Inspections, Compliance, Enforcement, and Criminal Investigations

Binh Bui-Nguyen, MD 5/4/15

  

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

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

 

WARNING LETTER
 
 
CERTIFIED MAIL
RETURN RECEIPT REQUESTED
 
Ref.: 15-HFD-45-05-01 
Binh Bui Nguyen, M.D.                                                                    
Institut Bergonié
229 cours de l’Argonne – CS 61283
33076 Bordeaux Cédex
France
 
Dear Dr. Bui:
 
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 September 17 and September 19, 2014. Ms. Barbara D. Wright and Ni A. Khin, M.D., representing FDA, reviewed your conduct of the following clinical investigations of the investigational drug (b)(4), performed for (b)(4):
  • Protocol (b)(4), “(b)(4)
  • Protocol (b)(4), “(b)(4)
 
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. Wright and Dr. Khin presented and discussed with you Form FDA 483, Inspectional Observations. We acknowledge receipt of your October 2, 2014, 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 October 2, 2014, we conclude that you did not adhere to the applicable statutory requirements and FDA regulations governing the conduct of clinical investigations. We wish to emphasize the following:
 
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 investigations are conducted in accordance with the investigational plan. The investigational plan for Protocol (b)(4) required that laboratory tests related to hematology, biochemistry [including thyroid stimulating hormone (TSH)], and urinalysis be performed at scheduled time points, and that serious adverse events (SAEs) be reported within a specified time frame. Similarly, the investigational plan for Protocol (b)(4) required that laboratory tests related to hematology be performed at scheduled time points, and that SAEs be reported within a specified time frame. For both trials, treatment modification rules were required to be followed if subjects experienced certain enumerated adverse events, including renal failure. You failed to adhere to these protocol requirements. Examples of this failure include, but are not limited to, the following:   
 
1.    Protocols (b)(4) and (b)(4) require that subjects in France undergo hematologic laboratory tests at Screening; Baseline; Weeks 1, 2, 3, 4, 5, 6, 7, 8, 10, and 12; and every four weeks thereafter, up to and including the End of Study/Final Visit.
 
The hematologic laboratory tests for both protocols include hematocrit and hemoglobin; red blood cell count; total and differential white blood cell counts, including neutrophils, lymphocytes, monocytes, eosinophils, and basophils; platelet count; prothrombin time; partial thromboplastin time; and international normalized ratio. These hematologic laboratory tests are safety assessments in the studies, because they are used to monitor for (b)(4)-related adverse events such as neutropenia, for which subjects will have their doses interrupted or discontinued, depending on its severity. Failure to diagnose neutropenia in a timely manner places subjects at increased risk of developing serious infections and sepsis. Therefore, missed protocol-required hematologic laboratory tests compromise subject safety. Specifically:
 
 
a.    Subject 033-008-03 in Protocol (b)(4) missed hematologic laboratory tests at Week 20.
 
b.    Subject 033-008-04 in Protocol (b)(4) missed hematologic laboratory tests at Weeks 5, 6, and 7.
 
c.    Subject 033-008-05 in Protocol (b)(4) missed hematologic laboratory tests at Week 20.
 
d.    Subject 1302 in Protocol (b)(4) missed hematologic laboratory tests at Week 1.
 
In your October 2, 2014, written response to the Form FDA 483, you indicated that these missed laboratory tests were mainly due to subject noncompliance. You stated that orders for laboratory tests were given to the subjects at each visit. You noted that corrective measures to address subject noncompliance taken at the time included phone calls to subjects and oral reminders during the following clinical visit.
 
Your response is inadequate because you have not provided sufficient details about your corrective action plan. You have not provided adequate documentation of your efforts to address subject noncompliance (e.g., phone calls, oral reminders during the following clinical visit) in the source records. Without those details in the records, we are unable to determine whether your corrective action plan is adequate to prevent similar violations in the future.
 
We acknowledge that the finding noted in Item 1.a above (Subject 033-008-03) was not included on the Form FDA 483 you received, and that therefore, your written response does not address this finding.
 
2.    Protocol (b)(4) requires that a urine dipstick test be performed at Screening; Baseline;  Weeks 4, 8, 12, 16, and 24; and every 12 weeks thereafter, up to and including the End of Study/Final Visit. The urine dipstick test includes measurement of blood, leukocytes, and protein. A 24-hour urine collection to measure protein is performed if protein ≥30 mg/dL is detected on the dipstick. In this study, the urine dipstick test is a safety assessment that is used to monitor for (b)(4)-related renal disorders, and the study protocol requires that a subject’s (b)(4) dose be interrupted, reduced, or discontinued, based on the number of times a subject experiences protein ≥30 mg/dL on the dipstick and confirmed by 24-hour urinary protein >1.5 g/24 hours. Therefore, missed protocol-required urine dipstick tests compromise subject safety, because subjects can develop (b)(4)-related renal disorders. Specifically:
 
a.    Subject 033-008-06 missed the urine dipstick test at Week 8.
 
b.    Subject 033-008-02 missed the 24-hour urine collection at Week 36. This subject’s protein on the urine dipstick measured 30 mg/dL.
 
In your October 2, 2014, written response to the Form FDA 483, you indicated that the Week 36 urine protein of 30 mg/dL for Subject 033-008-02 showed traces of blood due to a urinary infection from prolonged urethral catheterization following surgery. You also indicated in your written response that missed laboratory tests were mainly due to subject noncompliance. You stated that orders for laboratory tests were given to the subjects at each visit. You noted that corrective measures taken at the time to address subject noncompliance included phone calls to subjects and oral reminders during the following clinical visit.
 
Your response is inadequate because, although Subject 033-008-02 had blood in the urine, the subject also had a level of protein in the urine that required a 24-hour urine collection, according to the protocol. You have not submitted a corrective action plan to address missed 24-hour urine collections. In addition, you have not provided adequate documentation of your efforts to address subject noncompliance (e.g., phone calls, oral reminders during the following clinical visit) in the source records.  Without those details in the records, we are unable to determine whether your corrective action plan is adequate to prevent similar violations in the future. 
 
We acknowledge that the finding noted in Item 2.a above (Subject 033-008-06) was not included on the Form FDA 483 you received, and that therefore, your written response does not address this finding.
 
3.    Protocol (b)(4) requires that TSH be performed at Baseline, Week 24, and every 24 weeks thereafter, up to and including the End of Study/Final Visit. TSH is a safety assessment in the study. Specifically:
 
a.    Subject 033-008-02 missed TSH collection at Weeks 48 and 72.
 
b.    Subject 033-008-03 missed TSH collection at Week 24.
 
c.    Subject 033-008-04 missed TSH collection at End of Study.
 
In your October 2, 2014, written response to the Form FDA 483, you indicated that missed laboratory tests were mainly due to subject noncompliance. You stated that orders for laboratory tests were given to the subjects at each visit. You noted that corrective measures taken at the time to address subject noncompliance included phone calls to subjects and oral reminders during the following clinical visit.
 
Your response is inadequate because you have not provided sufficient details about your corrective action plan. You have not provided adequate documentation of your efforts to address subject noncompliance (e.g., phone calls, oral reminders during the following clinical visit) in the source records. Without those details in the records, we are unable to determine whether your corrective action plan is adequate to prevent similar violations in the future.
 
We acknowledge that the findings noted in Items 3.a (Subject 033-008-02) and 3.b (Subject 033-008-03) above were not included on the Form FDA 483 you received, and that therefore, your written response does not address these findings.
 
4.    Protocol (b)(4) requires that (b)(4) treatment be altered if one of the following three events occurs: 
  • Protein ≥30 mg/dL on the urine dipstick, confirmed by 24-hour protein >1.5 g/24 hours.
  • Creatinine clearance <50 mL/min (Cockcroft and Gault formula).
  • Urea >2 times the upper limit of normal.
 
If one of the three events noted above occurs, the study protocol requires that (b)(4) be interrupted until the noted level returns to baseline, and (b)(4) will then be restarted at the same dose. If one of the three events noted above occurs a second time, (b)(4) will be interrupted until the noted level returns to baseline, and (b)(4) will then restarted with a dose reduction of 1.5 mg/kg/day (i.e., the new dose will be 6 mg/kg/day). If one of the three events noted above occurs a third time, (b)(4) will be permanently discontinued. Failure to adhere to the treatment modification rules noted above compromises subject safety, because subjects can develop (b)(4)-related renal disorders. 
 
On January 16, 2013, Subject 1313 in Protocol (b)(4) had a baseline creatinine level of 0.5 mg/dL. This subject’s creatinine clearance on February 27, 2013, was 49.7 mL/min (Cockcroft and Gault formula); therefore, the protocol required that (b)(4) treatment be interrupted until a return to baseline renal function. This action was not taken, however. On March 13, 2013, the subject’s creatinine level had increased to 1.6 mg/dL, indicating worsening renal function. The subject’s final dose of (b)(4) was given on the morning of March 18, 2013, and the subject was discontinued from the study on the same day due to progressive disease.
 
In your October 2, 2014, written response to the Form FDA 483, you indicated that the subject’s grade 2 renal insufficiency was “considered related to a major fluid retention, mainly with ascites and inferior vena cava compression, related to tumor evolution.” You also indicated that “this functional renal deficiency was considered non-threatening,” and that “continuation despite renal functional dysfunction was a medical choice” in the subject’s best interest.
 
Your response is inadequate because the cause of renal insufficiency is not a factor in adhering to the protocol’s treatment modification rules for renal disorders, and you have not provided a corrective action plan to address this issue. Without a corrective action plan describing how you will adhere to protocol-specified treatment modification rules for renal disorders, we are unable to determine whether similar violations will be prevented in the future.  
 
5.    Protocols (b)(4) and (b)(4) require that SAEs, whether they are considered related to study drug or not, will be reported on an SAE form and will be faxed to the sponsor by the end of the next working day (Protocol (b)(4)) or within 24 hours (Protocol (b)(4)) of occurrence or investigator’s knowledge of the event, even if the event does not appear to be treatment-related. SAE reporting is not required for surgeries and other invasive procedures planned before the start of the study.
 
Protocols (b)(4) and (b)(4) define an SAE as any untoward medical occurrence that at any dose results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or is another important medical condition that may jeopardize the subject’s health or may require intervention to prevent one of the preceding outcomes.
 
Examples of SAEs that were not reported to the sponsor within the protocol-required time frames include, but are not limited to, the following:
 
a.    Subject 033-008-05 in Protocol (b)(4) experienced grade III skin toxicity from October 3 to October 10, 2013. Your sub-investigator noted the subject’s skin toxicity in a progress note dated October 10, 2013. However, your site did not report the skin toxicity to the sponsor on a SAE form until November 21, 2013.
 
b.    Subject 1302 in Protocol (b)(4) was hospitalized and received blood transfusions for grade 3 anemia from (b)(6). Your sub-investigator noted the subject’s hospitalization in a progress note dated (b)(6). However, your site did not report the hospitalization to the sponsor on a SAE form until August 26, 2010.  
 
c.   Subject 1311 in Protocol (b)(4) had surgery on (b)(6), for knee arthritis complicated by an episode of phlebitis. You noted the subject’s surgery in a progress note dated March 15, 2013. However, your site did not report the hospitalization to the sponsor on an SAE form until April 10, 2013. In your response to the FDA Form 483, you state that this surgery was not planned before the start of the study. Therefore, the surgery should have been reported as an SAE form according to the protocol-specified time frame (i.e., within 24 hours).
 
In your October 2, 2014, written response to the Form FDA 483 concerning Subjects 1302 and 1311, you indicated that the failure to report SAEs in a timely manner occurred in a limited number of cases, and the SAEs in question were not events related to study drug treatment.
 
While you subsequently discussed Subject 1302’s anemia with the sponsor and attempted to gather more details about Subject 1311’s surgery, these SAEs were required to be reported within the protocol-specified time frames, and they were to be reported regardless of relationship to study drug. Also, a follow-up SAE report could have been submitted with additional information about Subject 1311’s surgery after the initial SAE report was submitted. Your response is inadequate because you have not provided a corrective action plan addressing how you will adhere to protocol-specified SAE reporting requirements. Without a corrective action plan, we are unable to determine whether similar violations will be prevented in the future.  
 
We acknowledge that the finding noted in Item 5.a above (Subject 033-008-05) was not included on the Form FDA 483 you received, and that therefore, your written response does not address this finding.
 
As detailed above, you failed to conduct these two investigations in accordance with the investigational plans. Specifically, you failed to perform protocol-required assessments; you failed to adhere to treatment modification rules for renal disorders; and you failed to report SAEs to the sponsor within protocol-specified time frames. These failures jeopardized subject safety and 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 Khin M. U, M.D., at 301-796-1156; Fax 301-847-8748. Your written response and any pertinent documentation should be addressed to:
 
                                          Khin M. U, M.D.
                                          Acting Branch Chief
                                          Compliance Enforcement Branch
                                          Division of Enforcement and Postmarketing Safety
                                          Office of Scientific Investigations
                                          Office of Compliance
                                          Center for Drug Evaluation and Research
                                          U.S. Food and Drug Administration
                                          Building 51, Room 5210
                                          10903 New Hampshire Avenue
                                          Silver Spring, MD 20993
                                                                                
Sincerely yours,
{See appended electronic signature page}
Sean Y. Kassim, Ph.D.
Director
Office of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
U.S. 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/
----------------------------------------------------
SEAN Y KASSIM
05/04/2015

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