Introduction to Returning of Individual Results Working Group - - PowerPoint PPT Presentation

Introduction to Returning of Individual Results Working Group

December 16, 2015

Time Topic Presenters 8:00 – 8:15 Welcome and Introductions Rebecca Li 8:15 – 9:15 Scope and background on returning individual research results Definition of key terms Barbara Bierer Debra Mathews 9:15 – 10:30 Brainstorming: common institutional barriers/challenges (white board brainstorming session) Sandy Prucka Dave Pulford Barbara Bierer 10:30 – 10:45 Break 10:45 –11:15 Discussion of workgroup logistics, workflow, timeline MRCT Center 11:15 – 12:15 Outline of first deliverable(s) to address identified barriers Sandy Prucka Dave Pulford Debra Mathews 12:15 –1:00 Working lunch: Next steps and responsibilities

December 16, 2015 - Agenda

Co-Chairs: Sandra Prucka, Eli Lilly and Company Debra Mathews, Johns Hopkins Berman Institute Team members: Academic/Medical Center: Carmen Aldinger, MRCT Center Barbara Bierer, MRCT Center Juan Carmona, MRCT Center Alisa Donnelly, formerly Univ of Manchester Felicitas Holzer, Univ of Cambridge Rebecca Li, MRCT Center Heather Marino, MRCT Center Ignacio Mastroleo, FLACSO Argentina Ramadhani Abdallah Noor, Harvard Chan School Usharani Pingali, Nizam's Institute of Medical Sciences Wasana Prasitsuebsai, HIV-NAT, AIDS Research Ctr Lynn Sleeper, Harvard Medical School Clinical Research Organization: Jules Mitchel, Target Health Inc. Government/Regulatory: Ricardo Eccard da Silva, Braz. Health Surv. Ag. - Anvisa Garbine Saruwatari Zavala – INMEGEN Industry: Mary Ellen Allen, Genentech, Inc. Karina Bienfait, Merck Karla Childers, Johnson & Johnson Kelly Coulbourne, AstraZeneca Patrick Cullinan, Takeda Pharmaceuticals Felipe Dolz, Sanofi Nicole Hinton, Biogen Jaime Houde, EMD Serono Barbara Kress, Merck Sarah Larson, Biogen Laurie Myers, Merck David Pulford, GlaxoSmithKline Jessica Scott, GlaxoSmithKline Institutional Review Boards: Linda Coleman, Quorum Review IRB David Forster, WIRB Copernicus Group Stephen Rosenfeld, Quorum Review IRB Non-Profit: Zachary Hallinan, CISCRP Ellie Okada, Boston Cancer Policy Institute Lauren Quattrochi, Sense About Science Patient Advocates: Deborah Collyar, Patient Advocates In Research Elizabeth Frank, Dana Farber/Harvard Cancer Ctr Cheryl Jernigan, Susan G. Komen Jane Perlmutter, Gemini Group Research/Consulting Firms: Barbara Godlew, The FAIRE Company, LLC Wendy Sanhai, Exponent, Inc Patricia Teden, Teden Consulting LLC

Current Working Group Members

Framing questions

• The MRCT Center has developed guidance and tools for return
• f aggregate results of research to participants. Often,

participants will ask, “What study arm was I on?” Do we, should we disclose? If yes, how do we ensure they have heard?

• Beyond study arm assignment, in the past, individual research

results were determined to be “actionable” or not, and only actionable results returned. Do individuals own or have a right to all or only some of their data?

• Individuals increasingly are requesting access to their

information; individuals are partners in research.

• Do we, should we, respect participant autonomy rights? And if

we do return results, what are our responsibilities to the participant?

4

Project statement: returning individual research results

• Problem: Patients and advocacy groups desire to receive individual &

aggregate research data from clinical studies in which they participated. While the MRCT Center has developed guidelines on the return of aggregate results, standard guidelines/criteria to facilitate the return of individual results are lacking, making it difficult to determine what, when, and how data are to be returned

• Summary: This project will focus on returning individual results to study

participants

• Approach: Launch diverse workgroup comprised of multi-stakeholders

coordinated and organized by MRCT Center that will provide guidance on return of individual-level data

Individual-level results may include incidental findings (IFs), clinical and research laboratory results, pharmacogenomic/genomic results, and results of the study arm

• Aggregate research results
• Assignment to and results of study arm
• Routine clinical results performed in the course of research

– USA: CLIA-approved or –unapproved laboratories and processes – What is global standard for trustworthiness and does it matter?

• Incidental findings discovered in the course of a clinical trial

(mass on an MRI done for research purposes) – Of potential clinical significance – Of uncertain significance

• Research results

– Of likely or uncertain significance – Of potential proprietary importance – Genetic/genomic results

• Other results

Spectrum of results to return to participants:

Easiest Hardest

Source of data Data types

• Clinical CLIA (or equivalent) laboratory results
• Clinical non-CLIA laboratory results
• Research results (e.g. biomarkers, experimental, proprietary)
• Imaging results

– Routine – Experimental

• Genetic/Genomic results
• Other: biometric, social/behavioral, etc.

Sources of data

• Clinical trials
• Secondary research
• Research using samples obtained from biobanks

1/22/2016 7

In the context of biobanking: Definitions

Wolf et. Al., specifically addressing biobanking policies, defined:

• Incidental Finding (IF): “a finding concerning an individual research

participant ... that has potential health or reproductive importance and is discovered in the course of conducting research but is beyond the aims of the study.”

• Individual Research Results (IRR): “a finding concerning an individual

contributor that has potential health or reproductive importance and is discovered in the course of research on the focal variables under study in meeting the stated aims of the research project.”

1/22/2016 8

Wolf SM, Crock, BN, Van Ness, B, et al. Managing incidental findings and research results in genomic research involving biobanks and archived data sets. Genet Med, 2012;14:361–384

In Biobanking, 4 key responsibilities: CARR: Clarifying, Analyzing, Re-identifying, Recontacting

• Clarifying the criteria to determine what kind of findings are

returnable, and the roster of returnable IFs and IRRs;

• Analyzing a particular finding to decide whether it should be
• ffered to the individual contributor;
• Re-identifying that contributor (or contributors, if more than one

is affected by the finding); and

• Recontacting the contributor(s) to offer the finding and genetic or
• ther appropriate counseling.

(in this context, contributor is donor or participant. Possible for contributor to be another investigator)

1/22/2016 9

Wolf SM, Crock, BN, Van Ness, B, et al. Managing incidental findings and research results in genomic research involving biobanks and archived data sets. Genet Med, 2012;14:361–384

Definition of key terms

Incidental Findings

• Are previously undiagnosed medical
• r psychiatric conditions that are

discovered unintentionally and are unrelated to the current medical or psychiatric condition which is being treated or for which tests are being performed.

Note: primarily directed to clinical care but applicable to research and DTC

Presidential Commission for the Study of Bioethical Issues

Recommendations: The Bioethics Commission offered specific recommendations

for handling incidental and secondary findings in clinical, research and direct-to- consumer settings. There are, however, some ethical principles and duties that span all three contexts for which the Bioethics Commission made five broad recommendations.

I.Practitioners should inform potential recipients, in any setting, about the possibility of

incidental or secondary findings, and if and how those findings will be disclosed, before the start of a test or procedure. Informed consent and open communication between providers and potential recipients is essential.

II.Professional representative groups should develop guidelines that categorize findings

likely to arise from each diagnostic modality, and develop best practices for managing them.

See more at: http://bioethics.gov/node/3186#sthash.stxRzbWm.dpuf (emphasis added)

Presidential Commission for the Study of Bioethical Issues (continued)

III.

Federal agencies and other interested parties should fund research to keep abreast of the rapidly evolving types and frequency of findings; potential costs, benefits, and harms; and recipient and practitioner preferences about incidental and secondary findings.

IV.

Public and private entities should prepare materials and enhance education of all stakeholders, including practitioners, institutional review boards, and potential recipients about the ethical, practical, and legal considerations raised by incidental and secondary findings.

V.

There is a need – based on justice and fairness – not just for a privileged few but for all individuals to have access to information and the guidance needed to make informed choices about what tests to undergo, what kind of information to seek, and what to do with information once received. Affordable access to care and quality information about incidental and secondary findings, before and after testing, can be potentially lifesaving.

• See more at: http://bioethics.gov/node/3186#sthash.stxRzbWm.dpuf (emphasis added)

Questions to address

• Is “actionable” or the “potential health or reproductive

importance” still the appropriate threshold for consideration of return?

• Is there any threshold requirement for return of individual results

to participants? What types of results should be returned, and what are the characteristics of those that should not be? If certain results are not returned, does time-dependent understanding impart a continuing obligation to reconsider whether to return?

• If results are returned, who should do so (and how) and who is

responsible and accountable for ensuring its execution?

• If results are returned, are participants availed of or entitled to

follow up medical care or counseling?

Workgroup Launch Define key terms; determine types of data that could be returned; identify obstacles, challenges & concerns of industry, academia, non-profit sponsors; discuss participant preferences Workgroup Study arm, clinical and research results, incidental findings Genetics/genomic s Subgroup Workgroup Harmonization Compilation of best practices to manage disclosure & follow-up of individual study participants Manage Global Framework of Clinical Trials Implement age-dependent & culturally-dependent norms of communication

Timeline

Conference & Deliverable

Dec 2016

Year 2

Incorporate global

• bjectives & priorities

Jan 2017 - Completion

Year 1 Conference

Launch and define the most important deliverables Dec 2015 Initiate collaborative subgroups as needed Jan 2016 - Nov 2016

Workflow

Returning of individual results to clinical study participants

Overarching objectives of our 2-year project

1.

Determine types of data to return and to whom and by whom

2.

Define stakeholder obligations

3.

Define practical methods to facilitate disclosure of results to individual participants

4.

Create best practices to manage disclosure and follow-up of individuals

5.

Develop relevant global framework to manage the global context of returning individual results of clinical trials

Summary of broad project goals

1. Determine types of data—e.g., whether and what data to return and to whom: clinical results; research results; study arm results; incidental findings; all in the context of variable international standards. Establish collaborative Genetics/Genomics Subgroup if/when needed 2. Define stakeholder obligations—e.g., who is responsible for what and for how long; what are the key roles and/or obligations when interfacing with individual participants and/or to their legally authorized representative? 3. Determine shared and/or unique concerns that stakeholders have regarding the ethical, legal, regulatory, & privacy issues regarding disclosure of individual- level results to clinical research study participants 4. Develop practical methodologies for return of individual results and methods to ensure compliance; follow-up of individuals 5. Develop points to consider for what information and support will be offered to participant and how

Workgroup: Specific objectives

Workgroup in Global Framework: Specific objectives (1)

1.

Describe challenges of communicating results to vulnerable populations and/or their legally authorized representative(s)

2.

Define age-dependent and culturally-dependent norms of communication, with particular focus on challenging data, such as genomics/pharmacogenomics

3.

Encourage and/or develop study-specific manuals to educate patients/patient communities about concepts related to return of individual-level findings, customized to the design of each study and the culture/country in which the trials took place

Workgroup in Global Framework: Specific objectives (2)

• 4. Understand the financial impact for patients: what next steps can be taken;

potential for follow-up procedures to confirm or further explore a result; provider may not offer care related to a research result

• 5. Consider the impact of exploratory data on participants
• 6. Develop process if local resources do not exist
• 7. Address whether liability or other concern may be disincentive to sharing

data.

• 8. Enumerate what further research is necessary to understand impact of

results return (e.g. impact on individuals in receipt of results)

Workgroup, Jan 2016 - Nov 2016

Return of Study Arm Results – Specific objectives

Define methods to facilitate disclosure of study-arm information to individuals

1.

Define study arm, post-trial results and relevant terminology needed for the return

• f individual study arm data

2.

Determine timeline of un-blinding, results availability & method of communication with principal investigator

3.

Address what to do if principal investigator is no longer available

4.

Ensure that study-arm disclosure is customized for the study

5.

Enable timely interaction with participant soon after completion of clinical trial— avoid prolonged time gaps; timelines may be customized

6.

Determine if there are settings in which study arm results will not be available

Workgroup, Jan 2016 - Nov 2016

Return of Clinical Results – Specific objectives

Define methods to facilitate disclosure of clinical study information to individuals

• 1. Address the conditions under which the test must be performed, and whether the

result must be validated; assess laws and regulations and global standards for performance

• 2. Determine what--and the significance of--data, proposed to return
• 3. Address to whom such results should be communicated. To the participant? To the

Principal Investigator? To the referring physician? And what to do if that person is no longer available.

• 4. Determine timing of return of clinical results and whether there are situations in

which the results will not be returned (e.g. if important for maintenance of blind or freedom from bias in study outcome)

Workgroup, Jan 2016 - Nov 2016

Return of Incidental Findings (IFs) – Specific objectives

Define methods to facilitate disclosure of IFs to individual participant

• 1. Define IFs and relevant terminology, and content of consent
• 2. Address the conditions under which the test must be performed, and whether the

result must be validated

• 3. Determine what--and the significance of--data, proposed to return
• 4. Address to whom such results should be communicated. To the participant? To the

Principal Investigator? To the referring physician? And what to do if that person is no longer available.

• 5. Ensure that IFs are customized given particular goal(s) of the study design
• 6. Enable timely interaction with participant/caregiver soon after discovery of IF

Initiate Workgroup, Jan 2016 - Nov 2016

Return of Research Results – Specific objectives

Define whether and how to facilitate disclosure of research results to individuals

• 1. Define types of research results, definitions, relevant terminology, and content of

consent

• 2. Develop educational materials for participants and community, both general and

specific

• 3. Address whether the result must be validated and whether results need be

significant or actionable; are considerations dependent on trial or study design

• 4. Address to whom such results should be communicated. To the participant? To the

Principal Investigator? To the referring physician? And what to do if that person is no longer available.

• 5. Enable timely interaction with participant/caregiver if to be returned.

Initiate Subgroup, as needed, Jan 2016 - Nov 2016

Genetics/genomics Subgroup – Specific objectives

Define ethical and practical dimensions relating to the disclosure of individual genomic results

1.

Establish appropriateness, extent of consent to research, including the right to future use of genomic data

2.

Discuss the actionability/utility of genomic results

3.

Return genomic results to participants if appropriate/requested; consider identifiability/risk to participant privacy

4.

Define whether and when to provide counseling, if appropriate, to facilitate interpretability and to address participant concerns and questions

Goal: December 2016 Conference

Workgroup Harmonization – Specific objectives

Create best practices to manage disclosure and follow-up of individuals

• Goal: Deliverable (Guidance document/toolkit) by Dec. 2016 annual meeting

1.

Ensure that information from Workgroup and any subgroup converges and harmonizes

2.

Integrate participant experiences and perspectives regarding the return of their individual results

3.

Consider participant preference(s) when returning individual data

4.

Develop framework for user-friendly database/archival system for users to access data; consider ability of participants to interpret; put context around their results

Definition of key terms

• Identifiability – degree to which data without traditional

identifiers can be connected to an individual’s name and other personal information; used extensively in the genomic literature

• De-identified – Removal of HIPAA identifiers and other

traditional identifiers from a data set

• Anonymized – True dissociation of a data set from personally

identifiable information

• Re-identification – connecting information that has been “de-

identified” or anonymized to an individual’s name and other personal information

Definition of key terms

• Incidental findings (IFs) – Medical test results that are not

sought through testing, but that the test nonetheless reveals

• Secondary findings – Medical test results that are not

themselves the focus of testing, but which are sought along with the primary information that is the focus of testing

• Personal research results – The individual test results of a

person participating in a research protocol

• Aggregate research results – The accumulated test results of all

individuals involved in a research protocol

Definition of key terms

• Actionable/actionability – The degree to which a personal

research result can be used to guide decision-making

• Medically actionable – The degree to which a personal

research result can be used to guide medical decision-making

• (Clinical) Utility – The usefulness of a test for clinical practice;

The impact of a test on patient outcomes; The impact of a test

• n patient outcomes, speed to diagnosis, patient management,

and the potential for prognosis on the individual being tested, the individual's family members, and society in general

Definition of key terms

• Principle Areas of Discussion (and any relevant terms

related to these areas)

– Return of:

• Incidental Findings
• Study Arm Results
• Clinical Results
• Research Results

Brainstorming: common institutional barriers/challenges

December 16, 2015

Sandra Prucka, M.S., CLGC

Consultant Scientist Tailored Therapeutics at Eli Lilly and Company

Dave Pulford, PhD

Senior Scientific Investigator at GlaxoSmithKline

One-size-does-not-fit-all

1/22/2016 30

International clinical trial

Variations in: Regulation, Clinical guidelines, Ethical practice, Legal Exploratory Data Clinical utility Opinion: medical relevance Researcher: subject relationship Consent Referral for downstream services Study complexity

Track decisions

Autonomy Power of attorney

Challenges of returning data Beneficence

What should be returned, findings with utility or all research data? Utility? Accredited laboratory? Research initiated years later Specialists? Genetic Counselors?

Organizing a complex topic

1/22/2016 31

Timing

Responsibilities

• What should be

returned?

• What is already

returned?

• Consider

differing international clinical guidelines

Consent

• Clarity :
• What will

be provided

• Choice to

receive information

• Patient

responsibilit ies

What will be provided

• Is there a time

period where an ethical

• bligation

exists to return results?

• What about

results generated years later?

• Delivery and

communication

• f results

(translations?)

• Follow-up and

associated costs

• Tracking

decision making What? When? Who? How?

Organizing a complex topic:

Should results be categorized?

• Support in the literature and by numerous organizations that:

– IRR should be returned if they relate to:

• “particular health status”, “information generated that has relevance to

current or future health or quality of life” and “findings that are clinical relevant to individual health”.

– IRR should not be returned include those that are not validated and where clinical utility has not been established

Lévesque, E., Joly, Y., Simard, J., 2011. Return of research results: general principles and international perspectives. J Law Med Ethics, 39(4), pp. 583-592. 1/22/2016 32

A suggested method to categorize results:

33

• Results that should be offered

1) Substantial risk for a serious health condition (clinically valid) 2) Significant potential to change the course of the condition/alter treatment (clinical utility) 3) Analytically valid & disclosed in a manner complying with local law 4) Recognize research participant autonomy

• Results that may be offered

1) Bullets 3&4 above and additionally the result demonstrates a: 2) Substantial risk of likely health/reproductive importance or personal utility [that is] likely to provide a net benefit with limited risk to this individual

• Results that should not be offered
• Uncertain health, reproductive, or personal utility & unlikely net benefit
• See appendix 1 for references

Relationships and Timing Matter

1/22/2016 34

RESULT RESULT

Sponsor Investigator Research Participant

RESULT

Investigator Research Participant

RESULT

Investigator Research Participant

RESULT

Primary Care physician Genetic Counselor Third Party Third Party Research Participant Laboratory Investigator

TIMING

Are all test equal?

1/22/2016 35

Clinical testing and interpretation Genetic/genomic research

• Imaging or other validated biomarker test
• Confirms presence of disease or high

likelihood of disease, e.g. hypertension, elevated LDL-C, presence of tumour

• Individual may already be affected. May or

may not have implications for family members

• Clinical utility likely established, e.g.

screening, early therapeutic intervention

• Research focused question that may not

intend but has the potential to identify risk factor(s) for disease

• Likely to be risk factors for multi-factorial
• r polygenic condition, e.g. APOE4 &

Alzheimer’s Disease

• Individual may/may not be affected.
• Implications for family members less clear
• Clinical utility may not be established

There may be important differences between clinical tests and genomic research tests conducted in a clinical trial

Returning genomic research results in clinical trials

• Whole exome/genome approaches increase risk of identifying

findings that are medically actionable

• Raises questions about communicating results to individual patients
• ACMG provided a list of pathogenic mutations in 56 genes to be

returned to patients undergoing clinical sequencing*

• Recommendation applies only when ordered in a clinical context currently
• ACMG has an open call for genes to add to the list as of March 2015
• NHGRI working group Nov 2015**
• Germline variants/mutations should be reported
• Fuelled debate with respect to the genomic research setting

Active debate, no clear consensus

*Green et al. Genet Med. 2013; 15: 565-574; ** Raymond et al. J Natl Cancer Inst. 2015; 108(4): doi.10.1093/jnci/djv351

Genomic IRRs and IFs

1/22/2016 37

Hypothetical study 1: PGx to evaluate medicine response – oncology Hypothetical study 2: PGx to evaluate medicine response – cardiovascular disease

• GWAS & targeted gene sequencing study to

evaluate whether gene variants influence PFS & OS in a colon cancer population in a phase 3 study of medicine X

• Exploratory analysis including genes

previously associated with colon cancer, e.g. APC

• Small number of individuals identified as

carriers of mutation in APC

• PGx study to evaluate response to

medicine in large (n=15k) cardiovascular study

• Exploratory GWAS, with imputation, based

approach

• Analysis identified 2 individuals as carrying

[likely] pathogenic mutations in APC

• There is a relationship between APC &

colon cancer. Since the study specifically focused on genes implicated in the disease, the finding would not be considered incidental

• The finding that 2 individuals were carriers
• f mutation in APC were incidental to the

study goals

Genomic research in international clinical trials

• Genomic research is often exploratory, retrospective & may not

be carried out

• Non-accredited vs. accredited environment
• What do research participants want?
• Clarity in consent about what to expect & respect for autonomy
• Raw data without interpretation vs. IRR that is medically actionable
• What does the researcher need to consider?
• Is there a duty to ‘hunt’ for medically actionable mutations?
• Knowledge of actionable genes changes over time – duty to update?
• Is genetic counselling required and when should it be provided?
• Is confirmatory testing required & who is responsible for this?
• What is the ethical duty of care & does this extend beyond the study?
• Difference in requirements across international boundaries

1/22/2016 38

What barriers/challenges does this raise?

• Differences of opinion regarding medical relevance
• Is the finding clinically actionable?
• What if the result adds no value to the research participant’s medical

management but may have value for relatives?

• Operational complexities
• Tracking changes relevant to the communication of IRR (e.g. death, interest

in results)

• For industry sponsored trials, how do you maintain a three way relationship

for years after trial completion?

• If raw data is provided how is this supplied?
• Are there legal implications, e.g. if results are not returned or individual

exploratory results are misinterpreted or misused?

• Complexity of international trial setting often not fully considered

1/22/2016 39

One-size-does-not-fit-all

1/22/2016 40

International clinical trial Genomic Research

Variations in: Regulation, Clinical guidelines, Ethical practice, Legal Exploratory Research Conducted in non-accredited environment Re-test in accredited laboratory Opinion: medical relevance Researcher: subject relationship Consent Genetic counselling Study complexity

Who has responsibility ? Track decisions

Autonomy Power of Attorney

Challenges of returning data Beneficence

What should be returned, finding with utility or all research data?

Would ACMG list be a solution?

Is there clinical utility?

Research initiated years later

Organizing a complex topic

1/22/2016 41

Timing

Responsibilities

• What should be

returned?

• What is already

returned?

• Consider differing

international clinical guidelines

Consent

• Clarity :
• What will be

provided

• Choice to

receive information

• Patient

responsibilities

What will be provided

• Is there a time

period where an ethical obligation exists to return results?

• What about results

generated years later?

• Delivery and

communication of results (translations?)

• Follow-up and

associated costs

• Tracking decision

making

What? When? Who? How?

Appendix 1

• E.B. Bookman et al. Reporting genetic results in research studies: summary and recommendations of

an NHLBI working group. Am J Med Genet A 2006; 140: 1033-1040

• E.W. Clayton & L.F. Ross. Implications of disclosing individual results of clinical research. JAMA 2006;

295

• E.W. Clayton & AL McGuire. The legal risks of returning results of genomic research. Genet Med

2012;14(4): 473-477.

• R.R. Fabsitz et al. Ethical and practical guidelines for reporting genetic research results to study

participants: Updated guidelines from a National Heart, Lung and Blood Institute working group. Circ Cardiovasc Genet 2010; 574-580

• R.C. Green et al. ACMG recommendations for reporting of incidental findings in clinical exome and

genome sequencing. Genet Med 2013;15(7): 565-574

• B.M. Knoppers & A. Dam. Return of results: towards a lexicon? J Law Med Ethics 2011; 39(4): 577-582
• B.M. Knoppers, M.H. Zawati, K. Senecal. Return of genetic testing results in the era of whole-genome
• sequencing. Nat Rev Genet 2015;16(9):553-559
• C. Kronenthal, S.K. Delaney, M.F. Christman. Broadening research consent in the era of genome-

informed medicine. Genet Med 2012;14(4): 432-436

1/22/2016 42

Appendix 1

• E. Lévesque, Y. Joly, J. Simard. Return of research results: general principles and international
• perspectives. J Law Med Ethics 2011; 39(4):583-592
• M.J. Mehlman. Predictive genetic testing in urology: ethical and social issues. World J Urol 2004; 21:

433-437

• Presidential Commission for the Study of Bioethical Issues. Anticipate and Communicate: Ethical

management of incidental and secondary findings in the clinical, research, and direct-to-consumer

• contexts. December 2013: www.bioethics.gov
• S.K. Prucka et al. An update to returning genetic research results to individuals: perspectives of the

industry pharmacogenomics working group. Bioethics 2015; 29:82-90

• V.M. Raymond et al. Germline findings in tumor-only sequencing: points to consider for clinicians and
• laboratories. JNCI J Natl Cancer Inst 2016;108(4) online Nov 21, 2015
• S.M. Wolf et al

Managing incidental findings and research results in genomic research involving biobanks and archived data sets. Genet Med 2012; 14:361-84

• S.M. Wolf et al Returning a Research Participant’s Genomic Results to Relatives: Analysis and
• Recommendations. J Law Med Ethics 2015;43(3): 440-463
• M.H. Zawati, BM Knoppers. International normative perspectives on the return of individual research

results and incidental findings in genomic biobanks. Genet Med 2012;14(4): 484-489

1/22/2016 43

Tentatively: Strategic goals & planning Timeline Launch the Workgroup, discuss scope of project, order of questions to be considered, pipeline, and workgroups Dec 2015 Gather research/ideas from Workgroup & possible subgroup to address institutional barriers for returning individual results Jan – May 2016 Develop & circulate deliverables in advance of Conference; edit and harmonize June – Sept 2016 Finalize first draft of deliverables to share and present in mid-December Oct – Dec 2016 Refine global framework of clinical trials Jan 2017 – beyond

Discussion of workgroup logistics, workflow, timeline

First Deliverables

December 16, 2015

Sandra Prucka, M.S., CLGC

Consultant Scientist Tailored Therapeutics at Eli Lilly and Company

Dave Pulford, PhD

Senior Scientific Investigator at GlaxoSmithKline

Debra Mathews, PhD, MA

Associate Professor, Johns Hopkins University

Organizing a complex topic

...is it provided

…is responsible

...is consent sought ...will be provided

What? When? Who? How? Team 1 Team 2 Team 3 Team 4

Current status: What is shared, what is not & why? Current status: Study & data generation/analysis timelines Current status: Consent content and process? For providing results? What should be shared? In what format? Delivery of results during or after study? What should be in the consent document? For counselling, confirmatory tests & associated costs? Future re-analysis (for genomic results)? When is specialist counselling required & delivered? How will participant autonomy be ensured & tracked? What are the participants’ responsibilities? Variations in clinical practice, ethical considerations, international guidelines & regulation Other considerations? Other considerations? Other considerations? Other considerations?

Timeline

1/22/2016 47

Protocol IC CTA

Considerations

• Global context for IRR
• Similar case studies
• Existing policy
• Regulation and guidance
• SOPs
• Data security
• Financial resources
• Age
• Vulnerability

Other Examples

• Biomarkers
• CTC circulating tumor

cells

• Co-development
• Companion diagnostic
• With consent biopsy

Site Investigator

• Lab
• Imaging
• Diagnostics
• Social/behavioral

Patient Enrolled

PLV

Medically actionable Personal Utility Sensitive or not Other Proprietary Pharmacokinetics? +genetic variation

Planning CT

Patient Last Visit

LPLV Thank you note Genomics

• Online ROR models
• To hunt or not to hunt (for

things not related to the condition studied)

• Obligation
• Relevance to family

members

• Pediatrics

Education Issues of Re-consent Genomic/genetic Interim analysis

Doctor’s responsibility: Summary of individual data “Clinical” & interpretation Investigator/doctor Last Patient Last Visit Patient wants to know

• % accrued
• length of time expected,
• results reported opt in/opt
• ut; contacts refreshed

Research Results

• Points to consider
• analytic validity
• clinical utility

Planning and information gathering phase Protocol development phase

Timeline Part 1: IRR planning prior to Last Patient Last Visit (LPLV)

Do no harm Who owns the data or specimens? Data Lock Analysis 12 Months Trial Results Un-blinding Public Disclosure

• 1st publication

(primary results)

• Aggregate results

(e.g., send a letter with aggregate results, opportunity to get individual results),

• Revisit study arm

(individual interpretation for each person) Incidental Findings (IFs)

Observed directly by Doctor/Study team Analysis later By whom?

Study Arm

Whether time-dependent analysis of significance

Secondary Result(s) Biobank [Research Results]

Exceptions:

• Cross-over
• Un-blinded
• Adaptive
• Open label
• Other

LPLV

Timeline Part 2: IRR planning from LPLV through Biobank and Secondary Results