Retention Refresher WebEx - ePharmaSolutions · An Academic Research Organization of Brigham & Women’s Hospital An Affiliate of Harvard Medical School Confidential, not for further

An Academic Research Organization of Brigham & Women’s Hospital An Affiliate of Harvard Medical School Confidential, not for further distribution

Retention Refresher

WebEx

WCT & TIMI Study Group

Please be in touch with your WCT In-house CRA regarding training requirements for this presentation


Agenda • TIMI

Retention Challenges Retention Scenarios

- Temporary Reduced Dose Option - Echocardiogram Sub-study (North America only)

• WCT Review of Current Retention Study Aids Retention Workbook Common eCRF Mistakes

• TIMI CEC Reminders

• Retention Refresher Quiz


Retention Challenges

TIMI Study Group


Subject Retention & Missing Data

• Intense awareness of the importance of missing data and subject retention in clinical trials.

• Both aspects were the focus of two recent FDA Panels reviewing DM and CV drugs.

• Recently published Recommendations from National Research Council.


• Study Drug Discontinuation – Non-serious AEs – Prohibited medications – Lack of efficacy (No weight loss experienced)

• Withdrawal of Consent – Trial fatigue – Subject awareness of all available follow-up options and importance

of continued follow-up while off study drug – Minimal communication between subject and Principal Investigator

• Lost to Follow-up – Lack of success following completion of Checklist – Lack of urgency, as trial will not be done for ~2 years

Retention Challenges


• Trial Duration: ~5 years • Visit schedule: every 3 months for the first 2 years,

every 4 months thereafter

Follow-up Expectations

Regular contact improves communication and minimizes study discontinuation.

EOT S R EOS

Visit

Month

1

-1

2 0

3 3

4 6

5 9

6

12

7

15

8

18

9

21

10

24

11

28

12

32

…

…

~18

~56

~19

~57

Screening Treatment Estimated median 3-4yrs; Minimum 2.5yrs

Follow-up

≤30d Every 3mo±10d for 24mo Every 4mo±10d 30+10d

S = screening, R = randomization, EOT = end of treatment, EOS = end of study


Study Drug Discontinuation

Most frequent reasons for

study drug discontinuation

AE/SAE

Subject Decision

Missed Visit

Prohibited Medication

15%

85%

Resumed IP Subjects who have discontinued IP at least once

Currently off IP (since discontinued)

Currently on IP


Withdrawal of Consent

90%

6%

3% 1%

Outcome of Reclassified Subjects

Early discontinuation LTF

Continuing on IP Restarting IP

Over half of subjects that have been entered as being Potentially Withdrawn Consent in the eCRF have been re-classified as permanently discontinued study drug but continuing follow-up after further discussion.


Potentially Lost to Follow-up

At the end of 2015:

~75% of subjects who had, at any point, been out of contact for

> 6 months remained potentially lost to follow-up.


Retention Scenarios

TIMI Study Group


• Need for a prohibited concomitant medication

• Subject’s own decision

• Missed study visit

• No weight loss experienced; does not recognize the

benefits of continuing

• Adverse event

Why might a subject discontinue study drug?


Phase III Trials: Most Common Adverse Reactions

Most Common Adverse Reactions for BELVIQ Patients (>5% and more common than placebo)

Patients without Diabetes Patients with Diabetes • Headache • Dizziness • Fatigue • Nausea • Dry mouth • Constipation

• Hypoglycemia • Headache • Back pain • Cough • Fatigue

1. Belviq [package insert]. Woodcliff Lake, NJ: Eisai Inc; 2012.


Summary of AE Data • Most common AEs include headache, dizziness,

nausea, fatigue and hypoglycemia (in diabetics). • Symptoms tended to:

– Occur early & be self-limited and mild-moderate in intensity.

• Only a minority of subjects on lorcaserin experienced AEs that lead to drug discontinuation & similar AEs occurred in placebo arm, therefore:

• Presence of symptoms ≠ active treatment arm • Absence of symptoms ≠ placebo arm


If symptoms develop: – Assess severity of symptoms. – Assess likelihood of relation to IP.

If symptoms are thought to be related to IP: – If tolerable and without a safety concern, continue IP. In many cases,

the symptoms will resolve within 1-4 weeks. – If symptoms persist (or are intolerable), attempt temporary

reduced dose regimen (upon approval of Protocol Amendment). – In the event that severe symptoms occur (eg serotonin syndrome or

NMS-like reactions) or there is a safety concern, study drug should be discontinued.

If symptoms are not thought to be related to IP: – Continue IP. – Continue evaluation and treatment of other potential causes.

Recommendations for Management


• CAMELLIA – TIMI 61 is a trial designed to evaluate the long term cardiovascular efficacy and safety of lorcaserin.

• Potential weight-dependent and weight-independent cardiovascular and metabolic effects of lorcaserin will be assessed. As a result, it is critical that patients remain on study drug irrespective of weight loss.

Key Recruitment & Retention Message


Weight-loss Independent Effects in BLOOM-DM*

HbA1c Fasting Glucose

Lorcaserin Placebo *Post-hoc analysis.


Subject who wants to discontinue study drug

• Involve the Investigator immediately! LISTEN to subject and empathize with issues.

SUGGEST new plan to adapt to complaints raised by subject.

EVALUATE side-effects and determine if possibly related to study drug.

RECOMMEND discontinuation of other concomitant meds that may be responsible.

DETERMINE subject’s willingness to remain on study drug for two weeks and re-assess. Transient adverse events are known to often subside after two weeks. Pursue reduced dose option (once daily dosing) if transient AEs

continue (refer to Protocol Amendment).

OFFER a “Drug Holiday”, in which subject stops taking Study Drug for a period of time, then re-challenge at each visit.

CAPTURE reason for premature discontinuation in eCRF.


Protocol Amendment & Memo #20: Temporary Dose Reduction

FOLLOWING APPROVAL OF PROTOCOL AMENDMENT

• Subjects can take study drug once daily (QD) for a limited duration (7 days) if they cannot continue to take study drug due to non serious AEs believed to be related to study drug.

• Dosing instructions: 1 tablet once daily, lorcaserin 10 mg or

placebo once daily dosing (QD), for a maximum of 7 days. Study drug cannot be split.

Subjects who had previously discontinued study drug due to a non-serious AE can be re-challenged on this

QD dosing option.


Potential Benefits for Subject Retention

• Newly Randomized Patients – Helpful for patients who experience an early side

effect

• Existing Patients – Allows subjects who previously discontinued study

drug due to an AE a chance to restart study drug • Sites to re-approach these patients and re-challenge

with lower starting dose

Temporary Dose Reduction


Efficacy and Side Effects of Lower Dose

BLOSSOM - J Clin Endocrinol Metab. 2011;96(10):3067-77

Weight Loss Side Effect (Dizziness)


• Upon permanent discontinuation from study drug: – EOT visit to be conducted within 30 days of last dose – Continue regular follow-up per protocol

• Minimum of 1 in-person visit annually • Other visits in-person or by phone

• Study drug may be re-started at any time and should be offered at each visit. – Always try to get patient back on study drug if there is

no safety concern – Reduced dosing may be a viable option

Premature Discontinuation from Study Drug


• The purpose of the ECHO sub-study is to establish the cardiac safety of lorcaserin as compared to placebo. – As such, retention in the sub-study is just as

important as retention in the main study.

• As indicated in the protocol, all ECHO sub-study subjects must continue with echocardiograms even if they have discontinued study drug.

Echocardiogram Sub-Study Reminder

Applicable to North American sites only


• If applicable subjects are continuing in the trial via phone or indirect follow up, please encourage them to come in for their predefined ECHO visits: V4, V6, V8, V10, V13, V16.

• Applicable subjects should be encouraged to continue sub-study if they miss a visit.

Echocardiogram Sub-Study Reminder


Clinical Follow-up after Premature Discontinuation from

Study Drug

Restart study drug IF YES:

Discuss these options for follow up: - Visit every 3-4 months

- Phone call every 3-4 months

- Visit or Phone call every year

- Visit or Phone call at Study Closure

IF NO:

Best Option

Less Preferable Option - Only access to medical

records

- Indirect contact with family, friends, or physician

Is the subject willing and able to resume study drug?


Study drug discontinuation does not equal

withdrawal of consent or withdrawal from study




A subject who withdraws consent to trial follow-up is a subject who has formally refused all three of the following in writing:

1. Any contact with site staff 2. Participation in any trial follow-up options 3. Usage of their medical information (e.g. medical

records, primary care physician contact)

Site must contact TIMI Hotline to confirm appropriate withdrawal of consent.

If confirmed, Withdrawal of Consent form is released in the eCRF.


Subjects are often incorrectly entered as “Potential Withdrawal of Consent” in the eCRF:

• Misclassified in the eCRF – Subject discontinued study drug, but agreed to some

form of follow-up contact.

• Subject unaware of alternate follow-up options – Subject discontinued study drug and expressed

unwillingness to come in for future clinic visits. – Subject is unaware of option to have phone visits or

indirect follow-up.



Study Team Communication

When a subject is entered as a Potential Withdrawal of Consent in the eCRF, TIMI or WCT will make an outreach to the study staff to do the following:

1. Confirm that the subject was offered all options for follow-up. 2. Confirm that the investigator had conversation with subject

prior to withdrawal. If either of these two steps were not completed by

study staff, a final outreach must be made to the subject, preferably by an investigator.


Reinitiating Contact with Subjects

Oftentimes subjects are unaware of the indirect follow-up options are available. These require minimal to zero time commitment.

Medical record review Contact between site PI and the subject’s PCP One final visit or phone call at the end of the trial

• Subjects are free to continue any form of contact, including resuming study drug, at any time. o Temporary Reduced Dose Option is now available (following

approval and training on protocol amendment).


Subjects who are potentially lost to follow-up:

• Utilize all available contact information, medical records, and databases to attempt to locate each subject.

• If permitted by local regulation, and is included in the informed consent form, submit the subject to the patient finder (once available).

• Document all efforts to locate a subject, including attempted phone calls, letters, and searches completed.

• Subjects will not be confirmed and classified as being lost to follow-up until the very end of the trial. – Repeat completion of Potential Lost to Follow-up Checklist throughout the

duration of the trial.

Potentially Lost to Follow-up (LTF)


A long term study commitment should be stressed and reinforced at

each visit.

Potentially Lost to Follow-up (LTF)


Review of Current Study Aids

WCT


Study Drug Discontinuation Study Aids

• Key Points for PI to Discuss with Subject Prior to Permanent IP Discontinuation

• White Paper (Numbered Memo 24a) Released October 16, 2015 in North America. To be released in

other countries upon approval of Protocol Amendment.

Subject Dose Card To be used following local approval of amendment

• Implementation of Reduced Dose Released January 26, 2016 in North America. To be released in

other countries upon approval of Protocol Amendment.


Numbered Memo #24a White Paper


Subject Dose Card


Implementation of Reduced Dose Option


Implementation of Reduced Dose Option


• Current tools to help prevent subjects become lost to follow-up:

– Healthy Lifestyle Program Continued engagement of subject through trial-provided study aids

– Subject Information Sheet Collect subject’s up-to-date phone, email, and physician information

– Subject Contact Sheet Lists up-to-date contact information for 3 other individuals who have a relationship with the subject

– Potential Lost to Follow-up Checklist

– Potential Lost to Follow-up Tracking Log

Lost to Follow-up Study Aids


Potential LTF Checklist and Log


• Patient Finder Services will be available in the future to assist in locating potentially lost to follow-up subjects.

Managed per local regulations, as approved by EC/IRB/REB. By signing the ICF, subjects agree to have their

information shared with third party vendors if the site is unable to make contact

Lost to Follow-up Study Aids


• Workbook identifies and tracks study drug discontinuations, potential withdrawal consents and potential lost to follow-up subjects

• Workbook includes subject data collected from: – eCRF entry – WCT/Site communication

• Study Drug Discontinuation follow-up • Lost to Follow-Up study aid • Amendment 01 Reduced Dose Option

– TIMI Hotline • Potential Withdrawal consent • Reduced Dose

Retention Workbook


• eCRF Data Entry – Subject Status – Study Medication – Early Discontinuation from Study Drug – Temporary Interruption – AE

Retention Workbook


WCT Site/Communication Data

• Study Drug Discontinuation – Was the PI made aware of the SD Disc? – Was a drug holiday offered? – Did the subject accept drug holiday? – Possibility to re-challenge in the future? – Is the subject a regular clinic patient?

Retention Workbook


Lost to Follow-Up • Data should be submitted to WCT from the

LTF study aids – Date Telephone Contact attempted – Date Emergency Contact attempted – Date Mail Contact attempted – Date Certified Letter sent – Were other treating physicians contacted

Retention Workbook


• Amendment 01- Reduced Dose Option – Did Site Agree Subject is Eligible for Reduced Dose

• If No, reason why. • If Yes, Date was Reduced Dose Offered?

– Was Reduced Dose Accepted? o If no, reason why.

Retention Workbook


• Not recording missed visits as “Visit Not Performed”

• Not entering status as “Subject Restarting Study Drug” at the first visit where IP is restarted

• Entering status as “Continuing on Study Drug” when IP has not been dispensed

• Providing SAE/AE as the reason subject discontinued IP, but not entering any corresponding SAE/AE as “Drug Withdrawn” on SAE/AE page

• Entering “Drug Withdrawn” on AE page, but “Subject Choice” as reason for discontinuing IP on Early Discontinuation from Study Drug Form

Common eCRF Mistakes


• Not removing data on Early Discontinuation from Study Drug when subject restarts previous permanent IP discontinuation

• Not removing last dose of study medication when subject restarts IP

• Not updating Study Drug Interruption when subject restarts IP

• Not entering Date of Last Dose on Study Medication Page • Not completing ED from Study Drug Form when subject

discontinues IP

Common eCRF Mistakes


CEC Reminders

TIMI Study Group


Endpoint Reporting Manual Version 2.1 Updates

Sponsored by Eisai, Inc. Confidential

CLINICAL EVENT SOURCE DOCUMENT CHECKLIST COVERSHEET

To submit documents, use one of the following methods:

1. Submit to WCT via Local Clinical Research Associate [email protected]

2. Fax: Please See Country Specific Fax Number

3. Submit to WCT via [email protected]

From: __________________________ Date: __________________________ Total Pages: ___________

Site #: __ __ __ __ Patient #: __ __ __ __ __ __ __ __ Visit #: _____________ Event Date: __ __ / __ __ __ / __ __ __ __ Event Time: __ __ : __ __

Included Not Available Not Done Admission History and Physical Examination............

ECG Tracings (prior to, during, and post event)……………..

Cardiac Biomarkers (trop/CKMB during hosp and 30d prior)…

Cardiac Biomarker ULN reference ranges..... ......…

Procedure Reports (cardiac cathetherization, PCI, CABG)…..

Discharge Summary……………………………..…….

Autopsy Report (if available)……………………………..

Other ...............................……………………………..

IMPORTANT NOTE

REMOVE ALL IDENTFYING INFORMATION FROM SOURCE DOCUMENTS PER EVENT REPORTING MANUAL

Complete this form for each CIE Event entered in Medidata Rave.

CARDIAC ISCHEMIC EVENT

(24 hr clock) (DD / MMM / YYYY)

To submit documents, use one of the following methods:

1. Submit to WCT via Local Clinical Research Associate [email protected]

2. Fax: Please See Country Specific Fax Number

3. Submit to WCT via [email protected]

From: __________________________ Date: __________________________ Total Pages: ___________

Site #: __ __ __ __ Patient #: __ __ __ __ __ __ __ __ Visit #: _____________ Event Date: __ __ / __ __ __ / __ __ __ __ Event Time: __ __ : __ __

Included Not Available Not Done Admission History and Physical Examination............

Cardiac Ischemia Biomarkers (trop/CKMB)……….……

Natriuretic Peptide Results (BNP or NT–proBNP).………..

Right Heart Catheterization Report (if performed)……...

Chest X-Ray or Chest Imaging Report……………….

Progress or Consultation Notes (if available).……...…..

Discharge Summary……………………………..…….

Echocardiogram Report……………………..…….......

Other ...............................……………………………..

IMPORTANT NOTE

REMOVE ALL IDENTFYING INFORMATION FROM SOURCE DOCUMENTS PER EVENT REPORTING MANUAL

Complete this form for each Heart Failure Event entered in Medidata Rave.

HEART FAILURE EVENT

(24 hr clock) (DD / MMM / YYYY)

CLINICAL EVENT SOURCE DOCUMENT CHECKLIST COVERSHEET


• Event adjudication is delayed when protected health information is not fully redacted before sending to WCT.

Redaction Reminders

Patient Identifiers: Patient name or initials Patient month and day of birth Patient address (including zip code and email address) Patient telephone number and fax number Family member’s names and addresses Patient social security number (or equivalent hospital number) Patient account, certificate or license numbers Patient chart number Patient medical records or health plan numbers Patient room number Any other unique identifying number, characteristic or code

Other Identifiers (Including Investigative Site or Member of Staff on the Study Delegation Form):

Hospital Name Hospital Address Physician Name Physician Address


• If two potential events occur simultaneously, a unique clinical event should be reported for both events.

• Source documents should be submitted to your local WCT

designee within 10 days of learning of the event.

• CEC queries should be responded to within 10 days. Please only respond to query to provide clarity or confirm missing documentation was submitted.

• When drafting Notes to File, ensure that all relevant information available on the event is included.

General CEC Reminders

Confidential


Review of Retention Follow-up Definitions

• Premature Discontinuation of Study Drug – Stops study drug – Agrees to ANY form of follow up

• Visits, phone, medical records, final status call

• Withdrawal of Consent (WOC) – Stops study drug – Refuses in writing to be followed up in any way – No further contact allowed

• Lost to Follow-up (LTF) – Extremely rare – Every attempt to contact the subject should be made until the

subject is located


1. A subject has stopped study drug due to a non-serious adverse event (AE). The AE has now resolved. At what time point is it too late for a subject to restart the study drug? A. After 4 months off study drug. B. After 2 years off study drug. C. A subject can restart study drug at any time. D. A subject can never restart study drug.

Refresher Quiz


2. You randomize a subject in CAMELLIA – TIMI 61 but they have not returned your calls to schedule their next appointment. Months later the subject informs you that they never took study drug and they do not want to in the future. What should you do?

A. Have the PI speak to the subject about their concerns. Continue all follow-up even if subject remains off study drug.

B. Classify the subject has having withdrawn consent from all follow-up procedures.

C. Ask your monitor to remove the subject from the trial, as they never took study drug.

Refresher Quiz


3. A subject comes to your office, places study drug on your desk, and walks out. You are subsequently unable to get in contact with them. What should you do?

A. Classify the subject as having withdrawn consent from all follow-up procedures.

B. Classify the subject as lost to follow-up and do not search for them for the remainder of the trial

C. Try and contact using lost to follow-up study aids. Once contact is made, offer follow-up even if subject remains off study drug.

Refresher Quiz


4. Which of the following constitutes a full withdrawal of consent to follow-up?

A. Subject refuses to take study drug. B. Subject provides written documentation that they refuse to

provide any additional information on their health (in person, by telephone, through contact with their PCP, through medical record review, or through one final contact at the end of the trial).

C. Subject will not return to the clinic for follow-up visits. D. Subject’s family member asks that the site not to call the

house anymore.

Refresher Quiz


Answers 1. C 2. A 3. C 4. B

Refresher Quiz

Confidential, not for further distribution

In an effort to assist your site have the best subject retention possible, TIMI (US) and WCT (all other countries) will be contacting sites with a certain number of discontinued, withdrawn, or lost to follow-up subjects.

This correspondence is meant to serve as an opportunity to openly discuss challenges and success in an effort to improve subject retention at your site.

What you can expect from TIMI/WCT: • Detailed information regarding subject status • Reminders/tips for subject retention • Additional support from TIMI physicians if needed

What is expected of you: • Timely response with details for each subject

o Plans for re-challenging subjects • Plans for future subject retention

Upcoming Retention Communication


Team Effort Retention is a team effort between: – Study Site – Primary Physician – Subject – Subject’s family – Study team

We all need to work together to make

CAMELLIA – TIMI 61 a success!


Retention Refresher

WebEx

WCT & TIMI Study Group

Documents

Retention Refresher WebEx - ePharmaSolutions · An Academic Research Organization of Brigham & Women’s Hospital An Affiliate of Harvard Medical School Confidential, not for further