Disclosure of research results: should policies be

changed?

Melanie B. Shulman, M.D., M.Phil.

Clinical Associate Professor of Neurology and PsychiatryAssociate Director, Cognitive and Behavioral Neurology

Barlow Memory Evaluation and Treatment CenterAssociate 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; 7:280-292 (DOI:10.1016/j.jalz.2011.03.003 )

Copyright © 2011 Terms 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 PersonnelNeurology 2013; 81; 1114-1121

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)

i.

Data Gathering

Participants were contacted via email 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

Role Total Contacted

Total Completed

Response Rate

Principal Investigator (primary or secondary)

74 47 64%

Study Physician 60 22 37%

Clinician 45 22 49%

Study Coordinator

(primary or back-up)

124 66 53%

Total 303 157* 52%

* Total 159 surveys complete, n = 2 missing response

Participants

Do you care for patients who are also ADNI research participants?

N (%)

Yes 109 (69%)

No 49 (31%)

TOTAL 158* (100%)

* Total 159 surveys complete, n = 1 missing response

Participant CharacteristicsWhat degrees do you hold?

(select all that apply)N (%)

MD/DO 69 (45%)

PhD 24 (16%)

RN/CRNP/PA 21 (14%)

MSW 0 (0%)

MPH 6 (4%)

Master’s 32 (21%)

BA/BS 46 (30%)

TOTAL 152*

* Total 159 surveys complete, n = 7 missing response

Participant Characteristics

What is your specialty? (Select all that apply)

N ( %)

Medicine 18 (13%)

Neurology 65 ( 46%)

Psychiatry 23 (16%)

Radiology 6 ( 4%)

Pathology/Laboratory Medicine 1 (1%)

Psychology/Neuropsychology 27 (19%)

Nursing 23 (16%)

Social work 1 (1%)

TOTAL 142*

* Total 159 surveys complete, n = 17 missing response

Return of Amyloid Imaging Results - dementia participants

Return to dementia participants N, %

Always 2 ( 1%)

Sometimes 11 ( 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 assessment 5 (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 participants N, %

Always 2 (1%)

Sometimes 12 (9%)

Never 125 (90%)

TOTAL 139 (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 assessment 6 (43%)

To clarify a diagnosis 8 (57%)

To guide therapy 6 (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, %

Always 2 (1%)

Sometimes 7 (5%)

Never 130 (94%)

TOTAL 139 (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 assessment 6, 67%

To clarify a diagnosis 4, 44%

To guide therapy 0, 0%

Other (please specify)

“the participant asked for information”

1, 11%

Participant request for amyloid imaging results (MCI)

% MCI who request results

N (%)

76-100% 25 (18%)

51-75% 6 (4%)

26-50% 16 (11%)

1-25% 37 (26%)

0% 55 (40%)

Total Responses 139 (100%)

Participant request for amyloid imaging results (Normal Cognition)

% normal who request results

N ( %)

76-100% 23 (16%)

51-75% 5 (4%)

26-50% 14 (10%)

1-25% 35 (25%)

0% 62 (45%)

Total Responses 139 (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 support 65 (41%)

Probably support 51 (32%)

Unsure 23 (14%)

Probably do not support 14 (9%)

Definitely do not support 6 (4%)

TOTAL 159 (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 support 33 (49%)

Probably support 24 (35%)

Unsure 2 (3%)

Probably do not support 6 (9%)

Definitely do not support 3 (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 support 45 (28%)

Probably support 48 (30%)

Unsure 36 (23%)

Probably do not support 18 (11%)

Definitely do not support 12 (8%)

TOTAL 159 (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 support 16 (24%)

Probably support 22 (32%)

Unsure 12 (18%)

Probably do not support 9 (13%)

Definitely do not support 9 (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”

0102030405060708090

100

MMSE GDSCDR

MRI (vas

c)

MRI (hippo)

FDG-PET

PIB-Florbetap

ir

CSF Abeta/

tau

Normal

MCI

AD

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.