Inspections, Compliance, Enforcement, and Criminal Investigations

Birhiray, Ruemu 4/28/14

  

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: 14-HFD-45-04-04
 
 
Ruemu E. Birhiray, M.D.                                                       
8301 Harcourt Road, Suite 200
Indianapolis, IN  46260
 
Dear Dr. Birhiray:
 
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 August 12 and September 5, 2013.  Ms. Andrea D. Swingle, representing FDA, reviewed your conduct of the following clinical investigations:
 
· Protocol (b)(4) and
 
· (b)(4)  Protocol (b)(4) of the investigational drug (b)(4) performed for (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. Swingle presented and discussed with you Form FDA 483, Inspectional Observations.  We acknowledge receipt of your September 22, 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 22, 2013, written response, 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: 
 
 
1.      You failed to ensure that the investigations were 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. Of note, Protocol (b)(4) is a study of (b)(4) which have significant effects on bone mineralization and resorption, and these three drugs are excreted through the kidneys. Therefore, monitoring the levels of creatinine, magnesium, and phosphate is important to determine whether to hold or adjust the dose of study drug to protect subject safety. 
 
The investigational plan for Protocol (b)(4) required that you (1) hold or adjust the dose of the investigational drug in managing specific drug-related adverse events, and (2) follow specific procedures for reporting adverse events. In addition, Protocols (b)(4) and (b)(4) required that you perform certain study procedures, such as physical examinations, bone scans, and specified laboratory tests, at specific times. You failed to adhere to these requirements. Specifically:
 
a.       Protocol (b)(4) requires that you stop dosing of (b)(4) in subjects with an increase of 0.5 mg/dL from a normal baseline creatinine that is greater than the institutional upper limit of normal (IULN), or any increase of at least 1 mg/dL from an abnormal baseline creatinine that is greater than the IULN, until serum creatinine returns to within 10% of baseline.
 
Subject 222626, who was randomized to Treatment Arm 2 (clodronate), met this protocol criterion for stopping the dosing of clodronate, and yet the subject continued to receive clodronate for more than one year after meeting the criterion. Serum creatinine for Subject 222626 was 0.9 mg/dL (within the institutional upper limit of normal) at baseline on January 28, 2010. However, the subject’s serum creatinine increased to 1.7 mg/dL on January 11, 2011, and remained more than 0.5 mg/dL above the institutional upper limit of normal (1.0 mg/dL) for over 10 months. The subject had creatinine levels of 1.6 mg/dL on March 29, 2011; 1.6 mg/dL on June 21, 2011; 1.8 mg/dL on September 13, 2011; and 1.98 mg/dL on November 29, 2011. For Subject 222626, you failed to stop dosing of clodronate until January 24, 2012, more than one year after you should have done so.
 
b.      Protocol (b)(4) specifies requirements for expedited reporting of serious adverse events for subjects randomized to Treatment Arms 2 or 3 (clodronate or ibandronate, respectively). In addition, the protocol requires that you utilize the Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0, in determining the classification and severity (grade) of serious adverse events. The protocol also requires you to report any Grade 3 adverse event precipitating hospitalization (or prolonging hospitalization) within 10 calendar days via the Adverse Event Expedited Reporting System (AdEERS), regardless of attribution or expectedness. The protocol also requires you to report any osteonecrosis of the jaw, regardless of grade, attribution, or expectedness, within 24 hours of event recognition, via AdEERS. 
 
You failed to report the following serious adverse events via AdEERS:
 
i)        Subject 214199, who was randomized to Treatment Arm 3 (ibandronate), was hospitalized on (b)(4), for community-acquired pneumonia (CAP) with bilateral pulmonary infiltrates observed on Computed Tomography (CT) scan. The subject was treated for CAP with an intravenous (IV) antibiotic, Levaquin. Based on CTCAE clinical descriptions of lung infection, a lung infection indicating the use of IV antibiotic intervention meets the criterion for a Grade-3 severity. You failed to report a Grade-3 lung infection precipitated by hospitalization via AdEERS for Subject 214199.
 
ii)      Subject 214835, who was randomized to Treatment Arm 3 (ibandronate), developed osteonecrosis of the jaw on April 6, 2010. You failed to report osteonecrosis of the jaw via AdEERS for Subject 214835. 
 
c.       Protocol (b)(4) requires you to perform the following study procedures at the Month-2 study visits:  a physical examination, weight measurement, an evaluation of performance status, toxicity notation, and laboratory tests (serum creatinine, calcium, phosphate, magnesium, albumin, electrolytes, liver-function tests, and CBC/differential/platelets). 
 
You failed to conduct Month-2 study visits for the following subjects:  213854, 214200, 214393, 214835, 221968, 222241, 222626, and 222698.
 
d.      Protocol (b)(4) requires that you perform magnesium, phosphate, and complete blood count (CBC) laboratory tests at Months 2, 4, 6, 9, 12, 15, 21, 24, 27, 30, 33, and 36 study visits. You failed to conduct the following laboratory tests at the specified intervals:
 
 

Subject ID
Laboratory tests not performed
Study month(s) when these tests were not performed
213854
Magnesium and phosphate
4, 6, and 9
214199
Magnesium and phosphate
2, 4, 6, and 21
214200
Magnesium and phosphate
9 and 15
214393
Magnesium and phosphate
4, 6, 9, and 12
214632
Magnesium and phosphate
2, 4, 6, 9, 12, 24, 27, 30, 33, and 36
214835
Magnesium and phosphate
4, 6, and 9
217799
Magnesium, phosphate, and CBC
2, 4, and 6
222242
Magnesium and phosphate
2, 4, and 6
222456
Magnesium and phosphate
2

 
 
e.       Protocol (b)(4) requires that you perform the following laboratory tests at the Month-4 study visits:  serum creatinine, calcium, phosphate, magnesium, albumin, electrolytes, liver-function tests, and CBC/differential/platelets.  
 
You failed to perform any of the required laboratory tests at the Month-4 study visit for Subject 222698.
 
f.       Protocol (b)(4) requires that you perform serum creatinine tests at screening and at Month-5 study visits. 
 
You failed to perform the required serum creatinine tests at screening for the following subjects: 213854, 214200, 214632, and 221819. In addition, you failed to perform a serum creatinine for Subject 214835 at the Month-5 study visit.
 
g.      Protocol (b)(4) requires that you perform a pre-study pregnancy test within 72 hours prior to initiation of study drug. 
 
You failed to perform pre-study pregnancy testing for Subject 221968, who was 31 years of age at enrollment.
     
h.      Protocol (b)(4) requires that you perform a bone scan at the end-of-treatment study visit.  
 
You failed to perform a bone scan at the end-of-treatment study visit for Subject 214632.
 
i.        Protocol (b)(4) requires that you perform a serum creatinine laboratory test prior to Cycle 7 of chemotherapy. 
 
You failed to perform a serum creatinine laboratory test prior to Cycle 7 of chemotherapy for Subject 81053082.
 
In your September 22, 2013, written response to the findings noted in Item 1 above, you stated that you are not currently conducting clinical research or actively recruiting subjects to any studies.  You noted that, had you continued to conduct clinical research, you would have appointed designated administrative and research staff to coordinate your clinical studies, to document delegation of responsibilities, to conduct routine weekly internal monitoring, to implement a new electronic medical record system, and to use a table/flowchart to monitor laboratory results. 
 
Your response is inadequate because you did not provide sufficient information to enable us to evaluate the adequacy of your corrective action plans for use in any future clinical research that you may conduct. For example, you did not provide details regarding how you will implement your corrective action plan to prevent protocol violations. In addition, you did not provide any details of a corrective action plan to ensure adequate training for you and your staff on protocol requirements, to prevent future violations. As a result, we are unable to evaluate whether the corrective actions outlined above are adequate to prevent the occurrence of similar violations in the future.  
 
Failure to perform protocol-required study procedures, including adverse event reporting and the performance of physical examinations and laboratory tests, jeopardizes subject safety and welfare. Of particular concern is the fact that, for Protocol (b)(4), laboratory tests to evaluate serum creatinine, magnesium, and/or phosphate were not done at all study visits for 10 of the 16 enrolled subjects whose records were reviewed. As mentioned above, Protocol (b)(4) is a study of bisphosphonate compounds, which have significant effects on bone mineralization and resorption; therefore, monitoring the levels of creatinine, magnesium, and phosphate is important to protect subject safety.
 
 
2.      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. For Protocols (b)(4) and (b)(4), case histories include signed and dated informed consent documents and study registration forms. You have failed to maintain adequate and accurate case histories with respect to these documents.  Specifically:
 
a.       The informed consent document for Protocol (b)(4) requires a “yes” or “no” response to six questions regarding subjects’ consent to participate in optional research studies in the future. You failed to record subjects’ consent to these optional studies adequately and accurately on the subjects’ study registration forms. Specifically:
 
i)        Subject 214199 did not provide a “yes” or “no” response to any of the six questions regarding consent to participate in optional future studies; however, a “yes” response to each of the six questions was recorded on the subject’s registration form, indicating that the subject had provided a response to all of these questions.  
 
ii)      Subject 214632 did not provide a “yes” or “no” response to three of the six questions regarding consent to participate in optional future studies; however, a “yes” response to all six questions was recorded on the subject’s registration form, indicating that the subject had provided a response to all of these questions.  
 
b.      For Protocol (b)(4), one copy of the informed consent document for Subject 810493082 shows that the subject consented to optional future research; however, another copy of the same informed consent document shows that the subject did not consent to optional future research. There is no documented explanation for this discrepancy, and no documentation of when this informed consent document was amended or by whom.
 
In your September 22, 2013, written response to the findings noted in Item 2 above, you stated that you are not currently conducting clinical research or actively recruiting subjects to any studies.  You noted that, had you continued to conduct clinical research, you would have appointed designated administrative and research staff to coordinate your clinical studies, to document delegation of responsibilities, to conduct routine weekly internal monitoring, to implement a new electronic medical record system, and to use a table/flowchart to monitor laboratory results. 
 
Your response is inadequate because you did not provide sufficient information to enable us to evaluate the adequacy of your corrective action plans for use in any future clinical research that you may conduct. For example, you did not provide details regarding how you will implement your corrective action plan to prevent protocol violations. In addition, you did not provide 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 required study data adequately. As a result, we are unable to evaluate whether the corrective actions outlined above are adequate to prevent the occurrence of similar violations in the future.  
 
Your failure to document informed consent properly, raises concerns about the extent to which subjects’ rights were protected 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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