1. ADAPTABLE The Aspirin Study
Limited Participation and WDC Process
Ajar Kochar, MD (Duke)

2. Limited Participation and WDC
34 (1.3%) of total enrolled have modified participation
2 Deceased
3 potential LTFU
13 Limited Participation
16 Withdrawn
High for this point compared to traditional trials
All site personnel to complete WDC/Limited Participation training by June 1, 2017.

3. Managing Participant Withdrawal
My patient wants to withdraw from ADAPTABLE, what do I do?
Quickly contact the patient by telephone to discuss the request and situation

4. Common Reasons for Withdrawal
Frustration with website interactions
Technical Issue (not infrequent) patients have interface challenges that can be resolved with assistance
Frustration with telephone and website follow-up
Frequency: we can modify frequency of follow-up
Concern regarding side effects (bruising, bleeding, GI upset) OR change in medical condition unrelated to the study
Stop or modify intervention: Don’t want to take randomized dose of aspirin, or aspirin at all – should be discussed directly with the patient and involve the primary treating physician (for questions about stopping aspirin completely)
Notify participant that they can still participate in the study even if no longer on aspirin

5. Important Questions to Address
Do you still want to take aspirin? Do you still want to take the randomized dose of aspirin?
If NO, are you still willing to complete the follow-up contacts in the ADAPTABLE web portal (Preferred)?
Can we modify the follow-up schedule?
If NO, can we contact you at the end-of-study?
Can we utilize your electronic health-records and claims data for follow-up without further ADAPTABLE web portal follow-up or telephone calls?
At a minimum, we want to strive for this option for all withdrawal requests

6. Limited Participation vs WDC
Allows for modified follow-up to help with retention
Reduced frequency of check-in visits or medical record only
Should be offered from highest level to lowest level of participation
All limited participation options should be offered before offering complete WDC
“Call me, Maybe?”

7. Limited Participation vs WDC
Withdrawal of Consent (WDC)
Complete withdrawal of consent
Last resort after all other options rejected
No additional data is collected after date of WDC
Still retain data up to date of WDC in study dataset
“We Are Never Ever Getting Back Together”

8. Limited Participation Options

9. Scenario 1: Participant Contacts Mytrus
Receive Call
Mytrus receives call or from Participant
Mytrus contacts Site Coordinator
Mytrus sends secure to designated Site Representative
Site Contacts Participant
Site contacts participant
Discusses why participant wants to withdraw
If participant still wants to WD, offer limited participation options first
Full WDC is last resort
Contact Call Center
Contact Coordinating Center/Call Center
Provide GT
Date participant indicated limited participation or WDC
Level of participation
Reason if given

10. Scenario 2: Participant Contacts Site
Receive Call
Participant indicates to site desire to withdraw from study
Site Personnel
Discusses why participant wants to withdraw
If participant still wants to WD, offer limited participation options first
Full WDC is last resort
Contact Coordinating Center
Contact Coordinating Center/Call Center
Provide GT
Date participant indicated limited participation or WDC
Level of participation
Reason if given

11. Scenario 3: Participant Contacts Call Center
Call Center triages call by assessing whether participant needs to be directed to the site for discussion or if patient clearly wants to withdraw
Site
Call Center
If interest in discussing with clinician prior to making decision:
call center will let participant know
the site will be notified and will follow-up
Site should follow Site Procedure in scenario 2
If interest in withdrawing is clear, call center will review limited participation options with last option of full WDC
Coordinating center will notify site for local dissemination of information as required.

12. Portal Management The Call Center Administration Page
Tracks participant level of participation
Completed by the call center
Adjusts notifications sent to participant
Participant access to the portal
Full access to the portal remains open to participants regardless of level of participation/WDC status
Participants will only be prompted to complete a visit in the portal based on participation level

13. Current Participant Status
In the portal (participant view as shown below):
Full Participation
Limited Participation
Withdrawn
Deceased
Mytrus reports
EnrollBySubject.csv Report
(‘Withdrawn’ column)
On demand in portal
Mytrus Data Extract
CCSTATUS Table
Sent quarterly to sites
*Sample data

14. FAQs Q: When can a participant choose limited participation/WDC
A: A participant can alter level of participation at any time
Q: Can a participate switch between levels of participation?
A: Yes, a participant can switch between limited participation and full participation at any time. Once indicate full WDC they would need to sign new ICF.
Q: Does the site need to enter anything in the portal for limited participation or WDC?
A: No
Q: How is participation level recorded in the portal?
A: The call center uses the call center admin page to record participation levels for participants. ONLY the call center should use the call center admin page.

15. FAQs
Q: Can a participant still continue in the study if they are no longer taking aspirin or the randomized dose?
A: Yes, once randomized it is important to follow all participants until the end of the study regardless of whether they continue taking the randomized dose.
Q: How important is retention for study quality?
A: Retention of all randomized participants is important for a complete, accurate study dataset. Retention loss can jeopardize the integrity of the study so every effort should be made to retain participants at the highest level of participation.
Q: What about data collected up to the point of WDC?
A: When a participant withdraws from the study, data collected up to the date of WDC is retained in the study database.

16. Summary Patients may withdraw at anytime
All requests should be discussed by telephone to engage the patients and clarify the options for follow-up
Data for withdrawn patients until the time of withdrawal will remain in the dataset
Investigate the reason and consider involving the primary treating physician with the discussion
Assess the degree of data collection they will permit and carefully delineate why follow-up is so important for trial integrity
Notify the call center and provide key information for updating the patient portal

17. Limited Participation and WDC Reference Slides
May, 2017
Follow us on
ClinicalTrials.gov: NCT

18. Guidelines from Office for Human Research Protections
45 CFR 46.11(a) patients have the right to withdraw from research at any time
Investigators are ALLOWED to retain and analyze ALREADY collected data relating to any patient who chooses to withdraw from a research study
This includes identifiable private information
Under 45 CFR part 46, patient withdrawal is NOT required to be reported to the IRB
However, reporting to the IRB may be most appropriate for research involving more than minimal risk

19. Guidelines from Office for Human Research Protections II
Sites do NOT need to prompt patients to expunge their entire collected data when withdrawal is requested
- Data collected until withdrawal should be retained
Sometimes a patient wants to withdraw from the primary intervention being tested but is willing to allow the investigator to continue other research activities
- Regular follow-up or limited follow-up should be pursued
ADAPTABLE example: a patient no longer wants to take Aspirin 325 mg due to nuisance bleeding, but may still be willing to participate in electronic follow-up

20. FDA: Guidance for Data Retention with Withdrawal Requests
FDA Law: data collected on patient up to the time of withdrawal MUST remain in the trial database for the study to be scientifically valid
Investigators may ask a withdrawing patient if they wish to provide continued follow up and further data collection
Patients wishing to continue follow up:
Can opt for limited participation
Patients NOT wishing to continue follow up:
Investigator may review data prior to withdrawal AND
Consult public records for vital status

21. Why is the FDA so Concerned about Withdrawal?
FDA law and regulations require collection and maintenance of complete clinical study data (including data from patients who withdraw from the trial)
Concerned, especially if removal is non-random
Non-random patient withdrawal may occur due to:
Dissatisfaction with the trial (research) experience
Failed to obtain desired effect from the intervention
Adverse events related to the intervention being studied
Loss of data could greatly distort trial efficacy results and obscure safety data, thus potentially compromising the altruism of the other patients who volunteered to participate in the trial

22. Source Documents OHRP:
policy/guidance/guidance-on-withdrawal-of-subject/
FDA:
s/ucm pdf