Inspections, Compliance, Enforcement, and Criminal Investigations

John Gabriel, MD 6/28/16

  

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
JUN 28, 2016
 
CERTIFIED MAIL
RETURN RECEIPT REQUESTED
 
Ref.: 16-HFD-45-06-01 
John D. Gabriel, M.D.                                                                                   
North Hills Medical Research, Inc.
4351 Booth Calloway Road, Suite 101
North Richland Hills, Texas 76180-7319
 
Dear Dr. Gabriel:
 
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 February 1 and 18, 2016. Mr. Travis M. Beard, representing FDA, reviewed your conduct of a clinical investigation (Protocol (b)(4) for 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, Mr. Beard presented and discussed with you Form FDA 483, Inspectional Observations. We acknowledge receipt of your March 4, 2016 written response to the Form FDA 483.
 
From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your March 4, 2016 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:
 
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 requires that you delay randomization for subjects who do not have key laboratory data by the end of Visit 1, and that if the subject’s estimated glomerular filtration rate (eGFR) drops to <30 mL/min/1.73 m2 (based on two consecutive serum creatinine determinations) the (b)(4) dose will be reduced from 50 mg once daily to 25 mg once daily. You failed to adhere to these requirements. Specifically: 
 
1.    The protocol requires collection of the most recent available serum creatinine and eGFR values at Visit 1 (i.e., the screening and randomization visit), and states that at least one of these values is required for randomization at Visit 1. Serum creatinine is used to calculate eGFR via the protocol-specified Modification of Diet in Renal Disease (MDRD) method, and the eGFR value is used to determine a subject’s eligibility[1] and initial study drug dose.[2] Subjects who satisfy all inclusion and exclusion criteria will be randomized at Visit 1; subjects who require a repeat visit (for example, key laboratory data are not available by the end of Visit 1) will not be randomized until that information is available. 
 
a.  Twenty-five subjects were randomized and received study drug prior to your receipt of their serum creatinine values. Specifically:
 

Subject
Date of Randomization and Start of Study Drug
Date Serum Creatinine Received
110746
January 9, 2012
January 21, 2012
110946
January 23, 2012
January 25, 2012
111043
January 27, 2012
April 19, 2012
111075
January 30, 2012
February 22, 2012
111400
February 17, 2012
April 26, 2012
111448
February 21, 2012
March 15, 2012
111588
February 28, 2012
March 12, 2012
111764
March 7, 2012
March 8, 2012
112138
March 21, 2012
May 4, 2012
112166
March 22, 2012
March 28, 2012
112194
March 23, 2012
April 19, 2012
112542
April 4, 2012
April 5, 2012
110943
January 23, 2012
January 25, 2012
110967
January 24, 2012
April 21, 2012
110991
January 25, 2012
January 27, 2012
111050
January 28, 2012
February 1, 2012
111140
February 2, 2012
April 9, 2012
111206
February 7, 2012
April 24, 2012
111304
February 13, 2012
February 16, 2012
111402
February 17, 2012
May 10, 2012
111521
February 24, 2012
March 15, 2012
111618
February 29, 2012
March 5, 2012
111797
March 8, 2012
March 16, 2012
111853
March 12, 2012
March 21, 2012
112195
March 23, 2012
April 9, 2012

 
We acknowledge that the finding in Item 1 above for Subject 112195 was not included on the Form FDA 483 you received and therefore, your written response does not address this finding.
 
We note it is particularly concerning that Subject 111075 was randomized and received study drug on January 30, 2012, when the serum creatinine and eGFR values, received on February 22, 2012, determined the subject to be ineligible (eGFR <30 mL/min/1.73 m2).  While Subject 111075 was discontinued from the study on February 22, 2012, this subject should never have been enrolled in the study.
 
b.  Subjects 110946 and 112166 were initially overdosed with study drug because you did not have required serum creatinine and eGFR values at the time the subjects were randomized and received study drug. Specifically:
 

Subject
Date of Randomization and Start of Study Drug
Initial Study Drug Dose
Date Serum Creatinine Received
Date of Down Titration
New Study Drug Dose
110946
January 23, 2012
100 mg
January 25, 2012
April 27, 2012
50 mg
112166
March 22, 2012
100 mg
March 28, 2012
April 25, 2012
50 mg

 
The failure to have serum creatinine and eGFR values at the time of randomization compromises subject safety as one subject was later found to be ineligible for the study and two other subjects received incorrect initial doses of study drug and required down titration.
 
In your March 4, 2016 written response to the Form FDA 483, you indicate that during the early part of the study, subjects were enrolled from your own clinic database and medical records were readily available so you followed the protocol. You state that in the later part of study, subjects were referred to your site using (b)(4) to help facilitate subject recruitment. At that point, you state you could not confirm the required serum creatinine value or obtain medical records at Visit 1, so you erroneously relied on subject verbal history.    
 
Further, you explain that you contacted subjects and made efforts to obtain documented laboratory values.  Once these values were obtained, you indicate that subjects were placed on the correct dose of study drug if adjustment was necessary. You describe how subject safety was ensured as all enrolled subjects had regular visits with their nephrologist or primary care physician (PCP).
 
With regard to Subjects 110946 and 112166 being overdosed with study drug and requiring down titration, you indicate that you relied on subject-reported kidney history and made the following assumptions about their diabetes medications: 
  • Subject 110946 was taking metformin 2000 mg as prescribed by her PCP. You explain that because that dose of metformin is only permissible in subjects with no renal impairment (i.e., eGFR >60 mL/min/1.73m2), the subject was assigned 100 mg of study drug, but was later down titrated to 50 mg when you received her medical records.
  • Subject 112166 was taking metformin 1000 mg with glyburide 5 mg. You explain that these medications and doses are indicative of no renal impairment, so the subject was assigned 100 mg of study drug, but was later down titrated to 50 mg when you received the medical records.
You acknowledge that the initial study drug dose should not have been determined without first obtaining the required laboratory results, and that a more thorough screening process should have been done prior to assigning study drug dose. You state that staff has been retrained on assigning correct study drug dose and to not randomize or dispense study drug based on subjects’ verbal history. Such that, your site will require subjects to have medical records in-hand at Visit 1, including current serum creatinine values, before randomization and assignment of study drug dose. 
 
We are unable to undertake an informed evaluation of your written response 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 adherence to protocol-specific requirements for other future studies.  
 
2.    The protocol states that since (b)(4) is cleared primarily through the kidneys, a dose adjustment is required for reduced renal function. If the eGFR drops to <30 mL/min/1.73m2, based on two consecutive serum creatinine determinations, the (b)(4) dose will reduced to 25 mg once daily. The protocol specifies that the most recent available serum creatinine and eGFR values should be obtained as part of usual care at Annual and Brief Visits,[3] and that study investigators will down-titrate the dose of blinded study medication if renal function deteriorates based on the most recently available serum creatinine/derived eGFR. If a dose adjustment is needed, the subject will be brought in for an unscheduled visit (unless a scheduled visit is planned within one month), and the dose adjustment managed through the Interactive Voice Response System (IVRS).
           
Despite two consecutive eGFR values < 30 mL/min/1.73m2 for Subject 112194, you failed to down titrate study drug as required by the protocol. Subject 112194 was taking 50 mg of study drug with an eGFR of 22 mL/min/1.73 m2 on March 10, 2013 (corresponding to the Month 12 Visit that occurred on March 26, 2013) and subsequently, had an eGFR of 23 mL/min/1.73 m2 on July 18, 2013 (corresponding to the Month 18 Visit that occurred on September 19, 2013). Despite this subject having two consecutive eGFR values <30 mL/min/1.73m2 , you did not down titrate Subject 112194 to 25 mg of study drug at the Month 18 Visit as required by the protocol. Study records indicate that Subject 112194 was still taking 50 mg of study drug at the Month 21 Visit that occurred on December 3, 2013.   
 
In your March 4, 2016, written response to the Form FDA 483, you indicate that Subject 112194 was seeing his nephrologist during the study. The nephrologist ordered labs for this subject with the following eGFR values:
  • March 23, 2012 (randomization/Visit 1) – 49 mL/min/1.73 m2
  • July 23, 2012 (Month 4/Visit 2) – 43 mL/min/1.73 m2
  • November 27, 2012 (Month 8/Visit 3) – 39 mL/min/1.73 m2
  • March 26, 2013 (Month 12) – 22 mL/min/1.73 m2 
You state that at the Month 18 Visit on September 19, 2013, the subject confirmed that his nephrologist ordered labs and after the visit, you requested the laboratory results from the nephrologist. Upon receiving the laboratory results several weeks later, you noted that the eGFR was 23 mL/min/1.73 m2, which met the protocol criteria for down titration of study drug. You explain that you were not able to contact the subject to come in for down titration of study drug, and that the subject withdrew from the study on January 15, 2014, prior to being down titrated. 
 
We are unable to undertake an informed evaluation of your written response 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 adherence to protocol-specific requirements for other future studies. 
 
As discussed above, you failed to conduct the investigation in accordance with the investigational plan. Specifically, your failure to delay randomization for subjects who did not have serum creatinine by the end of Visit 1 and your failure to reduce the dose of study drug based on a drop in eGFR to less than 30 mL/min/1.73m2 (based on two consecutive serum creatinine determinations), jeopardized subject safety and welfare, and compromised the interpretability 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 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 explain 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 Douglas B. Pham, Pharm.D., J.D., at 301-796-1955; FAX 301-847-8748. Your written response and any pertinent documentation should be addressed to:
 
                                          Douglas B. Pham, Pharm.D., J.D.
                                          Branch Chief (Acting)
                                          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 5348
                                          10903 New Hampshire Avenue
                                          Silver Spring, MD 20993
                                                                                
 
 
Sincerely yours,
{See appended electronic signature page}
David C. Burrow, Pharm.D., J.D.
Office Director (Acting)
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/
----------------------------------------------------
DAVID C BURROW
06/28/2016

[1] Subjects with an eGFR <30 mL/min/1.72 m2 must be excluded from enrollment in the study. 
[2] Initial dose of (b)(4) or placebo (taken once daily in morning) is as follows: If eGFR ≥50 mL/min/1.73 m2, determined via the MDRD method, starting dose is 100 mg. If eGFR is 30 to <50 mL/min/1.73 m2, starting dose is 50 mg. Subjects with eGFR <30 mL/min/1.73 m2 at screening are excluded.
[3] Annual Visits occur at Months 12, 24, 36, 48, 60, and 72. Brief Visits occur at Months 18, 30, 42, 54, and 66. Study drug is dispensed via IVRS at Annual and Brief Visits. Phone contacts occur at Month 15 and every 6 months thereafter.

 

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