Disclosure of research results: should policies be changed? Melanie B. Shulman, M.D., M.Phil. Clinical Associate Professor of Neurology and Psychiatry Associate Director, Cognitive and Behavioral Neurology Barlow Memory Evaluation and Treatment Center Associate Leader, Clinical Core Alzheimer’s Disease Center New York University School of Medicine

Return of Research Results (RORR): an old problem This is not a problem or issue exclusively faced by AD researchers Relevant to any research result Particularly in the news related to genetic research

Today’s “state of the art”: little agreement Nothing should be returned After all, it’s research and not clinical care Return only if: Result has analytic and clinical validity as well as clinical utility Result is serious and “actionable” Return everything People have a right to know

Definitions Analytic validity – refers to how well a test predicts the presence or absence of an abnormality (reliability, repetition, accurate measurement of a specific clinical target) Clinical validity – refers to how well a test relates to the presence or absence of a disease Clinical utility – refers to whether the test can provide information about diagnosis, treatment, management, or prevention of a disease that will be helpful to an individual

Fig. 1 Source: Alzheimer's & Dementia: The Journal of the Alzheimer's Association 2011; 7: (DOI: /j.jalz )Alzheimer's & Dementia: The Journal of the Alzheimer's Association 2011; 7: Copyright © 2011 Terms and ConditionsTerms and Conditions

What are the biomarkers of AD? IMAGING MRI of brain FDG-PET β – Amyloid imaging with PET SPINAL FLUID Amyloid (Aβ42) and tau assays GENETIC 3 dominantly inherited genes for AD (PSEN1, PSEN2, APP) Apo E

ADNI: Alzheimer Disease Neuroimaging Initiative the NIH’s largest public-private partnership on brain research that began in 2004 tasked with tracking biomarker changes in volunteers with normal cognition, probable Alzheimer’s disease (AD), and mild cognitive impairment (MCI) includes scientists at 55 research centers in the US and Canada, involving over 800 participants has collected and analyzed 1000s of brain scans, genetic profiles, and biomarkers in blood and CSF in an effort to establish better tools for carrying out effective clinical trials and predicting clinical outcomes. to date, ADNI has endorsed a policy of nondisclosure of research results to its participants.

Disclosing Research Results: Views and Experiences of ADNI Investigators and Personnel Neurology 2013; 81; Melanie Shulman, MD, New York University Jason Karlawish, MD, University of Pennsylvania Robert C. Green, MD, MPH, Brigham and Women’s Hospital and Harvard Medical School

Background Purpose: to learn ADNI investigator and personnel views and practices regarding disclosing biomarker information to research participants. Design: One-time, anonymous online survey Population: All ADNI investigators & personnel Context: Immanent FDA approval for florbetapir, a biomarker used to image amyloid (approved in April 2012) The A4 prevention trial was planning to recruit subjects based on amyloid imaging (hence discosure of amyloid-imaging would be required)

Data Gathering Participants were contacted via with a link to the online survey. The time period for completion was 2 weeks, with a weekly reminder to participants who had not yet completed the survey.

Response Rate RoleTotal Contacted Total Completed Response Rate Principal Investigator (primary or secondary) % Study Physician602237% Clinician452249% Study Coordinator (primary or back-up) % Total303157*52% * Total 159 surveys complete, n = 2 missing response

Participants Do you care for patients who are also ADNI research participants? N (%) Yes109 (69%) No49 (31%) TOTAL158* (100%) * Total 159 surveys complete, n = 1 missing response

Participant Characteristics What degrees do you hold? (select all that apply) N (%) MD/DO69 (45%) PhD24 (16%) RN/CRNP/PA21 (14%) MSW0 (0%) MPH6 (4%) Master’s32 (21%) BA/BS46 (30%) TOTAL152* * Total 159 surveys complete, n = 7 missing response

Participant Characteristics What is your specialty? (Select all that apply) N ( %) Medicine18 (13%) Neurology65 ( 46%) Psychiatry23 (16%) Radiology6 ( 4%) Pathology/Laboratory Medicine1 (1%) Psychology/Neuropsychology27 (19%) Nursing23 (16%) Social work1 (1%) TOTAL142* * Total 159 surveys complete, n = 17 missing response

Return of Amyloid Imaging Results - dementia participants Return to dementia participantsN, % Always2 ( 1%) Sometimes11 ( 8%) Never 126 (91%) TOTAL 139 (100%) When you returned an amyloid imaging result to a participant with dementia, was it: (select all that apply) Total Responses (N=13) To provide risk assessment5 (38%) To clarify a diagnosis 10 (77%) To guide therapy 4 (31%) Other (please specify) “the volunteer asked for information” “because they specifically asked” 2 (15%)

Return of Amyloid Imaging Results - MCI participants Return to MCI participantsN, % Always2 (1%) Sometimes12 (9%) Never125 (90%) TOTAL139 (100%) When you returned an amyloid imaging result to a participant with MCI, was it: (select all that apply) Total Responses (N=14) To provide risk assessment6 (43%) To clarify a diagnosis8 (57%) To guide therapy6 (43%) Other (please specify) “the participant asked for information” “they specifically asked” 2 (14%)

Return of Amyloid Imaging Results - normal cognition participants Return to participants with normal cognition N, % Always2 (1%) Sometimes7 (5%) Never130 (94%) TOTAL139 (100%) When you returned an amyloid imaging result to a participant with normal cognition, was it: (select all that apply) TOTAL Responses (N=9) To provide risk assessment6, 67% To clarify a diagnosis4, 44% To guide therapy0, 0% Other (please specify) “the participant asked for information” 1, 11%

Participant request for amyloid imaging results (MCI) % MCI who request results N (%) %25 (18%) 51-75%6 (4%) 26-50%16 (11%) 1-25%37 (26%) 0%55 (40%) Total Responses139 (100%)

Participant request for amyloid imaging results (Normal Cognition) % normal who request results N ( %) %23 (16%) 51-75%5 (4%) 26-50%14 (10%) 1-25%35 (25%) 0%62 (45%) Total Responses139 (100%)

Suppose the FDA approves PET amyloid imaging with florbetapir. Would you support a policy that allows you to tell ADNI participants with mild cognitive impairment their amyloid imaging result? Definitely support65 (41%) Probably support51 (32%) Unsure 23 (14%) Probably do not support14 (9%) Definitely do not support 6 (4%) TOTAL159 (100%)

Suppose the FDA approves PET amyloid imaging with florbetapir. Would you support a policy that allows you to tell ADNI participants with mild cognitive impairment their amyloid imaging result? Definitely support33 (49%) Probably support24 (35%) Unsure2 (3%) Probably do not support6 (9%) Definitely do not support3 (4%) Total (only those with direct patient contact and ADNI clinical responsibilities) 68 (100%)

Suppose the FDA approves PET amyloid imaging with florbetapir. Would you support a policy that allows you to tell ADNI participants with normal cognition their amyloid imaging result? Definitely support45 (28%) Probably support48 (30%) Unsure36 (23%) Probably do not support18 (11%) Definitely do not support12 (8%) TOTAL159 (100%)

Suppose the FDA approves PET amyloid imaging with florbetapir. Would you support a policy that allows you to tell ADNI participants with normal cognition their amyloid imaging result? Definitely support16 (24%) Probably support22 (32%) Unsure12 (18%) Probably do not support9 (13%) Definitely do not support9 (13%) Total (only those with direct patient contact and ADNI clinical responsibilities) 68 (100%)

ADNI researchers endorsing a policy of disclosure of amyloid-imaging information to participants with mild cognitive impairment ADNI researchers overall (N=159) 73% support (definitely or probably) 14% unsure 13% do not support (probably or definitely) ADNI physician-researchers (N=68) 84% support (definite or probable) 3% unsure 13% do not support (probably or definitely)

ADNI researchers endorsing a policy of disclosure of amyloid-imaging information to participants with normal cognition ADNI researchers overall (N=159) 58% support (definitely or probably) 23% unsure 19% do not support (probably or definitely) ADNI physician-researchers (N=68) 56% support (definite or probable) 18% unsure 26 % do not support (probably or definitely)

% of ADNI researchers (N=155) deeming an ADNI collected measure “clinically meaningful”

Open-ended Response Analysis: Data analyzed Please indicate whether you support a policy that allows you to tell ADNI participants with mild cognitive impairment their amyloid imaging result. In the space below, please feel free to write any comments or thoughts on your answer. Please indicate whether you support a policy that allows you to tell ADNI participants with normal cognition their amyloid imaging result. In the space below, please feel free to write any comments or thoughts on your answer. In the space below, please feel free to write out any other thoughts or comments on returning amyloid imaging results to persons enrolled in ADNI. We are especially interested in your views on persons with MCI or normal cognition.

6 Themes Identified in Open-Ended Responses I. ADNI participant preferences regarding disclosure should be respected II. ADNI participant characteristics should determine whether results are disclosed III. Disclosure of amyloid imaging results requires development of standard procedures and participant education IV. Disclosure of amyloid imaging results has potential harms and benefits to ADNI participants V. A need for standardization of data gathering and improved quality of data about amyloid imaging VI. Disclosure could affect the conduct and results of ADNI studies

Examples In general, I agree with returning results. The concern is that is is not clear what the results mean and there is always the risk that subjects will interpret results incorrectly, regardless of how much we explain that we are still in the early stages of trying to determine the meaningfulness of these results. At the end of the day though, they are adults capable of making their own decisions in the MCI and normal cohort, and in large part, in the AD cohort too.

Examples We are not the participant’s physician. Results such as this should come from someone who has an ongoing role and will be able to deal with the participants emotional and medical needs if they were PET PIB positive. Would only support if disclosure was done as part of the research study – with outcome measurements about the knowledge as may affect the subject’s wellbeing and the integrity of the ADNI data.

Summary The vast majority of ADNI investigators do not currently return amyloid imaging results to ADNI participants (~90% across all diagnostic groups). Requests for amyloid imaging results from ADNI participants are not uncommon -- 20% of ADNI investigators report requests from more than half of participants with normal cognition, and 22% report requests from more than half of participants with MCI. The majority of ADNI investigators would support the return of amyloid imaging results to participants with MCI and normal cognition, given FDA approval of Florbetapir.

Changes already underway Amyloid imaging results may be returned to ADNI participants with dementia. Amyloid imaging results are presently being disclosed to cognitively normal individuals as an entry criterion for the A4 prevention study with rigorous study of the consequences of disclosure. Amyloid imaging results are now being disclosed to those with early AD as an entry criterion for LZAX anti-amyloid treatment trial.