Inspections, Compliance, Enforcement, and Criminal Investigations

Samudrala, Sreedhar 11/19/13


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

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

 NOV 19, 2013

 Ref: 13-HFD-45-11-01 
Sreedhar Samudrala, M.D.                                     
377 Riverside Drive, Suite 202
Franklin, TN 37064
Dear Dr. Samudrala:
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 March 12 and March 28, 2013.  Ms. Laura Staples and Ms. Bonnie Pierson, representing the FDA, reviewed your conduct of the following clinical investigations:
  • Protocol HZC113782,“A Clinical Outcomes Study to Compare the Effect of Fluticasone Furoate/Vilanterol Inhalation Powder 100/25 mcg with Placebo on Survival in Subjects with Moderate Chronic Obstructive Pulmonary Disease (COPD) and a History of or at Increased Risk for Cardiovascular Disease”, of the investigational drug fluticasone furoate, performed for GlaxoSmithKline
  • Protocol (b)(4), “(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, Investigators Staples and Pierson presented and discussed with you Form FDA 483, Inspectional Observations. We acknowledge receipt of your April 15, 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 April 15, 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: 
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 Protocol HZC113782 requires that you enroll subjects who meet specific inclusion criteria. You failed to adhere to these requirements. Specifically:
a.   Protocol HZC113783 requires enrolled subjects to have a measured post-albuterol/salbutamol Forced Expiratory Volume in One Second (FEV1)/Forced Vital Capacity (FVC) ratio of ≤0.70 at screening (Visit 1). However, 11 of 31 subjects enrolled at your site did not meet this enrollment criterion, as shown in Table 1 below. 

Table 1. Enrolled subjects with post-albuterol/salbutamol
FEV1/FVC ratios > 0.70 at screening
Subject #
Screening Visit Date
FEV1/FVC Ratios
May 25, 2011
0.79 (best value)
May 25, 2011
0.77 (best value)
 June 6, 2011
0.87 (best value)
June 6, 2011
0.80 (best value)
June 14, 2011
0.80 (best value)
June 20, 2011
0.77 (best value)
June 28, 2011
0.80 (best value)
July 14, 2011
0.74 (best value)
July 12, 2011
0.80 (best value)
July 26, 2011
0.75 (best value)
August 3, 2011
0.75 (best value)

b.   Protocol HZC113783 requires enrolled subjects to have a measured post-albuterol/salbutamol FEV1 ≥50% and ≤0.70% of predicted normal values calculated using the National Health and Nutrition Examination Survey (NHANES) III reference equations at screening (Visit 1).  However, 4 of 31 subjects enrolled at your site did not meet this enrollment criterion, as shown in Table 2 below. 

Table 2. Enrolled subjects without a post-albuterol/salbutamol FEV1 >50% and ≤ 70% of predicted normal value at screening
Screening Visit Date
FEV1  Percentage(s) of Predicted Normal Value
May 24, 2011
June 6, 2011
June 6, 2011
June 26, 2011

c.   Protocol #HZC113783 requires enrolled subjects 60 years of age or older to be under treatment for any 2 of the following conditions: hypercholesterolemia, hypertension, diabetes mellitus, or peripheral vascular disease. Subject 300296 was 73 years of age at enrollment and was not being treated for any of the conditions listed above. In addition, Subject 300555 was 63 years of age at enrollment and was being treated for peripheral vascular disease only.  
In your written response, you indicate that you have the following corrective action plan: “Investigators are required to sign a document prior to randomization that states that whether [sic] Inclusion/Exclusion Criteria have been met. All Investigators and study staff personnel were re-educated. A new spirometer was purchased to replace the spirometer that was inadequate for this study.”
Your response is inadequate because it is insufficiently detailed with respect to your corrective action plan. You have not provided details regarding the document that investigators are required to sign, and you have not submitted a copy of that document. You also have not provided details or documentation regarding the re-education that took place. Without this information, we cannot assess whether these corrective actions are adequate to prevent future occurrences of this type of violation. 
Enrollment of subjects who do not meet eligibility criteria mayjeopardize subject safety and welfare and raises concerns about 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 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 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}
Thomas N. Moreno, M.S.
Acting Director
Office of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
Food and Drug Administration

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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