- Sandeep Bagla, 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
March 21, 2014
VIA UNITED PARCEL SERVICE
Sandeep Bagla, M.D.
INOVA Alexandria Hospital
Cardiovascular & Interventional Radiology
4320 Seminary Road
Alexandria, VA 22304
Dear Dr. Bagla:
This Warning Letter is to inform you of objectionable conditions observed during the Food and Drug Administration (FDA or the Agency) inspection conducted at your clinical site from July 8, 2013, to July 31, 2013, by investigatorsfrom the FDA Baltimore District Office. This inspection was conducted to determine whether your activities as both sponsor and clinical investigator (CI) of the clinical study entitled “Prospective Pilot Study of Prostatic Artery Embolization in the Treatment of Benign Prostatic Hyperplasia” complied with applicable federal regulations. The prostatic artery embolization (PAE) procedure utilized theCelonova Embozene Microspheres. The Celonova EmbozeneMicrospheres is a device as that term is 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 requests prompt corrective action to address the violations cited and discusses your written response dated August 16, 2013, to the noted observations on the Form FDA 483.
The inspection was conducted under a program designed to ensure that data and information contained in requests for Investigational Device Exemptions (IDE), Premarket Approval applications, and Premarket Notification (510(k)) 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 several violations of Title 21, Code of Federal Regulations (CFR)Part 812 – Investigational Device Exemptions and Part 50 - Protection of Human Subjects, which concern requirements prescribed under section 520(g) of the Act, 21 U.S.C. § 360j(g). At the close of the inspection, the FDA investigators 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 submit an IDE application to the FDA to use a significant risk (SR) device in an investigation, and failure to obtain FDA approval of the IDE prior to beginning the investigation. [21 CFR 812.20(a)(1), 21 CFR 812.42, and 21 CFR 812.110(a)]
Your investigation, “Prospective Pilot Study of Prostatic Artery Embolization in the Treatment of Benign Prostatic Hyperplasia,” studied the CeloNova Embozene Microspheres device for a use that does not fall within the FDA clearance of the device (K073417). FDA cleared the device for “the embolization of hypervascular tumors and arteriovenous malformations.” Your study investigated the device for PAE in the treatment of benign prostatic hyperplasia (BPH). BPH is not typically hypervascular nor is it an arteriovenous malformation. Your use of the device constituted a major change or modification in the intended use of the device.
FDA has determined that your investigation of this device constituted a study of an SR device. The investigational device is intended as an implant, is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment of human health, and the investigational device presents a potential for serious risk to the health, safety, or welfare of a subject. Subjects implanted with the investigational device are at risk of, among other things, non-target embolization, hematoma or bruising, infection, arterial aneurysm or arterial thrombosis at the site of arterial access, vascular injury with hemorrhage, vasospasm, and clot formation at the tip of the catheter. FDA identified “Arterial Embolization Devices” as an example of an SR device in FDA’s guidance “Significant Risk and Nonsignificant Risk Medical Device Studies” (available at http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm126418.pdf
To use an SR device in an investigation, a sponsor must submit an IDE application to FDA and receive FDA approval. You failed to submit an IDE application and receive FDA approval before you began your investigation, and have failed to submit an IDE application to date. Your written response states that you have taken the following corrective actions:
- voluntarily suspended all potential subjects’ enrollment and study related procedures including the PAE procedure on July 11, 2013;
- contacted all study subjects and informed them in writing about the PAE study suspension;
- removed all recruitment material (e.g., web page trial information and poster signage); and
- notified the INOVA IRB that you have suspended enrollment into the trial, and met with INOVA IRB, Human Research Protection, Departmental and Hospital Leaders to review all research related activities.
Your response is inadequate. You have not provided documentation of notification to the subjects of the study’s suspension. Please provide a copy of the letter sent to the subjects and documentation that all subjects were notified.
2) Failure to conduct the investigation according to the signed agreement, the investigational plan, applicable FDA regulations, and any conditions of approval imposed by an IRB. [21 CFR 812.110(b)]
A CI is responsible for conducting an investigation according to the investigational plan, which includes the study protocol. You failed to adequately assess study subjects post-PAE, as required by the study protocol.
Section 3.1.5 of the protocol (“Initial follow up period”; version 3) requires a clinical evaluation that includes a review of patients’ history, a physical examination, and an adverse event evaluation as part of the 2 week follow-up evaluation post-PAE procedure. You conducted the 2 week post-PAE procedure follow-up evaluations by telephone for 7 subjects. No physical examination was performed, as required by protocol, for these subjects:
2 Week Follow-up
Your failure to perform follow-up physical examinations increased the risks to subjects because of the potential delay in recognizing and treating any study related complications.
In response to the above violations, you state the following:
- The protocol was amended and filed with the IRB to conduct a “telephone interview” for clinical assessments for the sub-group from the early enrolled cohort (subjects: 25, 26, 27, 28, 30, 31 & 32) who were identified as “out of town”;
- The research team determined that because these subjects were not going to be available for a clinic visit, telephone interviews would enable the investigators to assess the subjects’ clinical status;
- There was a typographical error within the track changes protocol sections that did not transfer through to all follow-up intervals and only changed for the 30-day follow-up visit; and
- Protocol amendments will be reviewed by the Agency and INOVA IRB per 21 CFR 812.35 and 21 CFR 812.40 in the proposed IDE application.
Your response is inadequate in that you failed to provide documentation of the steps that you have taken or plan to take to prevent recurrence of the violation. In addition, the IRB-approved protocol (revised on August 9, 2012), which you submitted (Attachment H) with your response, does not include “telephone interviews” on the 2 week follow-up period. Please provide a new and/or revised protocol to address the above violation and a list of study staff trained with the date of training and implementation.
3) Failure to include a description of the procedure to be followed in the informed consent document (ICD). [21 CFR 50.25(a)(1)]
Although the IRB reviews and approves the ICD, as the sponsor and CI, you are responsible for ensuring the informed consent process meets the regulatory requirements. The ICD must contain all the elements listed in 21 CFR 50.25(a), including a description of the procedures to be followed. In order to make an informed decision to participate, subjects must be given all applicable information. Your ICD does not include all of the essential elements listed in 21 CFR 50.25.
For example, section 3.1.5 of the protocol requires that enrolled subjects undergo follow-up blood tests -- including a complete blood count, basic metabolic panel, and prostate specific antigen test -- at 6, 12, and 24 months subsequent to the completion of the PAE procedure. Moreover, section 3.1.5 of the protocol states that an MRI with and without contrast must be performed after the PAE procedure, and an ultrasound must be performed if the MRI is clinically contraindicated of the prostate. Notably, the ICD does not reference these follow-up procedures at 6, 12, and 24 months nor does it address the need for an MRI/ultrasound.
In your response, you state that the ICD clearly includes all pre-operative, operative, and post-operative procedures in detail. We reviewed all the ICD versions and none include the information discussed above. You committed to addressing these observations in your future IDE application, and noted the corrective actions indicated in response to observation number 1 above.
This response is inadequate in that it lacks a corrective and preventive action plan to ensure that adequate ICDs will be provided to subjects prior to any study-related procedures. In addition, you did not provide documentation that you contacted the subjects to complete follow-up evaluations and/or diagnostic tests as required by the investigational plan. Please provide us with copies of any communications to subjects and the results of your follow-up attempts. Also, please provide copies of new or revised policies, procedures, and trainings that you have developed and implemented to ensure that ICDs contain all the essential elements in accordance with 21 CFR 50.25. In addition, please indicate the expected completion dates for all trainings that you have developed or implemented regarding this issue.
4) Failure to prepare and submit reports to the reviewing IRB of unanticipated adverse device effects (UADE) occurring during an investigation as soon as possible, but in no event later than 10 working days after the investigator first learns of the effect. [21 CFR 812.150(a)(1)]
An investigator shall prepare and submit complete, accurate, and timely reports of UADEs to the reviewing IRB as soon as possible, but in no event later than 10 working days after the investigator first learns of the effect. You failed to adhere to the above stated regulation. For example, Subject #2 (b)(6) underwent the PAE procedure on (b)(6). The operation dictation indicates no complication. In the (b)(6) post-PAE follow-up visit, Subject #2 reported that he was unable to obtain an erection on (b)(6). On (b)(6), Subject #2 (b)(6) also reported that urinary urgency was more bothersome post embolization and he has been unable to have an erection post embolization.
In your response, you state that Subject #2 has a pre-existing condition of Erectile Dysfunction/Male Impotence, diagnosed (b)(6) prior to study enrollment. The subject’s self-performed International Index of Erectile Function Scale (IIEF) at baseline, 1, 3, and 6 months all indicated the level/grade of severe erectile dysfunction that was unchanged. In addition, you indicated you reported all adverse events according to INOVA IRB’s policies.
Your response is inadequate in that it does not address the subject’s complaint of increased urinary urgency since the procedure and does not describe your corrective and preventive actions for properly reporting UADEs such as this one to the reviewing IRB. Please provide copies of the correspondence submitted to the IRB regarding the subject’s urinary urgency complaints, and the corrective action you have taken to prevent the recurrence of this violation. In your response, please provide copies of the policies and procedures that you have developed and implemented to ensure reporting of UADEs is performed in accordance with the protocol, the reviewing IRB requirements, and applicable FDA regulations. In addition, please indicate the expected completion dates for all trainings that you have developed or implemented regarding this issue.
5) Failure to ensure proper monitoring of the investigation. [21 CFR 812.40]
As a sponsor, you are responsible for ensuring proper monitoring of the investigation. Proper monitoring helps ensure that the safety, rights, and well-being of the subjects are protected and that the data is complete and accurate. Monitoring should be an on-going program performed with the frequency necessary to ensure that the investigation is conducted according to the investigational plan, FDA regulations, and any conditions of approval required by FDA or the reviewing IRB.
Section 3.5 of your protocol, “Monitoring Subjects and Criteria for Withdrawal of Subjects from the Study,” states that site monitoring visits will be conducted as needed by authorized representatives of the Principal Investigator. There is no documentation indicating that monitoring was done since the initiation of your study. Monitoring was needed in order to review records, source documents and study procedure for the presence and appropriate documentation of adverse events and protocol deviations.
Your response states that the Clinical Research Coordinator and the Clinical Investigator conducted weekly data monitoring and reported adverse events per INOVA IRB policies and surgical/intraoperative procedural complications were monitored in the (b)(4). However, when the FDA investigator asked you to provide all monitoring documentation/communications with the reviewing IRB for the study, you told the FDA investigator that monitoring activities were not documented. You also indicated that no adverse events were related to the surgical procedure.
Your response is inadequate because it does not identify any corrective or preventive actions either taken or planned to ensure that this violation does not recur. Please describe in detail the actions you plan to take to correct this observation and prevent any recurrence. Please include how you plan to provide training with expected completion date to Sub-Investigators and the Clinical Research Coordinator to ensure adequate monitoring for future studies.
6) Failure to maintain accurate, complete, and current records. [21 CFR 812.140(a)(3)]
An investigator shall maintain accurate, complete, and current records relating to the investigator’s participation in an investigation, including records of each subject’s case history and exposure to the device. Your files (i.e., labs, consent forms, medical records, etc.) for subjects who participated in the PAE procedure were incomplete and/or missing documents.
Please provide copies of policies, procedures, and training with expected completion dates that are being developed and implemented to ensure subjects’ case histories are complete and accurate.
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 study sponsor to ensure compliance with the Act and applicable regulations.
In addition to the violations described above, the FDA investigators also discussed with you the following two concerns related to the ICD:
- The ICD lacked a description of reasonable foreseeable risks or discomfort to the subjects. Specifically, all versions of the study protocol include bladder necrosis as a procedural risk for the PAE procedure. However, bladder necrosis was not included as a known risk factor on any version of the ICD.
- The ICD did not contain a complete description of appropriate alternative procedures or treatments, if any, that might be advantageous to the subjects. Specifically, alpha-blockade medication and anti-adrenergic medications were listed as alternative procedures or courses of treatment in the protocol. However, these were not included as alternative treatments in any version of the ICD. This is a significant omission as subjects should have been made aware that these non-surgical treatment alternatives existed. This would have allowed them to adequately consider and weigh all the risks associated with participating in the study.
Within 15 working days of receiving this letter, please provide documentation of the additional 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 study sponsor and/or CI. Include the projected completion dates for each action to be accomplished as well as a plan for monitoring the effectiveness of your corrective actions. Failure to respond to this letter and take appropriate corrective action could result in FDA taking regulatory action without further notice to you.
Your response should reference “CTS # EC130297/E001” 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 Baltimore District Office, 6000 Metro Drive, Suite 101, Baltimore, MD 21215. 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/ucm162015.htm
Steven D. Silverman
Office of Compliance
Center for Devices and