Inspections, Compliance, Enforcement, and Criminal Investigations

UVLRX Therapeutics Inc 9/25/17

 

 

  

Black HHS-Blue FDA Logo

 

 

 
10903 New Hampshire Avenue
Silver Spring, MD 20993 

 

September 25, 2017
 
WARNING LETTER
 
VIA UNITED PARCEL SERVICE
 
Victor Scheeren
Executive Vice President
UVLrx Therapeutics, Inc.
640 Brooker Creek Blvd, Ste. 455
Oldsmar, FL 34677-2934
 
Dear Mr. Scheeren:
 
This Warning Letter is to inform you of objectionable conditions observed during the Food and Drug Administration (FDA) inspection conducted at UVLrx Therapeutics, Inc. from March 27, 2017, to April 4, 2017, by an investigator from the FDA BIMO EAST Division. This inspection was conducted to determine whether activities and procedures as sponsor in the clinical study “UVL_0001 A Polychromatic Light Emitting Diode System to Deliver Low Dose Light Directly into a Peripheral Intravascular Catheter: A Safety and Feasibility Study”, complied with applicable federal regulations. The UVLRX Station 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 also requests prompt corrective action to address the violations cited and discusses your firm’s written response dated April 25, 2017 to the noted violations.
 
The inspection was conducted under a program designed to ensure that data and information contained in requests for Investigational Device Exemptions, 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 inspectional observations Form FDA 483 for your firm’s review and discussed the observations listed on the form with you. The deviations noted on the Form FDA 483, your firm’s written response, and our subsequent review of the inspection report, are discussed below:
 
1.    Failure to obtain Institutional Review Board approval of the investigation [21 CFR 812.2(b)(1)(ii)]
 
As a sponsor, you are responsible for obtaining IRB approval of the investigation after presenting the reviewing IRB with a brief explanation of why the device is not a significant risk device and maintains such approval. For multiple studies, your firm failed to obtain approval of protocols, increasing enrollment and the number of clinical investigators.  Examples of this failure include but are not limited to the following:
 
a.  There were no approval for studies: “(b)(4)”, and the “(b)(4)
 
b.  On February 25, 2016, the IRB only approved enrollment for 1000 subjects in Protocol (b)(4). Yet approximately 3,063 subjects were enrolled.
 
c.  There is no approval of at least ten Clinical Investigators (CIs) for the approved study under Protocol UVL_0001, although they received investigational devices and began treating subjects. Unapproved investigators include, but are not limited to the following:
 

Unapproved Investigators Shipped/Received
Number of Devices
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)

 
d.  There was no IRB approval of a number of CIs prior to the beginning of study investigations for: (b)(4).
 
Your firm’s failure to obtain IRB approval is a serious violation of your responsibilities as a sponsor. Without IRB approval, there is no assurance that the rights and welfare of subjects were adequately protected. This includes verifying that the informed consent (IC) was adequate and subjects fully understood the study objectives, procedures, risks and benefits.
 
2.    Failure to comply with the requirements of 812.46 with respect to monitoring investigations [21 CFR 812.2(b)(1)(iv)]
 
As a sponsor your firm is responsible for ensuring proper monitoring of the investigation whether the study is significant risk (SR) or non-significant risk (NSR). Your firm did not monitor studies or maintain documentation, as a result investigational products were shipped to unapproved and unqualified investigators, subject enrollment exceeded the approved number of 1000 subjects, and documentation that CIs were provided training and information needed to conduct the investigation properly were not provided. These studies included Protocols (b)(4). Examples of this failure include but are not limited to the following:
 
a.  There is no documentation of monitoring activities of your studies.
 
b.  Your firm’s staff shipped investigational devices to un-qualified investigators. Examples include, but are not limited to the following:
 
-  (b)(4), an unapproved investigator participating in the (b)(4), treated 16 subjects
-  Two devices were shipped to the site (b)(4); one on October 23, 2014 to (b)(4) and one on August 8, 2016 to (b)(4) who were listed as qualified clinical investigators
-  Approximately five investigators who participated in (b)(4) were shipped devices after the site had been administratively closed by the IRB
-  No documentation was provided which listed a physician in (b)(4) as a qualified CI after four devices were shipped to his office on August 2, 2016
-  At least one device was shipped to a physician in (b)(4) who was not listed as a qualifying investigator for any investigation involving the investigational device
 
c.    Your firm’s staff failed to provide documentation that clinical investigators completed training on the device.
 
Inadequate monitoring can put subjects at risk: potential defects with the device and its performance; adverse events which may affect subject safety; and protocol deviations that may affect subject safety and data integrity. Sponsor monitoring is also necessary to confirm that the investigational device is shipped and used only by qualified investigators on subjects appropriately enrolled in the study. If the device were used by unqualified individuals on patients not enrolled in the study there could be an increased risk of harm to the patient.
 
3.    Failure to maintain the records required under 812.140(b) (4) and (5) [21 CFR 812.2(b)(1)(v)]
 
As a sponsor your firm is responsible for maintaining complete and accurate records. You failed to maintain records of adverse device effects and any other information required by the Agency (e.g., device use and disposition records). Examples of this failure include but are not limited to the following:
 
a.  There were no documents/records of anticipated or unanticipated adverse device effects.
 
b.  Failure to maintain complete records of disposition of a device which describe the batch number or code marks of any devices returned to the sponsor, repaired and disposed of by an investigator or another person, and the reasons for any method of disposition reports.
                               
By failing to maintain complete, accurate, and current records related to your firm’s clinical studies, study subjects’ safety and welfare as well as study data may have been impacted.
 
4.    Failure to label the device in accordance with 812.5 [21 CFR 812.2(b)(1)(i)]
 
As a sponsor your firm is responsible for labeling the investigational device to include: the name and place of business of the manufacturer, packer, or distributor, the quantity of contents, if appropriate, and the following statement: “CAUTION-Investigational device. Limited by Federal (or United States) law to investigational use”.  Your firm failed to apply proper device labeling, to include the investigational device caution statement, prior to the shipment of devices to study sites.
 
The lack of appropriate caution labeling may prevent the investigational device from being used correctly and adverse events are tracked correctly. In addition, proper labeling helps ensure that the investigational devices are used correctly by qualified investigators on subjects appropriately enrolled in the study.
                                   
In addition to the violations above, the inspection also revealed that your firm did not have any documentation demonstrating that each investigator participating in the investigation of the device obtained from each subject under the investigator’s care, informed consent under part 50 and documents it, unless documentation is waived by an IRB under 21 CFR 56.109(c). This is required under 21 CFR 812.2(b)(1)(iii). To meet the abbreviated requirements for devices that are not significant risk devices, sponsors must ensure that each investigator participating in the investigation obtains from each subject under the investigator's care. In seeking informed consent, basic elements, and additional elements when appropriate, must be provided to each subject. Informed consent shall be documented by the use of a written consent form approved by the IRB and signed and dated by the subject or the subject's legally authorized representative at the time of consent.
 
Your firm’s overall response acknowledged the violations above but also stated that the issues were the result of inadequate management received from the former CRO, Ryan Maloney. However, as sponsor your firm is responsible for all oversight governing the clinical studies. Therefore, your response is inadequate. Your firm’s response indicates that changes have been made with personnel and training. Additionally, drafts of Standard Operating Procedures (SOPs) have been instituted and you made corrective actions to include ensuring that the investigational devices that were shipped prior to receiving the caution label have been removed from circulation. Although you provided a list of dates that training was completed and a list of staff that completed the training, final copies of the related SOPs including the implementation date were not provided with your response. You also stated that a new IRB Project Manager was hired to oversee all IRB protocol activities and establish training modules to ensure that investigators follow proper procedures. You have not provided instructions on how to complete these forms. As a result, your firm’s response is incomplete. Please provide the following:
  • Documentation of all new and revised SOPs in the finalized version.
  • Documentation demonstrating that all research staff at your firm that are involved in clinical trials have been adequately trained on all newly created and modified SOPs.
  • A preventive action plan demonstrating how you will ensure that all of anticipated and unanticipated adverse device effects will be adequately received and documented.
  • A preventive plan to ensure that for future studies all shipment and disposition of devices will be adequately monitored and documented.
  • A preventive action plan to ensure that for future studies all participating investigators will obtain informed consent under part 50 and documents it, unless documentation is waived by an IRB under 21 CFR 56.109(c). In addition, ensure that the informed consent document will contain all the required basic elements.
  • Documentation demonstrating that all clinical research staff has been adequately trained on the above preventive action plans above.
  • Documentation on your firm’s plan to address labeling and training that will be provided to staff responsible in the labeling of all investigational devices.
  • Timeline for the implementation of the corrective actions, finalized SOPs, and follow-up. 
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.  
 
Within 15 working days of receiving this letter, please provide documentation of the additionalcorrective 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 study sponsor. Any submitted corrective action plan must include 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 the FDA taking regulatory action without further notice to you. 
 
Your response should reference “CTS # EC170026/E001 and be sent to:   
 
Attention: Sheena Green
Food and Drug Administration
Center for Devices and Radiological Health
Office of Compliance
Division of Bioresearch Monitoring
10903 New Hampshire Avenue
Building 66, Room 3520
Silver Spring, Maryland 20993-0002.
                       
A copy of this letter has been sent to Bioresearch Monitoring Operations Division 1 (BIMO EAST) ­­­­.  Please send a copy of your response to that division via email at ORABIMOE.Correspondence@fda.hhs.gov.
 
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/.
 
We are interested in having a teleconference with you to discuss the issues outlined in this letter and provide you with guidance on future FDA-regulated studies in which you may participate in. Please contact Cynthia Bushee at (301)796-6114 or Cynthia.bushee@fda.hhs.gov after you respond to this letter in writing with proposed dates and times for the teleconference. If you have any questions about the content of this letter, please also contact Cynthia Bushee.
 
Sincerely yours,
/S/ 
Robin W. Newman, MSN, EdD
Director
Office of Compliance
Center for Devices and Radiological Health

Page Last Updated: 10/23/2017
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