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  5. Laveeza (nmi) Bhatti, M.D. - 538090 - 08/04/2017
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WARNING LETTER

Laveeza (nmi) Bhatti, M.D. MARCS-CMS 538090 — 04/08/2017

Laveeza (nmi) Bhatti, M.D. - 538090 - 08/04/2017


Delivery Method:
Certified Mail

Recipient:
Recipient Name
Laveeza (nmi) Bhatti, M.D.
Laveeza (nmi) Bhatti, M.D.

99 North La Cienga Boulevard
Suite 200
Beverly Hills, CA 90211
United States

Issuing Office:
Center for Drug Evaluation and Research

United States


 

  

Black HHS-Blue FDA Logo

 

 

 
10903 New Hampshire Avenue
Silver Spring, MD 20993 

 

WARNING LETTER
 
 
CERTIFIED MAIL
RETURN RECEIPT REQUESTED
 
 
Laveeza Bhatti, M.D., Ph.D.                                       Ref.: 17-HFD-45-07-01
99 North La Cienga Boulevard
Suite 200
Beverly Hills, California  90211
 
Dear Dr. Bhatti:
 
This Warning Letter informs you of objectionable conditions observed during the U.S. Food and Drug Administration (FDA) inspection conducted at your clinical site between October 27 and December 16, 2016. Ms. Yvonne T. LaCour, representing FDA, reviewed your conduct of the following clinical investigations of the investigational drug (b)(4), performed on behalf of (b)(4) by (b)(4):
  • (b)(4)
  • (b)(4)
This inspection was conducted as a part of FDA’s Bioresearch Monitoring Program, which includes inspections designed to evaluate the conduct of research and to help ensure that the rights, safety, and welfare of the human subjects have been protected.
 
At the conclusion of the inspection, Ms. LaCour presented and discussed with you Form FDA 483, Inspectional Observations. We acknowledge receipt of your January 3, 2017, written response to the Form FDA 483. 
 
From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your written response dated January 3, 2017, we conclude that you did not adhere to the applicable statutory requirements and FDA regulations governing the conduct of clinical investigations and the protection of human subjects. We wish to emphasize the following:
 
1.    You failed to ensure that the investigation was conducted according to the investigational plan [21 CFR 312.60].
 
As a clinical investigator, you are required to ensure that your clinical studies are conducted in accordance with the investigational plan. The investigational plans for the (b)(4) and (b)(4) protocols required you to ensure that subjects met the eligibility criteria before enrollment (that is, to enroll subjects who met inclusion criteria and not to enroll subjects who met exclusion criteria). Further, both protocols also required you to perform electrocardiograms (ECGs) at specific times. You failed to adhere to these requirements. Specifically: 
 
a.  The investigational plan for the (b)(4) protocol required that subjects be excluded if there is any clinically significant finding on screening or baseline ECG. The protocol specified that QRS duration >120 milliseconds (msec) and QTc interval >450 msec are two such clinically significant findings. 
 
i.  Subject 492 was randomized and received study drug on October 22, 2012, despite meeting the exclusion criteria, with a QRS duration of 138 msec during the screening visit on October 1, 2012.  In addition, triplicate ECGs were performed during the baseline visit on October 22, 2012, that demonstrated QRS durations of 132 msec, 132 msec, and 140 msec, thus confirming the subject’s ineligibility for the study. 
 
In your January 3, 2017, written response to the Form FDA 483, you indicated that you conferred with your site’s Director of Research, two other site clinicians, and a cardiologist about this ECG finding.  While abnormal, it was not considered clinically significant, and you subsequently enrolled Subject 492 into the study. You stated that this subject has done well for the past four years, with no significant ECG changes. You also noted that because this subject is now enrolled in the study at a different site, you spoke with the subject’s current clinical investigator (CI), who reported that the subject is doing well. You explained that you notified the sponsor of this issue on November 17, 2016, and the sponsor notified the current CI that this subject would not be removed from the study. You acknowledged that while this ECG finding was not clinically significant, it did make the subject ineligible, and you should have received permission from the sponsor before enrolling the subject.
 
ii.  Subject 498 was randomized and received study drug despite meeting the exclusion criteria.  Triplicate ECGs were performed during the baseline visit on October 30, 2012, showing QTc intervals of 509 msec, 525 msec, and 512 msec.
 
In your January 3, 2017, written response to the Form FDA 483, you acknowledged that Subject 498 was given the first dose of study drug before you reviewed the ECGs. You explained, however, that after the ECGs were reviewed later in the day, you notified the subject that he did not meet the eligibility criteria.  You stated that the subject brought study drug back to the site, and he reported taking one dose of study drug. You referred the subject for urgent cardiac evaluation, and you notified both the sponsor and the IRB of this issue on October 30, 2012.
 
b.  The investigational plan for the (b)(4) protocol required that you enroll subjects who have taken no more than 10 days of prior therapy with any (b)(4) agent following a diagnosis of (b)(4)(that is, subjects who are (b)(4)). The protocol further specified exclusion of subjects with any previous exposure to an (b)(4) or non-nucleoside reverse transcriptase inhibitor.
 
Subject 19 was ineligible for the (b)(4) study because she was previously enrolled in another study at your site and received an (b)(4). However, Subject 19 was screened on June 19, 2014, randomized on July 10, 2014 (Baseline/Week 20 Visit), and dosed with study drug until the withdrawal visit on September 8, 2014.
 
In your January 3, 2017, written response to the Form FDA 483, you explained that you focused on the protocol language stating that subjects should be on no more than 10 days of prior therapy with any (b)(4) agent. Consequently, you overlooked the language stating that use of an (b)(4) was exclusionary. You indicated that the monitor identified this issue on August 14, 2014; the subject’s last dose of study drug was on September 7, 2014; the subject was withdrawn from the study on September 8, 2014; and the Institutional Review Board (IRB) was notified on September 11, 2014.
 
To address the enrollment of ineligible subjects, your written response indicated that you will perform the following as a corrective action:
  • Train all study staff on the protocol and emphasize eligibility criteria
  • Use an eligibility criteria checklist even if the sponsor does not provide one
  • Determine eligibility by source document review and by checking whether that information is verifiable
  • Confirm eligibility by using two qualified individuals (who will initial and date the eligibility checklist), with one of these individuals being the CI
  • Randomize subjects only after the eligibility checklist is complete
  • Train study staff on a revised Standard Operating Procedure (effective date February 1, 2017) for eligibility and enrollment 
If they are properly carried out, your corrective actions appear adequate to prevent the recurrence of similar violations in the future.
 
c.  The investigational plan for the (b)(4) protocol required that ECGs be performed at Screening, on Day 1, at Weeks 2, 4, 12, 24, 26, 28, 36, and 48, and every 12 weeks thereafter, up to and including withdrawal from the study. The investigational plan for the Maintenance Period in the (b)(4) protocol required that ECGs be performed on Day 1, at Weeks 1, 4, 8, 24, 32, 48, 64, 80, and 96, and upon withdrawal from the study. 
 
ECGs are safety assessments in both the (b)(4) and (b)(4) protocols because they are used to monitor the QTc interval.  Subjects have their study drug discontinued if the average QTc interval >500 msec (for the (b)(4) study), or if the average QTc interval >500 msec or if there is a >60 msec increase from baseline (for the (b)(4) study) from three or more ECG tracings separated by at least five minutes. Failure to diagnose a prolonged QTc interval in a timely manner places subjects at risk of developing torsades de pointes, a potentially fatal arrhythmia. Therefore, missing protocol-required ECGs compromises subject safety. Specifically:
 
i.  Subject 160 in the (b)(4) study missed ECGs at Weeks 4, 120, and 156.
 
ii.  Subjects 491, 499, and 500 in the (b)(4) study all missed an ECG at Week 168.
 
iii.  Subject 492 in the (b)(4) study missed an ECG at Week 120.
 
In your January 3, 2017, written response to the Form FDA 483 for the (b)(4) protocol, you indicated that ECGs were placed in a separate folder, and that you delegated ECG interpretation to a subinvestigator. You explained that only the abnormal ECGs were brought to your attention, and that this created the potential for ECGs not to be performed as required, or for ECGs to be misplaced because they were not placed in one folder meant for your review, as laboratory and safety reports were.
 
You stated that subjects were called back to the site to have ECGs performed after it was discovered that either ECGs were not performed or the subinvestigator had not carried out his or her responsibility. These ECGs were compared to previous ECGs, and you noted no significant changes. You explained that all subjects have done well on study drug, and that data from misplaced ECGs were entered by your Study Coordinator into subjects’ medical records and were routed for your signature.
 
We are unable to undertake an informed evaluation of your written response for the (b)(4) protocol because you did not provide a corrective action plan that, if properly carried out, would prevent this type of violation in the future. Specifically, you did not provide sufficient details on how you will ensure the performance of protocol-specific assessments in future studies.
 
iv.  Subject 12 in the (b)(4) study missed an ECG at Week 64.
 
In your January 3, 2017, written response to the Form FDA 483 for the (b)(4) protocol, you indicated that you reported this protocol violation to the IRB in a memo to file dated April 28, 2016. Your site was trained in ECG processing, and you instituted your corrective action plan on September 23, 2016. If they are properly carried out, your corrective actions appear adequate to prevent the recurrence of similar violations in the future.
 
d.  The investigational plan for the (b)(4) protocol required an ECG approximately two hours post-dose and just before the two-hour post-dose pharmacokinetic sampling at Week 32. As discussed above, an ECG is a safety assessment in this study.
 
i.  During the Week 32 Visit, Subject 11 received (b)(4) at 13:50, and (b)(4) at 13:52. However,  there was a handwritten note stating that the “2nd [ECG] (Post Dose) was inadvertently missed.”
 
ii.  During the Week 32 Visit, Subject 12 received (b)(4) at 12:40, and (b)(4) at 12:42.  However, Subject 12 had an ECG performed at 12:20.
 
In your January 3, 2017, written response to the Form FDA 483, you indicated that you reported this protocol violation to the IRB in a memorandum to file dated April 28, 2016. You instituted your corrective action plan on September 23, 2016, and your site was trained on ECG processing. If they are properly carried out, your corrective actions appear adequate to prevent the recurrence of similar violations in the future.
 
Enrollment of subjects who do not meet eligibility criteria, and failure to perform ECGs at protocol-required times, jeopardize subject safety and welfare and compromise the validity and integrity of the data collected at your site.
 
2.    You failed to retain records required to be maintained under 21 CFR Part 312 for a period of two years following the date a marketing application is approved for the drug for the indication for which the drug is being investigated; or, if no application is filed or if the application is not approved for such indication, until two years after the investigation is discontinued [21 CFR 312.62(c)].
 
As a clinical investigator, you are required to retain records of adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation. You are required to retain these records for a period of two years following the date a marketing application is approved for the drug for the indication for which it is being investigated, or if no application is filed or the application is not approved for such indication, until two years after the investigation is discontinued and FDA is notified.
 
You failed to adhere to these requirements. For the (b)(4) study, you failed to retain case histories that include ECG tracings and the Columbia-Suicide Severity Rating Scale (C-SSRS). Specifically:
 
a.  ECG tracings were not retained for the following:
 
i.  Subject 152 for Weeks 60, 108, 120, 132, and 156
 
ii.  Subject 156 for Week 72
 
iii.  Subject 160 for Week 108
 
iv.  Subject 491 for Weeks 12 and 120
 
v.  Subject 492 for Week 96
 
vi.  Subject 499 for Week 48
 
vii.  Subject 500 for Weeks 28, 108, 120, and 132
 
In your January 3, 2017, written response to the Form FDA 483, you indicated that ECGs were performed and the data were captured in subjects’ medical records and electronic case report forms (eCRFs) by the Study Coordinator, but that the original ECGs could not be located. You explained that ECGs were read by a subinvestigator and were placed in a separate folder, and that only abnormal ECGs were brought to your attention. You stated that you “instituted strict measures to rectify this process failure” but did not provide details. You notified the sponsor that you did not report these missing ECG tracings to the IRB.
 
b.  C-SSRS was not retained for Subject 152 at Week 36.
 
In your January 3, 2017, written response to the Form FDA 483, you acknowledged that your previous process for signing the C-SSRS led to the loss of the original C-SSRS. You indicated that subjects had the C-SSRS data captured, but the original C-SSRS was misplaced. You stated that you notified the sponsor of this loss, and that going forward, you will sign the C-SSRS on the day of the subject’s visit and file it immediately after signing it.
 
We are unable to undertake an informed evaluation of your written response for your failure to retain ECG tracings and the C-SSRS because you did not provide a corrective action plan that, if properly carried out, would prevent this type of violation in the future. Specifically, you did not provide sufficient details on how you will properly retain records of adequate and accurate case histories for future studies.
 
Failure to retain study records as required by FDA regulations jeopardizes subject safety and welfare and compromises the validity and integrity of the data collected at your site.
 
This letter is not intended to be an all-inclusive list of deficiencies with your clinical study of an investigational drug. It is your responsibility to ensure adherence to each requirement of the law and relevant FDA regulations. You should address these deficiencies and establish procedures to ensure that any ongoing or future studies will comply with FDA regulations.
 
Within fifteen (15) working days of your receipt of this letter, you should notify this office in writing of the actions you have taken to prevent similar violations in the future. Failure to address the violations noted above adequately and promptly may result in regulatory action without further notice. If you believe you have complied with FDA regulations, include your reasoning and any supporting information for our consideration. 
 
If you have any questions, please contact Adam Donat, M.S., at 301-796-5316.  Your written response and any pertinent documentation should be addressed to:
 
Adam Donat, M.S.
Branch Chief
Compliance Enforcement Branch
Division of Enforcement and Postmarketing Safety
Office of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
Food and Drug Administration
Building 51, Room 5352
10903 New Hampshire Avenue
Silver Spring, MD 20993
                                                                   
Sincerely yours,
 
{See appended electronic signature page}
 
David C. Burrow, Pharm.D., J.D.
Acting Director
Office of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
Food and Drug Administration

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This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature.
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/s/
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DAVID C BURROW
08/04/2017