Corrective Action: Documentation of deviation serves as the corrective action.

Impact: No impact to study integrity apparent at this time.

Subject # 4093 was randomized 42 days outside of the window visit. A waiver was sent to Dr. Dixon for approval after the randomization occurred.

Noted.

On 09 APR 2009, it was discovered that 11 study participants (001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011) had been consented with an outdated ICF (version “12/30/08”). The following ICF versions available are:

Version dated 11/18/08 – IRB approved 18 NOV 2008
Version dated 12/30/08 – IRB approved 30 DEC 2008
Version dated 1/20/09 – IRB approved 20 JAN 2009
Version dated 3/16/09 – IRB approved 16 MAR 2009
Version dated 3/16/09 (corrected document) – IRB approved 13 APR 2009

At the time of screening, which occurred between 05 MAR 2009 and 24 MAR 2009, 11 participants had consented to the study by signing an ICF version dated and approved on 30 DEC 2008. At the time of the screening visits, the 11 participants should have been consented with the available ICF version dated and approved on 20 JAN 2009.

Of the 11 participants, 6 had enrolled into the study as allowed per protocol eligibly requirements. The baseline visits (test material dispensing visit) had occurred between the dates of 13 MAR 2009 and 26 MAR 2009. Three of the six enrolled subjects with screening numbers 001, 002, and 003 completed their baseline visit prior to 16 Mar 2009. These subjects were not re-consented with the available 20 JAN 2009 dated ICF upon their baseline visit. The remaining 3 enrolled subjects with screening numbers 005, 008, and 009 completed their baseline visits between the dates of 23 MAR 2009 and 26 Mar 2009. These subjects with screening numbers 005, 008, and 009 were not re-consented upon their baseline visits with the latest available ICF version dated and approved on 16 MAR 2009.

The ICF dated “1/20/09” differs from the ICF dated “12/30/08” in that additional wording was added to include a lab test (FSH) for women between the ages of 45 and 55 to confirm their post-menopausal status. The difference between the ICFs dated “1/20/09” and “3/16/09”, is additional added wording which clarifies "Nicoderm" and Nicorette" as a "Nicotine Replacement Therapy". The “3/16/09” version of the ICF was re-approved by the IRB on 13 APR 2009 in regards to minor typographical errors.

Of the 11 participants, subject with screening number 005 had the FSH test added to their lab panel as per a requirement of the protocol. For clarification, the FSH test was conducted without the subject's consent as only the ICF dated 12/30/08 was signed by the participant upon her screening visit.

With the exception of subject 001 who withdrew consent on 13 APR 2009, the following 5 enrolled subjects were re-consented with the latest (13 APR 2009) IRB approved version of the ICF at their week 6 in-clinic visit (baseline visit):
002 29-Apr-2009
003 28-Apr-2009
005 04-May-2009
008 05-May-2009
009 07-May-2009
Attached to this eNote is a copy of a submitted “Potential Unanticipated Problem or Serious or Continuing Non-Compliance” Investigational Review Board (IRB) form which was acknowledged by the IRB on 21 APR 2009.

RE: Subject 4053

The above-referenced subject used Chantix and did not report this to the staff until the early termination visit. This is a protocol violation and there is no impact on the study.

Subject #5027 did not complete the Week 1 Phone call per protocol and there is no source documentation regarding attempts to reach them in error.

Noted.

Acknowledged

Subject lost diary for weeks 10-16. This diary was never returned to the site. Diary pages will be marked blank.

Subject R5013 inadvertently completed her diaries from Week 1 - Week 6 on a daily basis (e.g. Week 1 Diary date 7/13/09, Week 2 Diary date 7/14/09, Week 3 Diary date 7/15/09).
Staff were able to salvage Week 1 and 2 data by taking the 7 days of data for the week and averaging it to obtain average number of cigarettes smoked and product used. The source was transcribed and stapled to her original daily dairies.
However, starting with Week 17 diary, the information gathered changes, the diary did not request the product usage information or the adverse events. Since the subject used all of the diaries through Week 28 (and then photocopied the Week 28 diary to continue her diary entry), she hand wrote the amount of product used on the bottom of the diaries that did not request this information. Staff has averaged those amounts up to create a weekly diary. While product usage can be collected, the adverse event question is missing from all diaries Week 3 forward.
In discussion with the subject, she informed staff that if she had an AE, she would have written it in the blank space at the bottom of the diary as she did the product usage. On a few diaries, subject wrote "have reported" in which she informed me this meant she did have an AE and that she reported it to the clinic staff. This note is to clarify that if there is not a note, there was not an adverse even experienced at that time.

During the week 6 visit for R5011, the Minnesota Test was not performed in error.

Noted.

Subject(b)/2022 missed Week 20 phone visit on 25 Nov 2009 due to being out of
state for a job. Study coordinator completed Week 20 phone visit on 03 Dec 2009
which leaves the subject out of the +/- 7 day window period.

Noted.

Study staff instructed subject at week 13 phone visit to fast 8 hours for Week 16 visit
on 01 Sep 2009. Subject stated his last meal was on 01 Sep 2009 at 06:00. Study staff in
error drew the subject's blood at 13:02 leaving the subject out of the 8 hour fasting time
by 58 minutes. Progress note has been documented in subject's binder and source
documents.

Subject(b))/3018 completed the week 16 visit 12 days out of window on 25Aug2009.
Subject had to leave town suddenly and was unable to get a flight before the visit was
already out of window. Subject was again counseled on the importance of completing
the visits as scheduled. The subject stated that the trip was unavoidable.

Subject (b) /3018 completed his week 10 visit 15 days out of the scheduled window, and therefore the week 13 visit was missed. The week 13 call was scheduled to be on 15Jul2009, but the subject completed the week 10 visit on 13Jul2009. To allow the subject to get back on schedule with visits, the week 13 call was missed.

Subject (b) /3018 completed his week 10 visit 15 days out of window. Subject was unable to complete the visit due to a scheduling conflict with his work. The week 10 visit was rescheduled several times to accomidate the subject's schedule. Subject was counseled on the importance of completing visits as scheduled.

Subject was out of town and unable to complete the visit as scheduled. Subject completed the week 6 visit on 01Jun2009, 1 day out of window.

Subject (b) /3029 completed the week 8 call 6 days out of window due to a scheduling conflict.

Due to previous scheduling issues with subject 3031/(b) the week 13 call was missed to allow the subject to finish out the rest of her visits for the study within the visit windows allowed per protocol.

Corrective Action: Documentation of deviation serves as the corrective action.

Impact: No impact to study integrity apparent at this time.

Subject 3031(b) completed the week 10 visit 18 days out of window due to previous error. Subject was expected to miss the week 8 call so that the week 10 visit would be within the visit window. This was an oversite by staff.

Subject's week 8 call was completed 13 days out of window. Per previous progress note the week 8 call was to be a missed visit to get the subject back on schedule for the study, however, the staff completing visits at that time did not see the note and completed the week 8 call.

Subject(b)/3031 completed the week 6 visit 13 days out of window due to a scheduling conflict.

Due to schedule conflict subject(b)/3022 completed his week 10 visit 4 days out of window. Subject was counseled on importance of completing visits as scheduled.

Due to a staff scheduling error subject(b)/3022 completed his week 13 visit 7 days out of window. A new calander has been provided to appropriate staff to avoid future errors.

Study Coordinator and Regulatory Specialist need to determine if this is reportable to the IRB.

Per the Protocol; Subjects are allowed to use Study Product from Baseline up to Week 16. Week 16 visit has a (+/- 1 wk) window. However, there is no window for product use.

Subject #1015 discontinued product use on 23-Aug-2009, an additional 6 days more than allowed by the protocol.

During the Early Termination visit subject(b) 3015 failed to complete the FTND due to a staff oversight. The appropriate staff have reviewed the protocol to avoid furture error.

Subject(b)/3015 failed to complete Fagerstrom Test for Nicotine Dependence at the early term visit.

Subject(b) 3001 did not complete the week 13 phone contact within window. Subject completed call 1 day out of window. Subject was counseled regarding importance of visit window to avoid future issues.

Study # 7694-105
RE: Outside of Window Visit (Screenig)
RE: Rand# 4093
The above-referenced subject was 42 days outside of the screening window. The screen visit was on 26 May 2009. The baseline visit was on 08 Jul 2009.

Corrective Action: Documentation of deviation serves as the corrective action.
4118 13 22 Oct 2009 12 Nov 2009 18 days
4119 28 04 Feb 2010 16 Feb 2010 9 days
4100 2 22 Jul 2009 27 Jul 2009 2 days
4099 2 22 Jul 2009 27 Jul 2009 2 days
4099 24 23 Dec 2009 18 Dec 2009 2 days
4099 28 20 Jan 2010 02 Feb 2010 10 days
4133 2 06 Aug 2009 10 Aug 2009 1 day
4109 4 20 Aug 2009 27 Aug 2009 4 days
4103 3 31 Jul 2009 20 Aug 2009 17 days
4103 4 07 Aug 2009 27 Aug 2009 17 days
4102 2 22 Jul 2009 27 Jul 2009 2 days
4102 24 23 Dec 2009 06 Jan 2010 11 days
4107 2 06 Aug 2009 10 Aug 2009 1 day
4093 20 25 Nov 2009 28 Oct 2009 28 days (early)
4093 24 23 Dec 2009 11 Jan 2010 16 days
4108 8 17 Sep 2009 24 Sep 2009 4 days
4101 1 15 Jul 2009 20 Jul 2009 2 days
4101 2 22 Jul 2009 27 Jul 2009 2 days
4094 2 22 Jul 2009 28 Jul 2009 3 days
4094 24 23 Dec 2009 23 Jan 2010 28 days
4092 1 09 Jul 2009 15 Jul 2009 3 days
4092 2 16 Jul 2009 24 Jul 2009 5 days
4092 3 23 Jul 2009 30 Jul 2009 4 days
4092 4 30 Jul 2009 18 Aug 2009 15 days
4092 6 13 Aug 2009 18 Aug 2009 2 days
4092 8 27 Aug 2009 31 Aug 2009 1 day
4092 13 01 Oct 2009 14 Oct 2009 10 days
4092 16 22 Oct 2009 28 Dec 2009 3 days
4092 20 19 Nov 2009 08 Jan 2010 16 days
4092 28 14 Jan 2010 20 Jan 2010 3 days
4097 2 22 Jul 2009 27 Jul 2009 2 days
4097 20 25 Nov 2009 15 Dec 2009 17 days
4097 24 23 Dec 2009 14 Jan 2010 19 days
4096 1 15 Jul 2009 20 Jul 2009 2 days
4096 2 22 Jul 2009 27 Jul 2009 2 days
4096 20 25 Nov 2009 08 Dec 2009 10 days
4096 24 23 Dec 2009 23 Feb 2010 28 days
4096 28 20 Jan 2010 23 Feb 2010 31 days
4033 2 11 May 2009 18 May 2009 4 days
4029 28 05 Nov 2009 12 Nov 2009 4 days
4057 3 02 Jul 2009 06 Jul 2009 1 day
4057 6 23 Jul 2009 31 Jul 2009 5 days
4057 16 01 Oct 2009 09 Oct 2009 5 days
4057 24 26 Nov 2009 21 Jan 2010 53 days
4057 28 24 Dec 2009 21 Jan 2010 25 days
4027 20 02 Sep 2009 23 Sep 2009 18 days
4053 6 14 Jul 2009 30 Jul 2009 13 days
4059 4 09 Jul 2009 11 Aug 2009 30 days
4072 1 03 Jul 2009 07 Jul 2009 1 day
4072 16 16 Oct 2009 22 Oct 2009 3 days
4087 1 09 Jul 2009 13 Jul 2009 1 day
4087 6 13 Aug 2009 24 Aug 2009 8 days
4087 8 27 Aug 2009 17 Sep 2009 18 days
4087 10 10 Sep 2009 23 Sep 2009 10 days
4070 6 07 Aug 2009 12 Aug 2009 2 days
4070 13 25 Sep 2009 01 Oct 2009 4 days
4070 28 08 Jan 2010 18 Feb 2010 38 days
4069 10 01 Sep 2009 09 Sep 2009 5 days
4089 3 23 Jul 2009 27 Jul 2009 1 day
4089 6 13 Aug 2009 10 Sep 2009 25 days
4089 8 27 Aug 2009 21 Sep 2009 22 days
4089 10 10 Sep 2009 24 Sep 2009 11 days
4084 6 12 Aug 2009 17 Aug 2009 2 days
4084 8 26 Aug 2009 11 Sep 2009 13 days
4083 13 28 Sep 2009 05 Oct 2009 4 days
4075 6 10 Aug 2009 14 Aug 2009 1 day
4088 3 23 Jul 2009 27 Jul 2009 1 day
4076 6 10 Aug 2009 18 Aug 2009 5 days
4079 16 19 Oct 2009 04 Nov 2009 13 days
4079 24 14 Dec 2009 18 Nov 2009 23 days (early)
4077 10 07 Sep 2009 31 Aug 2009 5 days
4055 20 22 Oct 2009 26 Oct 2009 1 day
4068 8 14 Aug 2009 20 Aug 2009 3 days
4068 16 09 Oct 2009 16 Oct 2009 4 days
4068 28 04 Jan 2010 08 Jan 2010 1 day
The following subjects were early terminations; therefore, the visits are not outside of the window:
- Rand#4014
- Rand#4098
An Enote was generated for the above-referenced subjects (#4014 and #4098) as documentation that the visits were outside of the window; however, this is an updated Enote to clarify that early termination subjects visits are not considered to be outside of the window.

Corrective action referenced in previous comment.

This NTF is to clarify how subject #1010 dated their weekly diaries for weeks 17 thru week 28. When the subject reported for their Final Visit/Week 28, on 06Oct2009, they had all data recorded for each week, but did not have the "Date of Completion" line filled out on their weekly diaries. The subject was confused as to which date they were to record, (the beginning of the week or the end of the week).

During the clinic visit on 06/Oct/2009, Subject #1010, made a late entry and entered the dates from their study calendar in the "Date of Completion" line, for each weekly diary , for Weeks 17 thru Week 28. For each late entry the subject included their initials and the date of entry which was 10-6-09.

This note to file serves to document the protocol deviations for subject #5025.

-There is no documentation regarding the week 13 phone call being completed.

-When the subject returned for the week 28 visit, he returned blank diaries for weeks 19-27. The subject reported that he is still smoking as of his Week 28 visit.

Corrective Action: Documentation of deviation serves as the corrective action.

RE: Information Session at the Screen Visit
Randomization # - 4065

The information session at the screen visit was not signed by staff to verify completion of this procedure. However, the purpose and nature of the study was explained to the subject and the staff did sign-off on this procedure. And, the clean-air booklet was dispensed to the subject and the staff did sign-off on this procedure.

Impact: No impact to study integrity apparent at this time.

No additional comments.

Per the protocol subjects that have received study product will come to the clinic for evaluation on Weeks 6, 10, 16 and 28.

The following subjects were unavailable for clinic visits and subsequently were out-of-window one or more days, for their scheduled clinic visits; (b) #1012, WK 10-1 day out of window & WK 16-11 days out of window, (b) #1018, WK 6-1 day out of window, (b) #1019, WK 10-3 days out of window, & WK 16-1 day out of window, (b) #1022, WK 28-1 day out of window, (b) #1028, WK 10-7 days out of window & WK 28-8 days out of window, (b) #1031, WK 6-1 day out of window & WK 10-8 days out of window, (b) #1037, WK 6-7 days out of window.

No corrective action indicated.

Per the Protocol, telephone contacts will occur at weeks 1 thru 4, 8 & 13, to review the subject's smoking status, use of study products, brief behavioral counseling and assess any Adverse Events. Telephone contacts will also be made at weeks 20 & 24 to assess any Adverse Events, review the subject's smoking status and to provide brief behavioral counseling.

The following subjects were unavailable for contact and subsequently were out-of-window one or more days, for their Follow-up telephone calls; (b) #1011 WK 8 was 1 day out of window, (b) #1012, WK 8 was 3 days out of window & WK 13 was 3 days out of window, (b) #1020, WK 8 was 1 day out of window, (b) #1021 WK 2 was 1 day out of window, (b) #1030, WK 3 was 1 day out of window, & WK 8 was 4 days out of window, (b) #1031, WK 8 was 1 day out of window, (b) #1032, WK 1 was 2 days out of window, (b) #1036, WK 8 was 1 day out of window & WK 13 was 2 days out of window.

Randomization number 4018 completed the week 13 visit outside of the window visit - +/- 3 days. The expected date of the visit was 12 Jun 2009 and the visit occurred on 17 Jun 2009 - 2 days outside of the window visit.

Randomization number 4017 completed the week 13 visit outside of the window visit - +/- 3 days. The expected date of the visit was 12 Jun 2009 and the visit occurred on 17 Jun 2009 - 2 days outside of the window visit.

Randomization number 4016 completed the week 13 visit outside of the window visit - +/- 3 days. The expected date of the visit was 12 Jun 2009 and the visit occurred on 17 Jun 2009 - 2 days outside of the window visit.

Impact: as above

Corrective Action: please verify dates

expected date does not correlate

Randomization number 4014 completed the week 28 visit outside of the window visit - +/- 3 days. The expected date of the visit was 23 Sep 2009 and the visit occurred on 06 Jul 2009 - 10 days outside of the window visit.

Randomization number 4007 completed the week 28 visit outside of the window visit - +/- 3 days. The expected date of the visit was 23 Sep 2009 and the visit occurred on 29 Sep 2009 - 3 days outside of the window visit.

Randomization number 4011 completed the week 24 visit outside of the window visit - +/- 3 days. The expected date of the visit was 26 Aug 2009 and the visit occurred on 02 Sep 2009 - 4 days outside of the window visit.

Impact: significant delay in visit noted

Randomization number 4011 completed the week 16 visit outside of the window visit - +/- 3 days. The expected date of the visit was 01 Jul 2009 and the visit occurred on 29 Jul 2009 - 25 days outside of the window visit.

Randomization number 4010 completed the week 16 visit outside of the window visit - +/3 days. The expected date of the visit was 01 Jul 2009 and the visit occurred on 07 Jul 2009 - 3 days outside of the window visit.

Randomization number 4007 completed the week 16 visit outside of the window visit - +/- 3 days. The expected date of the visit was 01 Jul 2009 and the visit occurred on 07 Jul 2009 - 4 days outside of the window visit.

Randomization number 4014 completed the week 13 visit outside of the window visit -(+/- 3 days). The expected date of the visit was 10 Jun 2009 and the actual date of the visit was 15 Jun 2009 - 2 days outside of the window visit.

Randomization number 4007 completed the week 13 visit outside of the window visit - (+/- 3 days). The expected date of the visit was 10 Jun 2009 and the actual date of the visit occurred on 18 Jun 2009 - 5 days outside of the window visit.

Corrective Action: Documentation of deviation serves as the corrective action.

Randomization number 4007 completed the week 10 visit outside of the window visit (+/-) 3 days. The expected date of the visit was 20 May 2009 and the visit occurred on 26 May 2009 - 3 days outside of the window visit.

Impact: No impact to study integrity apparent at this time.

In error, no week 1 phone call was completed for the above referenced subject. In reviewing the call logs, no documentation is available for any attempts. The site implemented a new call log to track attempts and contacts. The study team actively reviews these logs weekly.

Subject R5009 returned to the clinic to perform his Early Termination Visit. In error, the team did not collect his Fagerstrom and Minnesota questionnaire at this time. This memo is to document the deviation.

In error, no week 1 phone call was completed for the above referenced subjects. In reviewing the call logs, no documentation is available for any attempts. The site implemented a new call log to track attempts and contacts. The study team actively reviews these logs weekly.

Corrective Action: As written.

Noted.

Subject(b) /2022 missed her scheduled Week 20 phone visit on 20 Nov 2009. Subject contacted site to complete phone visit on 03 Dec 2009 leaving her out of the +/- 7 day window period.

Corrective Action: As written.

Noted.

Subject(b) /2022 missed her Week 24 visit that was scheduled on 18 Dec 2009. Subject contacted site on 30 Dec 2009 to complete the phone visit therefore subject is out of the +/- 7 day window period.

See attached source. I could find no documentation of review on 10 Nov. Review was signed off on 16 Nov 2009.

At Week 10 visit on 18 Sep 2009 for subject(b) /2022 the systolic blood pressure was out of range. Repeat was not performed due to staff error. Out of range vital signs were not assessed by the investigator(s) until 10 Nov 2009. Please refer to page 2 of 4 of Week 10 visit source documents.

No corrective action indicated.

This note to file is to clarify that the subject did not complete a weekly diary for Week 6 and misdated the following diaries for Week 7 thru Week 9.

The subject entered their Week 6 diary information, on their Week 7 diary, dated 04/26/09. They entered their Week 7 diary information on their Week 8 diary, dated 03/May/09 Also, they entered their Week 8 diary information, on their Week 9 diary dated 10/May/09.

This was confirmed on 07/Oct/2009 with the monitor and the subject's entries of "dates of completion".

Error reviewed with responsible staff member. Reminded to review and adhere to protocol requirements when performing procedures.

Re: Subject #1002 ((b) Subject's weight was not taken at Week 10 visit, in error. Per the Protocol, subject's body weight is to be taken whenever vital signs are taken.

Error reviewed with responsible staff member. Reminded to adhere to timing in protocol when performing procedures.

Subject #1020(b) was only seated (1) minute prior to vitals being taken at week 6 visit. Per the protocol, subjects must be seated for (5) minutes prior to vitals.

Reviewed 20Mar2009 Y. Taylor - No corrective action recommended.

Subject #01002(b) was only seated (1) minute prior to screening vitals. Per the protocol, subjects must be seated for (5) minutes prior to vitals.

Corrective Action: Documentation of deviation serves as the corrective action.

Due to subject's week 6 visit being out of window subject 3031(b) did not complete diary pages at week 6 or 7.

Impact: No impact to study integrity apparent at this time.

Due to staff error a return questionnaire was not completed for subject 3013(b) during the week 16 visits. Staff has been retrained to avoid future error.

Subject 3022(b) failed to complete the diary entries for weeks 10-16. Subject completed the entries during the week 16 visit and was re-educated on diary completion to avoid furture issue.

RE:3003(b)

Due to staff error during the week 6 visit, the number of cigarettes smoked during the past week was not documented.

Subject #5010 returned to the clinic on 08Sep2009 to complete early termination events. Due to staff error, the Serum, EDTA, and Sodium Citrate Plasma were all placed in the freezer greater than 1 hour after collection. This deviation has been notated on the source.

Continuing training on blood processing will occur for all staff members.

Subject #R5023 returned on week 9 to complete her week 6 visit due to being unavailable. The staff member performing the event did not get the PD biomarker in error. Upon return to the clinic the following week, this marker was drawn (during week 10 visit).

Corrective Action: Documentation of deviation serves as the corrective action.

Impact: No impact to study integrity apparent at this time.

Subject # 4093 was randomized 42 days outside of the window visit. A waiver was sent to Dr. Dixon for approval after the randomization occurred.

RE: Subject 4053

The above-referenced subject used Chantix and did not report this to the staff until the early termination visit. This is a protocol violation and there is no impact on the study.

Subject #5027 did not complete the Week 1 Phone call per protocol and there is no source documentation regarding attempts to reach them in error.

Subject lost diary for weeks 10-16. This diary was never returned to the site. Diary pages will be marked blank.

During the week 6 visit for R5011, the Minnesota Test was not performed in error.

Subject was out of town and unable to complete the visit as scheduled. Subject completed the week 6 visit on 01Jun2009, 1 day out of window.

Subject (b) /3029 completed the week 8 call 6 days out of window due to a scheduling conflict.

Due to previous scheduling issues with subject 3031/(b) the week 13 call was missed to allow the subject to finish out the rest of her visits for the study within the visit windows allowed per protocol.

Corrective Action: Documentation of deviation serves as the corrective action.

Impact: No impact to study integrity apparent at this time.

Subject(b)/3031 completed the week 6 visit 13 days out of window due to a scheduling conflict.

Due to schedule conflict subject(b)/3022 completed his week 10 visit 4 days out of window. Subject was counseled on importance of completing visits as scheduled.

Due to a staff scheduling error subject(b)/3022 completed his week 13 visit 7 days out of window. A new calander has been provided to appropriate staff to avoid future errors.

Study Coordinator and Regulatory Specialist need to determine if this is reportable to the IRB.

During the Early Termination visit subject(b) 3015 failed to complete the FTND due to a staff oversight. The appropriate staff have reviewed the protocol to avoid furture error.

Subject(b)/3015 failed to complete Fagerstrom Test for Nicotine Dependence at the early term visit.

Subject(b) 3001 did not complete the week 13 phone contact within window. Subject completed call 1 day out of window. Subject was counseled regarding importance of visit window to avoid future issues.

Corrective action referenced in previous comment.

Corrective Action: Documentation of deviation serves as the corrective action.

Impact: No impact to study integrity apparent at this time.

Randomization number 4011 completed the week 24 visit outside of the window visit - +/- 3 days. The expected date of the visit was 26 Aug 2009 and the visit occurred on 02 Sep 2009 - 4 days outside of the window visit.

Impact: significant delay in visit noted

Randomization number 4010 completed the week 16 visit outside of the window visit - +/3 days. The expected date of the visit was 01 Jul 2009 and the visit occurred on 07 Jul 2009 - 3 days outside of the window visit.

Randomization number 4007 completed the week 16 visit outside of the window visit - +/- 3 days. The expected date of the visit was 01 Jul 2009 and the visit occurred on 07 Jul 2009 - 4 days outside of the window visit.

Randomization number 4007 completed the week 10 visit outside of the window visit (+/-) 3 days. The expected date of the visit was 20 May 2009 and the visit occurred on 26 May 2009 - 3 days outside of the window visit.

Corrective Action: Documentation of deviation serves as the corrective action.

Impact: No impact to study integrity apparent at this time.

Subject R5009 returned to the clinic to perform his Early Termination Visit. In error, the team did not collect his Fagerstrom and Minnesota questionnaire at this time. This memo is to document the deviation.

Subject(b) /2022 missed her scheduled Week 20 phone visit on 20 Nov 2009. Subject contacted site to complete phone visit on 03 Dec 2009 leaving her out of the +/- 7 day window period.

Subject(b) /2022 missed her Week 24 visit that was scheduled on 18 Dec 2009. Subject contacted site on 30 Dec 2009 to complete the phone visit therefore subject is out of the +/- 7 day window period.

See attached source. I could find no documentation of review on 10 Nov. Review was signed off on 16 Nov 2009.

Error reviewed with responsible staff member. Reminded to review and adhere to protocol requirements when performing procedures.

Re: Subject #1002 ((b) Subject's weight was not taken at Week 10 visit, in error. Per the Protocol, subject's body weight is to be taken whenever vital signs are taken.

Error reviewed with responsible staff member. Reminded to adhere to timing in protocol when performing procedures.

Subject #1020(b) was only seated (1) minute prior to vitals being taken at week 6 visit. Per the protocol, subjects must be seated for (5) minutes prior to vitals.

Reviewed 20Mar2009 Y. Taylor - No corrective action recommended.

Subject #01002(b) was only seated (1) minute prior to screening vitals. Per the protocol, subjects must be seated for (5) minutes prior to vitals.

Due to subject's week 6 visit being out of window subject 3031(b) did not complete diary pages at week 6 or 7.

Corrective Action: Documentation of deviation serves as the corrective action.

Due to staff error a return questionnaire was not completed for subject 3013(b) during the week 16 visits. Staff has been retrained to avoid future error.

Impact: No impact to study integrity apparent at this time.

Subject 3022(b) failed to complete the diary entries for weeks 10-16. Subject completed the entries during the week 16 visit and was re-educated on diary completion to avoid furture issue.

RE:3003(b)

Due to staff error during the week 6 visit, the number of cigarettes smoked during the past week was not documented.


Subject # 4093 was randomized 42 days outside of the window visit. A waiver was sent to Dr. Dixon for approval after the randomization occurred.

Noted.

On 09 APR 2009, it was discovered that 11 study participants (001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011) had been consented with an outdated ICF (version “12/30/08”). The following ICF versions available are:

Version dated 11/18/08 – IRB approved 18 NOV 2008
Version dated 12/30/08 – IRB approved 30 DEC 2008
Version dated 1/20/09 – IRB approved 20 JAN 2009
Version dated 3/16/09 – IRB approved 16 MAR 2009
Version dated 3/16/09 (corrected document) – IRB approved 13 APR 2009

At the time of screening, which occurred between 05 MAR 2009 and 24 MAR 2009, 11 participants had consented to the study by signing an ICF version dated and approved on 30 DEC 2008. At the time of the screening visits, the 11 participants should have been consented with the available ICF version dated and approved on 20 JAN 2009.

Of the 11 participants, 6 had enrolled into the study as allowed per protocol eligibly requirements. The baseline visits (test material dispensing visit) had occurred between the dates of 13 MAR 2009 and 26 MAR 2009. Three of the six enrolled subjects with screening numbers 001, 002, and 003 completed their baseline visit prior to 16 Mar 2009. These subjects were not re-consented with the available 20 JAN 2009 dated ICF upon their baseline visit. The remaining 3 enrolled subjects with screening numbers 005, 008, and 009 completed their baseline visits between the dates of 23 MAR 2009 and 26 Mar 2009. These subjects with screening numbers 005, 008, and 009 were not re-consented upon their baseline visits with the latest available ICF version dated and approved on 16 MAR 2009.

The ICF dated “1/20/09” differs from the ICF dated “12/30/08” in that additional wording was added to include a lab test (FSH) for women between the ages of 45 and 55 to confirm their post-menopausal status. The difference between the ICFs dated “1/20/09” and “3/16/09”, is additional added wording which clarifies "Nicoderm" and Nicorette" as a "Nicotine Replacement Therapy". The “3/16/09” version of the ICF was re-approved by the IRB on 13 APR 2009 in regards to minor typographical errors.

Of the 11 participants, subject with screening number 005 had the FSH test added to their lab panel as per a requirement of the protocol. For clarification, the FSH test was conducted without the subject's consent as only the ICF dated 12/30/08 was signed by the participant upon her screening visit.

With the exception of subject 001 who withdrew consent on 13 APR 2009, the following 5 enrolled subjects were re-consented with the latest (13 APR 2009) IRB approved version of the ICF at their week 6 in-clinic visit (baseline visit):
002 29-Apr-2009
003 28-Apr-2009
005 04-May-2009
008 05-May-2009
009 07-May-2009
Attached to this eNote is a copy of a submitted “Potential Unanticipated Problem or Serious or Continuing Non-Compliance” Investigational Review Board (IRB) form which was acknowledged by the IRB on 21 APR 2009.

RE: Subject 4053

The above-referenced subject used Chantix and did not report this to the staff until the early termination visit. This is a protocol violation and there is no impact on the study.

Subject #5027 did not complete the Week 1 Phone call per protocol and there is no source documentation regarding attempts to reach them in error.

Noted.

Acknowledged

Subject lost diary for weeks 10-16. This diary was never returned to the site. Diary pages will be marked blank.

Subject R5013 inadvertently completed her diaries from Week 1 - Week 6 on a daily basis (e.g. Week 1 Diary date 7/13/09, Week 2 Diary date 7/14/09, Week 3 Diary date 7/15/09).
Staff were able to salvage Week 1 and 2 data by taking the 7 days of data for the week and averaging it to obtain average number of cigarettes smoked and product used. The source was transcribed and stapled to her original daily dairies.
However, starting with Week 17 diary, the information gathered changes, the diary did not request the product usage information or the adverse events. Since the subject used all of the diaries through Week 28 (and then photocopied the Week 28 diary to continue her diary entry), she hand wrote the amount of product used on the bottom of the diaries that did not request this information. Staff has averaged those amounts up to create a weekly diary. While product usage can be collected, the adverse event question is missing from all diaries Week 3 forward.
In discussion with the subject, she informed staff that if she had an AE, she would have written it in the blank space at the bottom of the diary as she did the product usage. On a few diaries, subject wrote "have reported" in which she informed me this meant she did have an AE and that she reported it to the clinic staff. This note is to clarify that if there is not a note, there was not an adverse even experienced at that time.

During the week 6 visit for R5011, the Minnesota Test was not performed in error.

Noted.

Subject(b)/2022 missed Week 20 phone visit on 25 Nov 2009 due to being out of
state for a job. Study coordinator completed Week 20 phone visit on 03 Dec 2009
which leaves the subject out of the +/- 7 day window period.

Noted.

Study staff instructed subject at week 13 phone visit to fast 8 hours for Week 16 visit
on 01 Sep 2009. Subject stated his last meal was on 01 Sep 2009 at 06:00. Study staff in
error drew the subject's blood at 13:02 leaving the subject out of the 8 hour fasting time
by 58 minutes. Progress note has been documented in subject's binder and source
documents.

Corrective Action: Documentation of deviation serves as the corrective action.

Subject(b))/3018 completed the week 16 visit 12 days out of window on 25Aug2009.
Subject had to leave town suddenly and was unable to get a flight before the visit was
already out of window. Subject was again counseled on the importance of completing
the visits as scheduled. The subject stated that the trip was unavoidable.

Impact: No impact to study integrity apparent at this time.

Subject (b) /3018 completed his week 10 visit 15 days out of the scheduled window, and therefore the week 13 visit was missed. The week 13 call was scheduled to be on 15Jul2009, but the subject completed the week 10 visit on 13Jul2009. To allow the subject to get back on schedule with visits, the week 13 call was missed.

Subject (b) /3018 completed his week 10 visit 15 days out of window. Subject was unable to complete the visit due to a scheduling conflict with his work. The week 10 visit was rescheduled several times to accomidate the subject's schedule. Subject was counseled on the importance of completing visits as scheduled.

Subject was out of town and unable to complete the visit as scheduled. Subject completed the week 6 visit on 01Jun2009, 1 day out of window.

Subject (b) /3029 completed the week 8 call 6 days out of window due to a scheduling conflict.

Due to previous scheduling issues with subject 3031/(b) the week 13 call was missed to allow the subject to finish out the rest of her visits for the study within the visit windows allowed per protocol.

Subject 3031(b) completed the week 10 visit 18 days out of window due to previous error. Subject was expected to miss the week 8 call so that the week 10 visit would be within the visit window. This was an oversite by staff.

Subject's week 8 call was completed 13 days out of window. Per previous progress note the week 8 call was to be a missed visit to get the subject back on schedule for the study, however, the staff completing visits at that time did not see the note and completed the week 8 call.

Subject(b)/3031 completed the week 6 visit 13 days out of window due to a scheduling conflict.

Due to schedule conflict subject(b)/3022 completed his week 10 visit 4 days out of window. Subject was counseled on importance of completing visits as scheduled.

Due to a staff scheduling error subject(b)/3022 completed his week 13 visit 7 days out of window. A new calander has been provided to appropriate staff to avoid future errors.

Study Coordinator and Regulatory Specialist need to determine if this is reportable to the IRB.

Per the Protocol; Subjects are allowed to use Study Product from Baseline up to Week 16. Week 16 visit has a (+/- 1 wk) window. However, there is no window for product use.

Subject #1015 discontinued product use on 23-Aug-2009, an additional 6 days more than allowed by the protocol.

During the Early Termination visit subject(b) 3015 failed to complete the FTND due to a staff oversight. The appropriate staff have reviewed the protocol to avoid furture error.

Subject(b)/3015 failed to complete Fagerstrom Test for Nicotine Dependence at the early term visit.

Corrective Action: Documentation of deviation serves as the corrective action.

Subject(b) 3001 did not complete the week 13 phone contact within window. Subject completed call 1 day out of window. Subject was counseled regarding importance of visit window to avoid future issues.

Impact: No impact to study integrity apparent at this time.

Study # 7694-105
RE: Outside of Window Visit (Screenig)
RE: Rand# 4093
The above-referenced subject was 42 days outside of the screening window. The screen visit was on 26 May 2009. The baseline visit was on 08 Jul 2009.

Corrective Action: Documentation of deviation serves as the corrective action.
4118 13 22 Oct 2009 12 Nov 2009 18 days
4119 28 04 Feb 2010 16 Feb 2010 9 days
4100 2 22 Jul 2009 27 Jul 2009 2 days
4099 2 22 Jul 2009 27 Jul 2009 2 days
4099 24 23 Dec 2009 18 Dec 2009 2 days
4099 28 20 Jan 2010 02 Feb 2010 10 days
4133 2 06 Aug 2009 10 Aug 2009 1 day
4109 4 20 Aug 2009 27 Aug 2009 4 days
4103 3 31 Jul 2009 20 Aug 2009 17 days
4103 4 07 Aug 2009 27 Aug 2009 17 days
4102 2 22 Jul 2009 27 Jul 2009 2 days
4102 24 23 Dec 2009 06 Jan 2010 11 days
4107 2 06 Aug 2009 10 Aug 2009 1 day
4093 20 25 Nov 2009 28 Oct 2009 28 days (early)
4093 24 23 Dec 2009 11 Jan 2010 16 days
4108 8 17 Sep 2009 24 Sep 2009 4 days
4101 1 15 Jul 2009 20 Jul 2009 2 days
4101 2 22 Jul 2009 27 Jul 2009 2 days
4094 2 22 Jul 2009 28 Jul 2009 3 days
4094 24 23 Dec 2009 23 Jan 2010 28 days
4092 1 09 Jul 2009 15 Jul 2009 3 days
4092 2 16 Jul 2009 24 Jul 2009 5 days
4092 3 23 Jul 2009 30 Jul 2009 4 days
4092 4 30 Jul 2009 18 Aug 2009 15 days
4092 6 13 Aug 2009 18 Aug 2009 2 days
4092 8 27 Aug 2009 31 Aug 2009 1 day
4092 13 01 Oct 2009 14 Oct 2009 10 days
4092 16 22 Oct 2009 28 Dec 2009 3 days
4092 20 19 Nov 2009 08 Jan 2010 16 days
4092 28 14 Jan 2010 20 Jan 2010 3 days
4097 2 22 Jul 2009 27 Jul 2009 2 days
4097 20 25 Nov 2009 15 Dec 2009 17 days
4097 24 23 Dec 2009 14 Jan 2010 19 days
4096 1 15 Jul 2009 20 Jul 2009 2 days
4096 2 22 Jul 2009 27 Jul 2009 2 days
4096 20 25 Nov 2009 08 Dec 2009 10 days
4096 24 23 Dec 2009 23 Feb 2010 28 days
4096 28 20 Jan 2010 23 Feb 2010 31 days
4033 2 11 May 2009 18 May 2009 4 days
4029 28 05 Nov 2009 12 Nov 2009 4 days
4057 3 02 Jul 2009 06 Jul 2009 1 day
4057 6 23 Jul 2009 31 Jul 2009 5 days
4057 16 01 Oct 2009 09 Oct 2009 5 days
4057 24 26 Nov 2009 21 Jan 2010 53 days
4057 28 24 Dec 2009 21 Jan 2010 25 days
4027 20 02 Sep 2009 23 Sep 2009 18 days
4053 6 14 Jul 2009 30 Jul 2009 13 days
4059 4 09 Jul 2009 11 Aug 2009 30 days
4072 1 03 Jul 2009 07 Jul 2009 1 day
4072 16 16 Oct 2009 22 Oct 2009 3 days
4087 1 09 Jul 2009 13 Jul 2009 1 day
4087 6 13 Aug 2009 24 Aug 2009 8 days
4087 8 27 Aug 2009 17 Sep 2009 18 days
4087 10 10 Sep 2009 23 Sep 2009 10 days
4070 6 07 Aug 2009 12 Aug 2009 2 days
4070 13 25 Sep 2009 01 Oct 2009 4 days
4070 28 08 Jan 2010 18 Feb 2010 38 days
4069 10 01 Sep 2009 09 Sep 2009 5 days
4089 3 23 Jul 2009 27 Jul 2009 1 day
4089 6 13 Aug 2009 10 Sep 2009 25 days
4089 8 27 Aug 2009 21 Sep 2009 22 days
4089 10 10 Sep 2009 24 Sep 2009 11 days
4084 6 12 Aug 2009 17 Aug 2009 2 days
4084 8 26 Aug 2009 11 Sep 2009 13 days
4083 13 28 Sep 2009 05 Oct 2009 4 days
4075 6 10 Aug 2009 14 Aug 2009 1 day
4088 3 23 Jul 2009 27 Jul 2009 1 day
4076 6 10 Aug 2009 18 Aug 2009 5 days
4079 16 19 Oct 2009 04 Nov 2009 13 days
4079 24 14 Dec 2009 18 Nov 2009 23 days (early)
4077 10 07 Sep 2009 31 Aug 2009 5 days
4055 20 22 Oct 2009 26 Oct 2009 1 day
4068 8 14 Aug 2009 20 Aug 2009 3 days
4068 16 09 Oct 2009 16 Oct 2009 4 days
4068 28 04 Jan 2010 08 Jan 2010 1 day
The following subjects were early terminations; therefore, the visits are not outside of the window:
- Rand#4014
- Rand#4098
An Enote was generated for the above-referenced subjects (#4014 and #4098) as documentation that the visits were outside of the window; however, this is an updated Enote to clarify that early termination subjects visits are not considered to be outside of the window.

Corrective action referenced in previous comment.

This NTF is to clarify how subject #1010 dated their weekly diaries for weeks 17 thru week 28. When the subject reported for their Final Visit/Week 28, on 06Oct2009, they had all data recorded for each week, but did not have the "Date of Completion" line filled out on their weekly diaries. The subject was confused as to which date they were to record, (the beginning of the week or the end of the week).

During the clinic visit on 06/Oct/2009, Subject #1010, made a late entry and entered the dates from their study calendar in the "Date of Completion" line, for each weekly diary , for Weeks 17 thru Week 28. For each late entry the subject included their initials and the date of entry which was 10-6-09.

This note to file serves to document the protocol deviations for subject #5025.

-There is no documentation regarding the week 13 phone call being completed.

-When the subject returned for the week 28 visit, he returned blank diaries for weeks 19-27. The subject reported that he is still smoking as of his Week 28 visit.

RE: Information Session at the Screen Visit
Randomization # - 4065

The information session at the screen visit was not signed by staff to verify completion of this procedure. However, the purpose and nature of the study was explained to the subject and the staff did sign-off on this procedure. And, the clean-air booklet was dispensed to the subject and the staff did sign-off on this procedure.

No additional comments.

Per the protocol subjects that have received study product will come to the clinic for evaluation on Weeks 6, 10, 16 and 28.

The following subjects were unavailable for clinic visits and subsequently were out-of-window one or more days, for their scheduled clinic visits; (b) #1012, WK 10-1 day out of window & WK 16-11 days out of window, (b) #1018, WK 6-1 day out of window, (b) #1019, WK 10-3 days out of window, & WK 16-1 day out of window, (b) #1022, WK 28-1 day out of window, (b) #1028, WK 10-7 days out of window & WK 28-8 days out of window, (b) #1031, WK 6-1 day out of window & WK 10-8 days out of window, (b) #1037, WK 6-7 days out of window.

No corrective action indicated.

Per the Protocol, telephone contacts will occur at weeks 1 thru 4, 8 & 13, to review the subject's smoking status, use of study products, brief behavioral counseling and assess any Adverse Events. Telephone contacts will also be made at weeks 20 & 24 to assess any Adverse Events, review the subject's smoking status and to provide brief behavioral counseling.

The following subjects were unavailable for contact and subsequently were out-of-window one or more days, for their Follow-up telephone calls; (b) #1011 WK 8 was 1 day out of window, (b) #1012, WK 8 was 3 days out of window & WK 13 was 3 days out of window, (b) #1020, WK 8 was 1 day out of window, (b) #1021 WK 2 was 1 day out of window, (b) #1030, WK 3 was 1 day out of window, & WK 8 was 4 days out of window, (b) #1031, WK 8 was 1 day out of window, (b) #1032, WK 1 was 2 days out of window, (b) #1036, WK 8 was 1 day out of window & WK 13 was 2 days out of window.

Randomization number 4018 completed the week 13 visit outside of the window visit - +/- 3 days. The expected date of the visit was 12 Jun 2009 and the visit occurred on 17 Jun 2009 - 2 days outside of the window visit.

Randomization number 4017 completed the week 13 visit outside of the window visit - +/- 3 days. The expected date of the visit was 12 Jun 2009 and the visit occurred on 17 Jun 2009 - 2 days outside of the window visit.

Randomization number 4016 completed the week 13 visit outside of the window visit - +/- 3 days. The expected date of the visit was 12 Jun 2009 and the visit occurred on 17 Jun 2009 - 2 days outside of the window visit.

Impact: as above

Corrective Action: please verify dates

expected date does not correlate

Randomization number 4014 completed the week 28 visit outside of the window visit - +/- 3 days. The expected date of the visit was 23 Sep 2009 and the visit occurred on 06 Jul 2009 - 10 days outside of the window visit.

Randomization number 4007 completed the week 28 visit outside of the window visit - +/- 3 days. The expected date of the visit was 23 Sep 2009 and the visit occurred on 29 Sep 2009 - 3 days outside of the window visit.

Randomization number 4011 completed the week 24 visit outside of the window visit - +/- 3 days. The expected date of the visit was 26 Aug 2009 and the visit occurred on 02 Sep 2009 - 4 days outside of the window visit.

Impact: significant delay in visit noted

Corrective Action: Documentation of deviation serves as the corrective action.

Randomization number 4011 completed the week 16 visit outside of the window visit - +/- 3 days. The expected date of the visit was 01 Jul 2009 and the visit occurred on 29 Jul 2009 - 25 days outside of the window visit.

Impact: No impact to study integrity apparent at this time.

Randomization number 4010 completed the week 16 visit outside of the window visit - +/3 days. The expected date of the visit was 01 Jul 2009 and the visit occurred on 07 Jul 2009 - 3 days outside of the window visit.

Randomization number 4007 completed the week 16 visit outside of the window visit - +/- 3 days. The expected date of the visit was 01 Jul 2009 and the visit occurred on 07 Jul 2009 - 4 days outside of the window visit.

Randomization number 4014 completed the week 13 visit outside of the window visit -(+/- 3 days). The expected date of the visit was 10 Jun 2009 and the actual date of the visit was 15 Jun 2009 - 2 days outside of the window visit.

Randomization number 4007 completed the week 13 visit outside of the window visit - (+/- 3 days). The expected date of the visit was 10 Jun 2009 and the actual date of the visit occurred on 18 Jun 2009 - 5 days outside of the window visit.

Randomization number 4007 completed the week 10 visit outside of the window visit (+/-) 3 days. The expected date of the visit was 20 May 2009 and the visit occurred on 26 May 2009 - 3 days outside of the window visit.

In error, no week 1 phone call was completed for the above referenced subject. In reviewing the call logs, no documentation is available for any attempts. The site implemented a new call log to track attempts and contacts. The study team actively reviews these logs weekly.

Subject R5009 returned to the clinic to perform his Early Termination Visit. In error, the team did not collect his Fagerstrom and Minnesota questionnaire at this time. This memo is to document the deviation.

In error, no week 1 phone call was completed for the above referenced subjects. In reviewing the call logs, no documentation is available for any attempts. The site implemented a new call log to track attempts and contacts. The study team actively reviews these logs weekly.

Corrective Action: As written.

Noted.

Subject(b) /2022 missed her scheduled Week 20 phone visit on 20 Nov 2009. Subject contacted site to complete phone visit on 03 Dec 2009 leaving her out of the +/- 7 day window period.

Corrective Action: As written.

Noted.

Subject(b) /2022 missed her Week 24 visit that was scheduled on 18 Dec 2009. Subject contacted site on 30 Dec 2009 to complete the phone visit therefore subject is out of the +/- 7 day window period.

See attached source. I could find no documentation of review on 10 Nov. Review was signed off on 16 Nov 2009.

At Week 10 visit on 18 Sep 2009 for subject(b) /2022 the systolic blood pressure was out of range. Repeat was not performed due to staff error. Out of range vital signs were not assessed by the investigator(s) until 10 Nov 2009. Please refer to page 2 of 4 of Week 10 visit source documents.

No corrective action indicated.

This note to file is to clarify that the subject did not complete a weekly diary for Week 6 and misdated the following diaries for Week 7 thru Week 9.

The subject entered their Week 6 diary information, on their Week 7 diary, dated 04/26/09. They entered their Week 7 diary information on their Week 8 diary, dated 03/May/09 Also, they entered their Week 8 diary information, on their Week 9 diary dated 10/May/09.

This was confirmed on 07/Oct/2009 with the monitor and the subject's entries of "dates of completion".

Error reviewed with responsible staff member. Reminded to review and adhere to protocol requirements when performing procedures.

Re: Subject #1002 ((b) Subject's weight was not taken at Week 10 visit, in error. Per the Protocol, subject's body weight is to be taken whenever vital signs are taken.

Corrective Action: Documentation of deviation serves as the corrective action.

Error reviewed with responsible staff member. Reminded to adhere to timing in protocol when performing procedures.

Subject #1020(b) was only seated (1) minute prior to vitals being taken at week 6 visit. Per the protocol, subjects must be seated for (5) minutes prior to vitals.

Impact: No impact to study integrity apparent at this time.

Reviewed 20Mar2009 Y. Taylor - No corrective action recommended.

Subject #01002(b) was only seated (1) minute prior to screening vitals. Per the protocol, subjects must be seated for (5) minutes prior to vitals.

Due to subject's week 6 visit being out of window subject 3031(b) did not complete diary pages at week 6 or 7.

Due to staff error a return questionnaire was not completed for subject 3013(b) during the week 16 visits. Staff has been retrained to avoid future error.

Subject 3022(b) failed to complete the diary entries for weeks 10-16. Subject completed the entries during the week 16 visit and was re-educated on diary completion to avoid furture issue.

RE:3003(b)

Due to staff error during the week 6 visit, the number of cigarettes smoked during the past week was not documented.

Subject #5010 returned to the clinic on 08Sep2009 to complete early termination events. Due to staff error, the Serum, EDTA, and Sodium Citrate Plasma were all placed in the freezer greater than 1 hour after collection. This deviation has been notated on the source.

Continuing training on blood processing will occur for all staff members.

Subject #R5023 returned on week 9 to complete her week 6 visit due to being unavailable. The staff member performing the event did not get the PD biomarker in error. Upon return to the clinic the following week, this marker was drawn (during week 10 visit).

Subject # 4093 was randomized 42 days outside of the window visit. A waiver was sent to Dr. Dixon for approval after the randomization occurred.

RE: Subject 4053

The above-referenced subject used Chantix and did not report this to the staff until the early termination visit. This is a protocol violation and there is no impact on the study.

Subject #5027 did not complete the Week 1 Phone call per protocol and there is no source documentation regarding attempts to reach them in error.

Subject lost diary for weeks 10-16. This diary was never returned to the site. Diary pages will be marked blank.

During the week 6 visit for R5011, the Minnesota Test was not performed in error.

Corrective Action: Documentation of deviation serves as the corrective action.

Impact: No impact to study integrity apparent at this time.

Subject was out of town and unable to complete the visit as scheduled. Subject completed the week 6 visit on 01Jun2009, 1 day out of window.

Subject (b) /3029 completed the week 8 call 6 days out of window due to a scheduling conflict.

Due to previous scheduling issues with subject 3031/(b) the week 13 call was missed to allow the subject to finish out the rest of her visits for the study within the visit windows allowed per protocol.

Subject(b)/3031 completed the week 6 visit 13 days out of window due to a scheduling conflict.

Due to schedule conflict subject(b)/3022 completed his week 10 visit 4 days out of window. Subject was counseled on importance of completing visits as scheduled.

Due to a staff scheduling error subject(b)/3022 completed his week 13 visit 7 days out of window. A new calander has been provided to appropriate staff to avoid future errors.

Study Coordinator and Regulatory Specialist need to determine if this is reportable to the IRB.

During the Early Termination visit subject(b) 3015 failed to complete the FTND due to a staff oversight. The appropriate staff have reviewed the protocol to avoid furture error.

Subject(b)/3015 failed to complete Fagerstrom Test for Nicotine Dependence at the early term visit.

Subject(b) 3001 did not complete the week 13 phone contact within window. Subject completed call 1 day out of window. Subject was counseled regarding importance of visit window to avoid future issues.

Corrective Action: Documentation of deviation serves as the corrective action.

Impact: No impact to study integrity apparent at this time.

Corrective action referenced in previous comment.

Randomization number 4011 completed the week 24 visit outside of the window visit - +/- 3 days. The expected date of the visit was 26 Aug 2009 and the visit occurred on 02 Sep 2009 - 4 days outside of the window visit.

Impact: significant delay in visit noted

Corrective Action: Documentation of deviation serves as the corrective action.

Randomization number 4010 completed the week 16 visit outside of the window visit - +/3 days. The expected date of the visit was 01 Jul 2009 and the visit occurred on 07 Jul 2009 - 3 days outside of the window visit.

Impact: No impact to study integrity apparent at this time.

Randomization number 4007 completed the week 16 visit outside of the window visit - +/- 3 days. The expected date of the visit was 01 Jul 2009 and the visit occurred on 07 Jul 2009 - 4 days outside of the window visit.

Randomization number 4007 completed the week 10 visit outside of the window visit (+/-) 3 days. The expected date of the visit was 20 May 2009 and the visit occurred on 26 May 2009 - 3 days outside of the window visit.

Subject R5009 returned to the clinic to perform his Early Termination Visit. In error, the team did not collect his Fagerstrom and Minnesota questionnaire at this time. This memo is to document the deviation.

Subject(b) /2022 missed her scheduled Week 20 phone visit on 20 Nov 2009. Subject contacted site to complete phone visit on 03 Dec 2009 leaving her out of the +/- 7 day window period.

Subject(b) /2022 missed her Week 24 visit that was scheduled on 18 Dec 2009. Subject contacted site on 30 Dec 2009 to complete the phone visit therefore subject is out of the +/- 7 day window period.

See attached source. I could find no documentation of review on 10 Nov. Review was signed off on 16 Nov 2009.

Error reviewed with responsible staff member. Reminded to review and adhere to protocol requirements when performing procedures.

Re: Subject #1002 ((b) Subject's weight was not taken at Week 10 visit, in error. Per the Protocol, subject's body weight is to be taken whenever vital signs are taken.

Corrective Action: Documentation of deviation serves as the corrective action.

Error reviewed with responsible staff member. Reminded to adhere to timing in protocol when performing procedures.

Subject #1020(b) was only seated (1) minute prior to vitals being taken at week 6 visit. Per the protocol, subjects must be seated for (5) minutes prior to vitals.

Impact: No impact to study integrity apparent at this time.

Reviewed 20Mar2009 Y. Taylor - No corrective action recommended.

Subject #01002(b) was only seated (1) minute prior to screening vitals. Per the protocol, subjects must be seated for (5) minutes prior to vitals.

Due to subject's week 6 visit being out of window subject 3031(b) did not complete diary pages at week 6 or 7.

Due to staff error a return questionnaire was not completed for subject 3013(b) during the week 16 visits. Staff has been retrained to avoid future error.

Subject 3022(b) failed to complete the diary entries for weeks 10-16. Subject completed the entries during the week 16 visit and was re-educated on diary completion to avoid furture issue.

RE:3003(b)

Due to staff error during the week 6 visit, the number of cigarettes smoked during the past week was not documented.