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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Opada Alzohalli, M.D. 7/17/14

  

Department of Health and Human Services logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration
 Silver Spring, MD  20993 

JULY 17, 2014

WARNING LETTER
 
 
CERTIFIED MAIL
RETURN RECEIPT REQUESTED
Ref.: 14-HFD-45-03-01 
 
Opada Alzohaili, M.D.                                                          
1331 Monroe Street, Suite 100
Dearborn, MI  48124                                                 
 
Dear Dr. Alzohaili:
 
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 July 18 and August 14, 2013.  Ms. L’Oreal F. Walker, representing FDA, reviewed your conduct of the following clinical investigations of the investigational drug Albiglutide, performed for GlaxoSmithKline:
 
  • Protocol GLP108486, “A Randomized, Open-Label, Active-Controlled, Parallel-Group, Multicenter Study to Determine the Safety and Efficacy of Albiglutide Administered in Combination With Insulin Glargine as Compared With the Combination of Insulin Glargine and Preprandial Lispro Insulin in Subjects With Type 2 Diabetes Mellitus”;
 
  • Protocol GLP114179, “A Randomized, Open-Label, Parallel-Group, Multicenter Study to Determine the Efficacy and Safety of Albiglutide as Compared With Liraglutide in Subjects With Type 2 Diabetes Mellitus”;
 
  • Protocol GLP112753, “A Randomized, Double-Blind, Placebo and Active-Controlled, Parallel-Group, Multicenter Study to Determine the Efficacy and Safety of Albiglutide When Used in Combination with Metformin Compared With Metformin Plus Sitagliptin, Metformin Plus Glimepiride, and Metformin Plus Placebo in Subjects with Type 2 Diabetes Mellitus”;
 
  • Protocol GLP112754, “A Randomized, Open-Label, Parallel-Group, Multicenter Study to Determine the Efficacy and Long-Term Safety of Albiglutide Compared With Insulin in Subjects With Type 2 Diabetes Mellitus”;
 
  • Protocol GLP112755, “A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study to Determine the Efficacy and Safety of Albiglutide When Used in Combination With Pioglitazone With or Without Metformin in Subjects With Type 2 Diabetes Mellitus”;
 
  • Protocol GLP112756, “A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study to Determine the Efficacy and Safety of Two-Dose Levels of Albiglutide Compared With Placebo in Subjects With Type 2 Diabetes Mellitus”; and
 
  • Protocol GLP112757, “A Randomized, Double-Blind, Placebo- and Active-Controlled, Parallel-Group, Multicenter Study to Determine the Efficacy and Safety of Albiglutide Administered in Combination With Metformin and Glimepiride Compared With Metformin Plus Glimepiride and Placebo and With Metformin Plus Glimepiride and Pioglitazone in Subjects With Type 2 Diabetes Mellitus.”
 
This inspection is a part of FDA's Bioresearch Monitoring Program, which includes inspections designed to evaluate the conduct of FDA-regulated research to ensure that the data are scientifically valid and accurate, and to help ensure that the rights, safety, and welfare of the human subjects of those studies have been protected.
 
At the conclusion of the inspection, Ms. Walker presented and discussed with you Form FDA 483, Inspectional Observations. We acknowledge receipt of your September 2, 2013, written response to the Form FDA 483.
 
From our review of the FDA establishment inspection report, the documents submitted with that report, and your September 2, 2013, written response, 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 protect the rights, safety, and welfare of subjects under your care [21 CFR 312.60].
 
As a clinical investigator, you are required to protect the rights, safety, and welfare of subjects under your care. 
 
a.    You failed to ensure that diabetic subjects who are experiencing persistent hyperglycemia will receive a timely rescue treatment in order to prevent complications of uncontrolled hyperglycemia. Specifically:
 
i.    Protocol GLP112756 states that after Visit 9 (Week 4) but before Visit 12 (Week 12), subjects who have a single fasting plasma glucose (FPG) > 250 mg/dL that is confirmed by a second sample drawn within 7 days and analyzed by the central laboratory, are to receive hyperglycemia rescue. 
 
Subject 001 had an FPG of 261 mg/dL at Week 8 on May 15, 2009, and an FPG of 304 mg/dL at Week 9 on May 19, 2009. According to the protocol, therefore, the subject should have received hyperglycemia rescue. However, study records show that the rescue medication was not prescribed until June 10, 2009 (approximately three weeks later), and the subject did not receive the medication until July 10, 2009.
 
In your September 2, 2013, written response to the Form FDA 483, you indicated that the delay in Subject 001’s hyperglycemia rescue was due to the subject’s noncompliance. You noted that on several occasions, you contacted Subject 001 and informed the subject of the importance of initiation of a rescue medication, but that the subject did not comply with your instructions and did not come to your study site until June 10, 2009, at which time a prescription for rescue medication was provided. However, the subject reportedly did not fill the prescription or start the rescue medication until July 10, 2009. 
 
As a corrective action, you indicated that after you communicated with the medical monitor, your site was re-educated on the importance of following protocol procedures and being timely in the titration of subjects.
 
Your response is inadequate because you have not provided documentation regarding your communications with Subject 001 and your attempts to bring the subject into compliance. In addition, you have not provided sufficient details about your corrective action plan to enable us to determine whether your corrective action appears sufficient to prevent similar violations in the future.
 
ii.    Section 4.6 of Protocol GLP108486 states that subjects would qualify for hyperglycemia rescue if HgbA1c > 9.0% and < 0.5% decrease from Baseline, at > Week 4 and < Week 8.
 
Subject 004 had a Baseline HbA1c of 7.8% on December 11, 2009, and a Week 4 HbA1c of 9.4% on January 8, 2010. Therefore, Subject 004 met hyperglycemia rescue criteria on January 8, 2010, but the subject was not provided rescue medication until January 29, 2010 (three weeks later). 
 
In your September 2, 2013, written response to the Form FDA 483, you indicated that Subject 004 had a delay in rescue medication due to your misunderstanding of the protocol and your assumption that HbA1c needed to be confirmed prior to rescue, given that other protocols contained this requirement. In addition, you indicated that your lack of documentation was the primary cause of the violations mentioned above, and that as a corrective action, your site will document all study-related data in the subjects’ source documents and memos-to-file. 
 
Your response is inadequate because you have not provided any details of a corrective action plan to ensure adequate training for you and your staff on protocol requirements to prevent future violations, and you have not provided sufficient details regarding your plan to document the required study data. Without these details, we are unable to determine whether your corrective action appears sufficient to prevent similar violations in the future.
 
We remind you that, as the clinical investigator, you are responsible for ensuring that you and your study staff personnel understand the protocol requirements prior to initiating the study.
 
b.    You failed to ensure the safety and welfare of those under your care by failing to ensure that subjects received the correct dose of investigational drug. Specifically:
 
i.    Subject 005 in Protocol GLP112756 was to receive an unscheduled replacement investigational drug, administered via a pen, at Visit 24/Week 16 on September 28, 2011. However, your study coordinator dispensed the wrong pen to the subject. The study coordinator placed a request into the Interactive Voice Response System (IVRS) for a replacement pen that was intended for Subject 006 enrolled in the same protocol, but the coordinator dispensed that pen to Subject 005. 
 
ii.    On October 29, 2009, Subject 007 in Protocol GLP112757 received and used the investigational drug pen #2039854 that was assigned to Subject 001 enrolled in a different protocol (Protocol GLP112755).   
 
In your written response to the Form FDA 483, you acknowledged that subjects received the wrong investigational drug pens and indicated that you and your staff take full responsibility for the protocol violations noted above.   
 
As a corrective action, you indicated that you developed new methods to prevent recurrence of similar violations in the future, including a requirement to have two study coordinators verify any assigned medication to subjects.   
 
Your corrective action as described, if properly carried out, appears adequate to prevent similar violations in the future.                    
 
Your failure to ensure that subjects receive the correct dose of investigational drug, and that subjects received timely rescue medication during persistent hyperglycemia, raises significant concerns about the protection of study subjects enrolled at your site in the studies mentioned above.
 
2.      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 plan for Protocols GLP112753, GLP112754, GLP112755, GLP112756, and GLP112757 required that randomized subjects with persistent hyperglycemia receive either a dose adjustment of study drug or hyperglycemia rescue. In addition, subjects who qualify for rescue medication should return to the study site for a rescue visit, which includes efficacy and laboratory assessments. You failed to adhere to these requirements. Specifically:
 
a.  Protocol GLP112754 states that subjects may qualify for dose adjustments if they are assigned to Albiglutide treatment and experience persistent hyperglycemia, as defined below.
 

Time Interval on Treatment
Dose Titration
≥ Week 12 and < Week 24
HbA1c > 7.0% with ≤ 0.5% reduction from Baseline
> Week 24 and < Week 143
HbA1c > 7.0%

 
The protocol also states that the site will contact the subject and schedule a return visit within 2 weeks from the time the site received confirmation of the laboratory results indicating a needed dose adjustment.
 
i.    You failed to adjust the dose of Albiglutide within 2 weeks of receiving the laboratory results for Subject 006. Subject 006 had an HbA1c of 8.4% at Week 24 on November 9, 2009. However, you did not adjust the dose of Albiglutide until December 23, 2009, which is a delay of over 1 month.
 
In your September 2, 2013, written response to the Form FDA 483, you indicated that the delay in dose adjustment occurred due to the subject’s noncompliance, despite site staff instructions. However, you have not provided any documentation of your or your staff’s attempts to contact the subject to schedule a return visit for dose adjustment within the 2-week time frame. 
 
ii.    You failed to adjust the dose of Albiglutide within 2 weeks of receiving the laboratory results for Subject 007. Subject 007 had a baseline HbA1c of 8.3% on July 2, 2009, and a Week 16 HbA1c of 7.8% (< 0.5% reduction in HbA1c) on October 19, 2009.  However, you did not adjust the dose of Albiglutide until December 28, 2009, which is a delay of almost 2 months.  
 
In your written response to the Form FDA 483, you indicated that you delayed dose adjustments for Subjects 007 due to your concerns about the risk of hypoglycemia and the downward trend of HbA1c.  You also indicated that with respect to subject safety, it was left to your discretion on how to proceed.  As a corrective action, you indicated that after you communicated with the medical monitor, your study staff personnel were re-educated on the significance of adherence to the protocol, specifically with regard to timely management of subjects who require dose adjustment.
 
Your response is inadequate because you have not provided any documentation of your evaluation of the subjects’ blood glucose levels. Your response is also inadequate because you have not provided details regarding how your corrective actions will be implemented or how you will ensure that you and your staff will follow the investigational plan, focusing on the steps to ensure that eligible subjects receive a dose adjustment within the protocol-specified window. Without these details, we are unable to determine whether your corrective actions appear sufficient to prevent similar violations in the future. 
 
b.    Protocol GLP112755 states, “Subjects who qualify for rescue should return to the study center for a rescue visit, which includes efficacy assessments. The laboratory assessments should include safety laboratory test (e.g. chemistry and complete blood count) [sic] and HbA1c.”
 
For Subjects 005 and 003 enrolled in Protocol GLP112755, you failed to perform laboratory assessments at rescue visits on August 11, 2009, and January 26, 2010, respectively.
 
In your September 2, 2013, written response, you acknowledged that laboratory assessments for Subjects 005 and 003 were not performed at the rescue visits. You indicated that these protocol violations occurred because you and your study staff misunderstood and/or overlooked the rescue visit laboratory assessment section of the protocol. As a corrective action plan, you indicated that your site has received numerous training sessions on the protocol and on the significance of completing all protocol-required procedures.
 
Your response is inadequate because you have not provided any documentation of your corrective action plan, including the details of any training you and your staff received on protocol requirements. Without these details, we are unable to determine whether your corrective actions appear sufficient to prevent similar violations in the future.
     
c.    Protocol GLP 112753 states that subjects are to return medication dispensed at their prior visits when returning for titration/rescue visits. The protocol also states that the subjects will be instructed to take their new medication at their next scheduled dosing time. 
 
You failed to collect all unused medication from Subject 005, who qualified for a dose adjustment and received an increased dose of the investigational drug on November 18, 2009. We note further that Subject 005 was administered the incorrect dose of medication on December 9, 2009.
 
In your September 2, 2013, written response to the Form FDA 483, you acknowledged that the failure to collect all unused medication from Subject 005 occurred due to your study coordinator’s mistake, and due to handling a large number of investigational drugs for multiple clinical studies conducted at your site. You indicated that Subject 005 was instructed to return the old pens to your study site when coming in to receive the dose-adjusted pens. However, the subject reportedly did not return the old pens, which resulted in the inadvertent use of an old pen instead of the more recently dispensed pen. 
 
As a corrective action, you indicated in your written response that you developed new methods of organization to prevent such occurrences, including a requirement to have two study coordinators verify any medication assigned to subjects.
 
Your response regarding how the violation occurred is inadequate, because it was your responsibility as the clinical investigator, and not the subject’s, to ensure that Subject 005 received the correct investigational drug pen at your site. 
 
Your described corrective action, if properly carried out, appears adequate to prevent similar violations in the future.
 
Failure to follow the protocol requirements jeopardizes subject safety and welfare, and raises concerns about the validity and integrity of the data collected at your site.
 
3.    You failed to maintain 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 [21 CFR 312.62(b)].
 
As a clinical investigator, you are required to prepare and maintain 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. Case histories include source documents such as physical exam worksheets. You have failed to maintain adequate and accurate case histories with respect to subjects’ physical examinations. Study records show discrepancies with regard to whether you completed required physical exams, including fundoscopy exams, at the required visits. Examples of this failure include, but are not limited to, the following:
 
For Subject 011 enrolled in Protocol GLP108486, the Source Document Worksheet for Visit 17/End of Treatment contains discrepancies regarding the fundoscopy exam. This document originally noted that the fundoscopy exam was performed on January 11, 2011, but the entry of “yes” for the performance of the exam was crossed out, and a notation of “Not Performed” was added next to the cross-out. On June 2, 2011, the words “Not Performed” were crossed out, with the word “Error” entered above that cross-out.  The document also contains another late entry, dated June 2, 2011, with fundoscopy exam findings. In addition, the document contains the undated entry, “visual acuity and fundoscopy were done but not documented – Missed on Documentation.” 
 
Because of the way corrections were made to this Source Document Worksheet, we are unable to determine whether the fundoscopy exam was performed on January 11, 2011, or June 2, 2011.
 
In your September 2, 2013, written response for the Form FDA 483, you acknowledged that all discrepancies in the study records were directly related to your poor documentation practices. You stated that you failed to document the fundoscopy exam properly because the physical exam worksheets did not contain a section to capture fundoscopy exams.  In addition, you indicated that missed assessments were due to a confusion of the protocols; the fundoscopy exams were not required for every visit, and some were inadvertently missed, while others were captured when they were not required.
 
As a corrective action, you indicated that you revised source documents to include the physical and fundoscopy exams on the required visit dates, as required by the protocol.  You also indicated that site staff were re-educated on proper source documentation and on Good Clinical Practices.  In addition, you indicated that moving forward, you would document all required assessments in your own writing at the time of subjects’ visits to avoid late entries.
 
Your response is inadequate because you did not provide documentation of the revised source documents or of site staff training regarding proper documentation. Without these details, we are unable to determine whether your corrective action appears sufficient to prevent similar violations in the future.
 
As the clinical investigator, you are responsible for ensuring that data recorded on subjects’ records are accurate. By failing to maintain adequate and accurate case histories, you have compromised the validity and integrity of data captured 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 be in compliance 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 Constance Cullity, M.D., M.P.H., at 301-796-3397; FAX 301-847-8748. Your written response and any pertinent documentation should be addressed to: 
 
Constance Cullity, M.D., M.P.H.
Branch Chief
Good Clinical Practice Enforcement Branch
Division of Good Clinical Practice Compliance
Office of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
Food and Drug Administration
Building 51, Room 5354
10903 New Hampshire Avenue
Silver Spring, MD 20993
 
Sincerely yours,
 
{See appended electronic signature page}
 
Sean Y. Kassim, Ph.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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SEAN Y KASSIM
07/17/2014