- Vivek K. Reddy, MD
- Issuing Office:
- Center for Devices and Radiological Health
| || |
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
| ||10903 New Hampshire Avenue|
Silver Spring, MD 20993
MAR 4, 2015
VIA UNITED PARCEL SERVICE
Vivek K. Reddy, M.D.
200 Lothrop St., PUH C-400
Pittsburgh, PA 15213
Dear Dr. Reddy:
This Warning Letter is to inform you of objectionable conditions observed during the Food and Drug Administration (FDA) inspection of your clinical site from November 9, 2015, to December 8, 2015, by an investigator from the FDA’s Philadelphia District Office. This inspection was conducted to determine whether your activities and procedures related to your participation as a clinical investigator in the significant risk clinical study, “Solitaire FR With the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke”, Investigational Device Exemption (IDE) G120142, De Novo DEN150024, complied with applicable federal regulations. Solitaire FR is a device as defined in section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. § 321(h),because it is intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or to affect the structure or function of the body. This letter also requests prompt corrective action to address the violations cited and discusses your written response dated December 28, 2015 to the noted violations.
The inspection was conducted under a program designed to ensure that data and information contained in requests for IDE, Premarket Approval applications, and Premarket Notification submissions are scientifically valid and accurate. Another objective of the program is to ensure that human subjects are protected from undue hazard or risk during the course of scientific investigations.
Our review of the inspection report prepared by the district office revealed serious violations of Title 21, Code of Federal Regulations (CFR) Part 812 - Investigational Device Exemptions which concerns requirements prescribed under section 520(g) of the Act, 21 U.S.C. § 360j(g). At the close of the inspection, the FDA investigator presented an Inspectional Observations Form FDA 483 for your review, and discussed the observations listed on the form with you. The deviations noted on the Form FDA 483, your written response, and our subsequent review of the inspection report, are discussed below:
1. Failure to ensure that an investigation was conducted in accordance with the investigational plan [21 CFR 812.100].
As a clinical investigator (CI), you are responsible for ensuring that an investigation is conducted according to the investigational plan and applicable FDA regulations. You failed to conduct the investigation in accordance with the protocol. Examples of your protocol deviations include the following:
a. For Subjects 103002 and 103008, your staff performed cervical internal carotid artery recanalization to reduce stenosis of the cervical carotid with non-standard catheter dilatation using a Neuron Max sheath after performing thrombectomy with the Solitaire device. This was performed without use of a balloon angioplasty catheter indicated for angioplasty of carotid stenosis.The Neuron Max sheath is only indicated for the introduction of interventional devices into the peripheral, coronary, and neuro vasculature. However, for subject 103002, it was passed several times through the stenotic region of the cervical internal carotid artery while an embolic protection device indicated for containing and removing embolic material during carotid angioplasty and stenting was placed distal to the region of stenosis. This type of non-standard angioplasty procedure placed these subjects at high risk of serious medical complications, such as cerebral emboli, arterial dissection, stroke and death.
b. The 90-day assessment for subject 103007 was not completed by an independent evaluator blinded to the treatment.
c. The NIH Stroke Scales for Subjects 103042 and 103038 were not performed by certified study personnel.
d. The following serious adverse events were not reported to the sponsor within 24 hours after first learning of the event:
Mural Thrombus and Hemorrhagic Infarct
*Correct dates on progress notes, imaging reports and other medical records
e. Subject 103008 experienced a “Stroke Progression” which was never reported to the sponsor as an adverse event. Proper reporting of adverse events according to the protocol is important to ensure the safety and welfare of study subjects. The events listed above should have been reported in timely fashion because they are serious, life threatening conditions that may indicate problems related to the investigational device.
Your response is inadequate in that it does not provide appropriate corrective actions. In instances where corrective actions are mentioned, your response lacked supporting documentation evidencing the implementation of these actions such as newly created procedures and training records to include content, names of attendees and dates of staff training. Additionally, your response does not include documentation to show that the Institutional Review Board was notified of these protocol deviations.
2. Failure to maintain accurate, complete and current records evidencing informed consent and case history records. [21 CFR 812.140(a)(3)(i) and 21 CFR 812.140(a)(3)(ii)]
As a clinical investigator, you are responsible for properly obtaining and documenting informed consent. You are also responsible for maintaining accurate, complete, and current subject records including signed and dated consent forms, as well as, records of subject’s case history and exposure to the device. Examples of your failure to fulfill these responsibilities include, but are not limited to the following:
a. The informed consent document for Subject 103003 was dated and timed by one of your staff members and not the legally authorized representative (LAR). This subject was re-consented, but dated the consent October 22, 1913 and the form was not witnessed or signed by any other study personnel.
b. There is no documentation that qualified study personnel determined that Subjects 103026 and103008 were eligible prior to randomization. Screening images for Subject 103026 showed a possible carotid dissection and occlusion prior to being randomized, and Subject 103008’s images showed stenosis. Your actions placed these subjects at increased risk of serious complications and death from their existing cerebral vascular disease. Qualified study personnel should have documented and confirmed, under your supervision, that all subjects met the study inclusion/exclusion criteria in order to be safely enrolled in the study.
Your response acknowledges the above deficiencies and includes updated standard operating procedures (SOPs) for obtaining informed consent. Additionally, you conducted re-education on the consent process and requirements but you did not include names of staff trained and when the training was performed. Also, you created an inclusion/exclusion form for study personnel to use when enrolling subjects. However, your response does not include the form nor does it include any related SOPs to provide instructions on this new process. In addition to this, your response does not include documentation to show that the Institutional Review Board was notified of these issues. Therefore, your response is inadequate due to lack of documentation and a preventative plan to prevent recurrence of the violations.
The violations described above are not intended to be an all-inclusive list of problems that may exist with your clinical study. It is your responsibility as a clinical investigator to ensure compliance with the Act and applicable regulations.
We believe a conference call with you is warranted to discuss the Form FDA 483 observations and the corrective actions that you have implemented or plan to implement for future FDA-regulated studies. We would like to also discuss and gain clarity on the adverse events deleted during the trial. Please contact CDR Tamika Allen within two weeks of receiving this letter with dates and times for this meeting.
Within 15 working days of receiving this letter, please provide documentation of the additional corrective and preventative actions that you have taken or will take to correct these violations and to prevent the recurrence of similar violations in current or future studies for which you are the clinical investigator. Failure to respond to this letter and take appropriate corrective action could result in the FDA taking regulatory action without further notice to you. In addition, FDA could initiate disqualification proceedings against you in accordance with 21 CFR 812.119.
You will find information to assist you in understanding your responsibilities and planning your corrective actions in the FDA Information Sheets Guidance for Institutional Review Boards and Clinical Investigators, which can be found at http://www.fda.gov/oc/ohrt/irbs/
. Any submitted corrective action plan must include projected completion dates for each action to be accomplished and a plan for monitoring the effectiveness of your corrective actions.
Your response should reference “CTS # G120142/E003” and be sent to:
Attention: Veronica J. Calvin, M.A.
Food and Drug Administration
Center for Devices and Radiological Health
Office of Compliance
Division of Bioresearch Monitoring
10903 New Hampshire Avenue
Building 66, Room 3508
Silver Spring, Maryland 20993-0002.
A copy of this letter has been sent to FDA’s Philadelphia District Office, US Customhouse, Room 900 2nd & Chestnut St. Philadelphia, PA 19106. Please send a copy of your response to that office.
The Division of Bioresearch Monitoring has developed introductory training modules in FDA-regulated device clinical research practices, which are available on the FDA website. The modules are for persons involved in FDA-regulated device clinical research activities. These modules are located at the following website address: http://www.fda.gov/Training/CDRHLearn/default.htm
If you have any questions, please contact CDR Tamika Allen at (301) 796-1164 or Tamika.Allen@fda.hhs.gov.
Office of Compliance
Center for Devices and