of trial before subject enrollmentRegistration of trial before subject enrollment Results posting now required as wellResults posting now required as well Differing definitions used by FDA and ICMJEDiffering definitions used by FDA and ICMJE FDA required language for consent documents FDA required language for consent documents

informing participants that the trial is registered informing participants that the trial is registered and that additional information may be obtained and that additional information may be obtained at clinicaltrials.govat clinicaltrials.gov

Two compliance issues with Two compliance issues with registrationregistration

Nationally, very poor compliance with Nationally, very poor compliance with posting of results according to posting of results according to requirementsrequirements

Some Yale researchers report being Some Yale researchers report being denied publication because the trial had denied publication because the trial had not been registered prior to subject not been registered prior to subject enrollmentenrollment


FDA definitionFDA definition

‘‘applicable clinical trial’:applicable clinical trial’:

Controlled interventional studies with one or Controlled interventional studies with one or more arms of drugs, or biologics if the trial more arms of drugs, or biologics if the trial is a controlled clinical investigation, other is a controlled clinical investigation, other than a phase I investigation, of a drug than a phase I investigation, of a drug subject to FDA regulationsubject to FDA regulation

For devices, the trial prospectively compares For devices, the trial prospectively compares a device-based intervention against a a device-based intervention against a controlcontrol


ICMJE definitionICMJE definition

Any research study that prospectively Any research study that prospectively assigns human participants or groups of assigns human participants or groups of humans to one or more health-related humans to one or more health-related interventions to evaluate the effects on interventions to evaluate the effects on health outcomeshealth outcomes Health-related interventions include any Health-related interventions include any

intervention used to modify a biomedical or intervention used to modify a biomedical or health-related measure including PK and AEshealth-related measure including PK and AEs



Tissue and/or Data BankingTissue and/or Data Banking

Evolving issues related to informed Evolving issues related to informed consent, privacy, and definition of future consent, privacy, and definition of future research.research.

Attention to when donation is required for Attention to when donation is required for participation versus when it may be participation versus when it may be optional.optional.


Ethical Issues in Tissue and Data Ethical Issues in Tissue and Data BankingBanking

Respect for PersonsRespect for Persons Informed consentInformed consent AutonomyAutonomy WithdrawalWithdrawal Privacy, confidentialityPrivacy, confidentiality

BeneficenceBeneficence Mostly indirect or societal benefitMostly indirect or societal benefit Need to Minimize riskNeed to Minimize risk

JusticeJustice Ownership issuesOwnership issues


Informed consentInformed consent

Purpose of collection, use and any future Purpose of collection, use and any future research must be specifiedresearch must be specified

Access to information Access to information What identifiers will be releasedWhat identifiers will be released Who will receive the information and Who will receive the information and Under what conditionsUnder what conditions

Where human genetic research is anticipated, Where human genetic research is anticipated, consent must describe consequencesconsent must describe consequences

Conditions whereby subjects may withdraw their Conditions whereby subjects may withdraw their participation: destruction vs anonymizationparticipation: destruction vs anonymization


Privacy/ConfidentialityPrivacy/Confidentiality

What identifiers are linked to samples or What identifiers are linked to samples or retained in data sets?retained in data sets?

If genetic testing is planned, can identities If genetic testing is planned, can identities really be protected?really be protected?

HIPAA RAF is limited to a single purpose HIPAA RAF is limited to a single purpose Government, law enforcement use of DNA Government, law enforcement use of DNA

biobanks (Patriot Act, Big Brother)biobanks (Patriot Act, Big Brother)


RisksRisks

Mainly involve breach of confidentialityMainly involve breach of confidentiality Some public health data bases cite deductive Some public health data bases cite deductive

disclosure risks where releasing 5 data fields (or disclosure risks where releasing 5 data fields (or more) has the potential to re-identify an individual.more) has the potential to re-identify an individual.(Add Health, PSI, ARIS/REDS) (Add Health, PSI, ARIS/REDS)

Coded sets with coded donor sites may also lead Coded sets with coded donor sites may also lead to deductive disclosure.to deductive disclosure.

Effect on access to or retention of benefits or Effect on access to or retention of benefits or entitlements, perceived harm of discrimination or entitlements, perceived harm of discrimination or stigmatization. (health insurance, altered family stigmatization. (health insurance, altered family relationships, etc.)relationships, etc.)


Ownership issuesOwnership issues

Courts seem to say subject forfeits ownership Courts seem to say subject forfeits ownership upon donation (signing informed consent) upon donation (signing informed consent) (Moore)(Moore)

Voluntary withdrawal from the research Voluntary withdrawal from the research (repository) does not equate to directing use or (repository) does not equate to directing use or transferring ownership (Catalona)transferring ownership (Catalona)

Proprietary rights belong to the subject if cells Proprietary rights belong to the subject if cells are still within the subject (Slavin)are still within the subject (Slavin)

Bioethicists may be more conservative on the Bioethicists may be more conservative on the issue than the general publicissue than the general public


Unresolved issuesUnresolved issues

Return of information to subjects?Return of information to subjects? Re-consent for future uses that were Re-consent for future uses that were

unanticipatedunanticipated When is waiver for future or secondary When is waiver for future or secondary

use not permissible?use not permissible? Tiered consent (how to track?)Tiered consent (how to track?) Assent/re-consent at age of majority for Assent/re-consent at age of majority for

minorsminors


Tissue ConclusionsTissue Conclusions

Evolving scenarioEvolving scenario Consent albeit broadly written should be Consent albeit broadly written should be

obtained for future research usesobtained for future research uses Put protections in place to minimize risksPut protections in place to minimize risks Check with HIPAA Security when storing Check with HIPAA Security when storing

and sharing data setsand sharing data sets Deal with ownership honestlyDeal with ownership honestly


Disclosure of External InterestsDisclosure of External Interests Individuals must disclose all interests required Individuals must disclose all interests required

by University policy to the COI Office.by University policy to the COI Office.

New regulations have prompted the University to New regulations have prompted the University to institute a branched policy and branched on-line institute a branched policy and branched on-line disclosuredisclosure

Mandatory training is now required, and training Mandatory training is now required, and training has been built into the on-line disclosurehas been built into the on-line disclosure


Significant Financial Interests Significant Financial Interests (SFIs)(SFIs)

New PHS regulations used by NIH define an SFI New PHS regulations used by NIH define an SFI as income over $5K from a for-profit entity or as income over $5K from a for-profit entity or stock ownershipstock ownership

Many other entities are using the PHS rules, such Many other entities are using the PHS rules, such as AHRQ, ACS, AHA, CDC, JDRFas AHRQ, ACS, AHA, CDC, JDRF

Travel must be disclosed and considered for PHSTravel must be disclosed and considered for PHS

NSF still defines SFI as income over $10K from a NSF still defines SFI as income over $10K from a for – profit entityfor – profit entity

If a researcher has neither PHS or NSF funding, If a researcher has neither PHS or NSF funding, University threshold is $10KUniversity threshold is $10K


Individual profile must be:Individual profile must be: Updated at least annually and whenever a Updated at least annually and whenever a

new interest is added, e.g., consulting for new interest is added, e.g., consulting for industry or new ownership interests (stock).industry or new ownership interests (stock).

On file with COIC BEFORE applying for NIH On file with COIC BEFORE applying for NIH funding funding

Kept current, especially when submitting a Kept current, especially when submitting a human research protocol to the IRB where human research protocol to the IRB where there is a related interest.there is a related interest.


HIC/COIC Harmonization EffortsHIC/COIC Harmonization Efforts

IRB will review annual disclosure status of IRB will review annual disclosure status of PI, co-investigator and those obtaining PI, co-investigator and those obtaining consent for new studies (non exempt), consent for new studies (non exempt),

IRB will also review at time of renewal and IRB will also review at time of renewal and when an amendment adds new PI, Co-I or when an amendment adds new PI, Co-I or “responsible person”.“responsible person”.

No more disclosures to IRB, but must note No more disclosures to IRB, but must note to PI and IRB, the names of researchers to PI and IRB, the names of researchers with protocol-related interests with protocol-related interests


IRB will not process the submission when IRB will not process the submission when the PI’s disclosure is expired or is pending.the PI’s disclosure is expired or is pending.

When the disclosure of a co-investigator or When the disclosure of a co-investigator or person obtaining consent is not current or person obtaining consent is not current or is pending, then the person will be is pending, then the person will be removed from the research team and removed from the research team and cannot take part in the study until the COI cannot take part in the study until the COI disclosure is updated.disclosure is updated.

ENSURE DISCLOSURES ON FILE with ENSURE DISCLOSURES ON FILE with COIC PRIOR TO SUBMITTING TO THE COIC PRIOR TO SUBMITTING TO THE IRB!IRB!


IRB assesses the interest and determines if it is IRB assesses the interest and determines if it is a COI that must be manageda COI that must be managed IRB needs to distinguish the risks that may IRB needs to distinguish the risks that may

compromise the protection of subjects, a scientist’s compromise the protection of subjects, a scientist’s objectivity or challenge the integrity of the research.objectivity or challenge the integrity of the research.

May require a plan to manage, reduce or eliminate May require a plan to manage, reduce or eliminate the interest.the interest.


Disclosing InterestsDisclosing Interests

Is it enough to inform research participants of Is it enough to inform research participants of the investigator’s financial or potential financial the investigator’s financial or potential financial interests?interests?

Will disclosing the information to a research Will disclosing the information to a research volunteer affect their decision to participate?volunteer affect their decision to participate?

Will it make the process any safer for them?Will it make the process any safer for them? Can financial conflicts be managed or reduced Can financial conflicts be managed or reduced

in a way that doesn’t adversely affect patient in a way that doesn’t adversely affect patient safety or influence the objectivity of the research safety or influence the objectivity of the research conclusions?conclusions?

Physician Payments Sunshine Physician Payments Sunshine ActAct

Applicable manufacturers of drugs, Applicable manufacturers of drugs, devices, biologicals or medical supplies devices, biologicals or medical supplies must report annually to the secretary of must report annually to the secretary of health and human services certain health and human services certain payments or transfers of value to payments or transfers of value to physicians or teaching hospitals. physicians or teaching hospitals. Government would then publish the Government would then publish the reported data on a public websitereported data on a public website


IOM InitiativeIOM Initiative Creation of a harmonized conflict of interest Creation of a harmonized conflict of interest

disclosure system that will be web-based to disclosure system that will be web-based to allow a single, flexible mechanism allowing allow a single, flexible mechanism allowing physicians and researchers to disclose, and physicians and researchers to disclose, and institutions and relevant entities to request, institutions and relevant entities to request, specific informationspecific information

Business plan being developed, with deployment Business plan being developed, with deployment expected late 2013 or early 2014expected late 2013 or early 2014

JAMA 2012; 308:2093-4JAMA 2012; 308:2093-4


Advance Notice of Proposed Advance Notice of Proposed Rule Making (ANPRM)Rule Making (ANPRM)

First revision of human subjects protection First revision of human subjects protection regulations since they were written in 1981regulations since they were written in 1981

Advance notice published Summer of Advance notice published Summer of 2011 for comment2011 for comment

Next step in process is still awaitedNext step in process is still awaited


Be careful what you wish for:Be careful what you wish for:

It might come true!It might come true!


Substantive changes proposedSubstantive changes proposed

Good news scenario: improvements on Good news scenario: improvements on several fronts that may lead to increased several fronts that may lead to increased efficiency (such as not requiring continuing efficiency (such as not requiring continuing review for studies involving minimal risk) review for studies involving minimal risk)

Bad news scenario: some proposals not Bad news scenario: some proposals not thought through carefully and can have thought through carefully and can have significant unplanned repercussionssignificant unplanned repercussions


Broad categories of proposed Broad categories of proposed changeschanges

Risk based protections: calibrate the type Risk based protections: calibrate the type of review to the risk posed by the of review to the risk posed by the research, with resultant elimination of the research, with resultant elimination of the need for annual review of minimal risk need for annual review of minimal risk studiesstudies

Revamp of informed consent, including Revamp of informed consent, including requiring consent up front for all samplesrequiring consent up front for all samples

Mandate use of a single IRB for multisite Mandate use of a single IRB for multisite studiesstudies


Single IRB for multisite studiesSingle IRB for multisite studies

Great example of inadequate conceptualization Great example of inadequate conceptualization of entire issueof entire issue

No universal model proposed/adaptedNo universal model proposed/adapted Resultant myriad of models which all differ Resultant myriad of models which all differ

significantly and require new systems to be put significantly and require new systems to be put in placein place

Researchers will need to understand and comply Researchers will need to understand and comply with multiple systemswith multiple systems

Yale currently deals with 5 different modelsYale currently deals with 5 different models


Strengthening data protectionStrengthening data protection Streamlining adverse event reporting and Streamlining adverse event reporting and

cataloging via a websitecataloging via a website Extension of Federal Regulations to all Extension of Federal Regulations to all

human subjects research regardless of human subjects research regardless of funding sourcefunding source

Harmonization of guidance from myriad Harmonization of guidance from myriad federal agenciesfederal agencies



ConclusionsConclusions

Conflicts of interest, and tissue banking, are evolving topics

Lapses and clinical trials registration present challenges for compliance

Evolving landscape in human subjects protections

Documents

Current Topics in Human Subjects Research 2012 Sandra L. Alfano, Pharm.D, CIP Research Scientist, GIM Chair, HIC II and IV December 13, 2012