- Wakai, Ronald, Ph. D.
- 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
December 19, 2014
VIA UNITED PARCEL SERVICE
Ronald Wakai, Ph.D.
UW Biomagnetism Lab
Department of Medical Physics
University of Wisconsin School of Medicine and Public Health
1111 Highland Avenue
Madison, Wisconsin 53705
Dear Dr. Wakai:
This Warning Letter is to inform you of objectionable conditions observed during the Food and Drug Administration (FDA) inspection of your clinical site from August 8, 2014, to August 22, 2014, by an investigator from the FDA’s Minneapolis District Office. This inspection was conducted to determine whether activities and procedures related to you as a sponsor and clinical investigator (CI) of the significant risk clinical study “(b)(4) Investigational Device Exemptions (IDE) (b)(4) and (b)(4),” IDE (b)(4), complied with applicable federal regulations. The (b)(4), are devices 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 they are 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 September 12, 2014, 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 and Part 50 - Protection of Human Subjects, 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 conduct the investigation according to the signed agreement, the investigational plan, applicable FDA regulations, and any conditions of approval imposed by an Institutional Review Board (IRB) or FDA [21 CFR 812.110(b)].
A clinical investigator is responsible for conducting an investigation according to the signed agreement, the investigational plan, applicable FDA regulations, and any conditions of approval imposed by an IRB or FDA. You failed to follow exclusion criteria, complete eligibility forms and obtain IRB approval of protocol revisions. Examples of these failures include the following:
a) The (b)(4) study protocol excludes subjects with pacemakers, metal implants, and other non-removable magnetic objects. However, you enrolled seven subjects (Subject # 568, 631, 642, 676, 700, 705 and 711) with implants. Enrolling subjects who met the exclusion criteria could result in an increased risk of harm to subjects and is in violation of your responsibility as a clinical investigator.
b) The (b)(4) Manual of Operations and Procedures (MOP), Version 1, requires completion of screening and eligibility forms before obtaining a reading with the investigational device. However, you did not complete or sign required forms for the following subjects until after the procedure:
- 5/14 Medical History Referral Forms (MP-004) - subjects 715, 718, 719, 722 and 723,
- 9/14 Referral Echocardiogram Forms (MP-006) - subjects 712, 713, 715, 716, 717, 721, 722, 723 and 725.
In addition, you completed the wrong versions of Eligibility Forms (MP-003) for subjects 713, 714, 715, and 716.
c) You did not submit the (b)(4) Versions 1 and 2 for IRB approval, per the Investigator Agreement. Obtaining IRB approval of any changes to the protocol before conducting study procedures helps ensure that the risks to study subjects are minimized by allowing the IRB to make any changes and decide whether any additional measures need to be implemented to protect the safety and welfare of study subjects.
Your failure to adhere to these requirements may call into question the integrity and reliability of the data you obtained during the course of the studies, and also increases the risk of harm to the participating subjects.
Your response states that you thought that it was permissible to study subjects with pacemakers that did not produce large magnetic interference. The device is investigational and your enrollment of pregnant study subjects with documented magnetic implants, including cardiac pacemakers, placed both the subject and their unborn fetus at increased risk of unknown but potentially harmful complications.
Your response also states that you have revised the forms to ensure that information essential for verification of study eligibility is documented prior to enrollment. In addition, you proposed to implement the following actions:
- Ensure that all study team members are aware of protocol changes and how to access the most currently approved protocol;
- Review with the study team Noncompliance Policy and various guidances;
- Clarify the screening process and submit revised protocol and medical forms for IRB review and approval;
- Work with the (b)(4) to ensure that the formal protocol includes relevant details from the (b)(4);
- Develop and finalize relevant study forms prior to subject enrollment, maintain a version history, and promptly alert team to any changes; and
- Work with the study monitor to correct deficiencies noted and promptly document corrective actions taken.
Your response is inadequate because it lacks adequate measures to prevent recurrence and documentation to substantiate your proposed actions or actions already taken. Please perform and document a root cause analysis, and provide documentation of your system for evaluating inclusion/exclusion criteria prior to enrollment. Please provide copies of new or revised policies, procedures, and trainings that you have developed or plan to implement, with expected completion dates.
2) Failure to ensure that informed consent is obtained in accordance with Part 50 [21 CFR 50.27(a)].
An investigator is responsible for obtaining informed consent from each subject using an IRB-approved version of the informed consent document (ICD) prior to involving the subjects in the clinical investigation. However, in both the (b)(4), you consented 5 out of 21subjects (# 705, 711, 718, 719, and 720) with the wrong IRB-approved informed consent version. The use of valid, IRB approved ICD’s helps confirm that the appropriate human subject protections measure are in place and that subjects are provided with all the information they need to make an informed decision on whether to participate in the study.
Your response states that you have corrected this error by re-stamping the forms signed by subjects 718, 719, and 720 without changes. In addition, you plan to utilize a shared drive to promptly download revised IRB-approved consent forms and to notify study personnel when the IRB has approved protocol changes.
Your response is inadequate. Please provide copies of any communications to subjects and results of your attempts to re-consent subjects with the correct IRB- approved consent version. Please provide copies of any policies, procedures, and training that you have developed, with expected completion dates, to ensure that ICDs are obtained in accordance with 21 CFR 50.27(a).
3) Failure to maintain accurate, complete, and current records [21 CFR 812.140(a)(1)] and [21 CFR 812.140(a)(3)].
A clinical investigator is responsible for maintaining accurate, complete, and current records relating to correspondence with the IRB, the sponsor, a monitor or FDA, and of each subject’s case history and exposure to the device, which encompasses the case report forms (CRFs) and supporting data. Examples of your failure to maintain accurate and complete records include the following:
a) There is no documentation that indicates that all 144 subjects enrolled in the study were evaluated per the (b)(4) study protocol for meeting inclusion/exclusion criteria.
b) There is no documentation for correspondence to Shared Medical Technology, Incorporated for changes made to the IC Forms and the Protocol for the (b)(4) study. Clear records of IRB approval of each study protocol version do not exist and records of IRB-approved protocol versions were not maintained.
c) Records of each subject's exposure to the investigational device are not all accurate. Specifically, subject 715 and 720’s records have inconsistent dates of study visit and exposure to the investigational device for the following documentation: Informed consent, Subject Questionnaire, Demographics Form, and Oncore Database for CRFs.
Your failure to maintain accurate and complete records compromises the consistency and reliability of the data collected from your site. Inconsistent documentation may also lead to errors in subjects’ medical care and as a result may harm subjects. The missing data includes clinically significant information regarding the subjects’ exposure to the device, visit dates and informed consent documentation. This information is necessary to ensure that subjects are receiving the correct study procedures and are appropriately consented.
Your response states that you were unaware that it was necessary to document that each subject met the inclusion/exclusion criteria. High-risk subjects were screened based on communications between the subject’s physician and (b)(4), a co-investigator on the study; however, these communications were not documented.
As the study clinical investigator, you are responsible for ensuring that all study related clinical information is clearly and accurately documented. Your study cohort included pregnant women who as a group are at relatively high risk of complications to both the subject and the unborn fetus. It is critically important that information documenting each subject’s evaluation prior to enrollment is clearly documented to confirm that they were appropriately enrolled in the study. This information is also needed to assess any study-related complications that may occur.
Your response states that Shared Medical Technology, Inc., was aware and supported the protocol changes. However, you acknowledged that you did not systematically document communication prior to the audits. Also, you acknowledged that you did not maintain adequate documentation of IRB review and approval and that the inconsistent documentation of dates was due to human error.
As part of your corrective actions, you have added the communication between you and the sponsor in the regulatory binder, corrected dates, and corrected subjects 715 and 720’s records. In addition, you have implemented (b)(4); created a table of the IRB submissions; and implemented a system to document IRB approval dates for the protocols. You state that you will work with the IRB to reconcile any gaps in documentation and to ensure that they have a complete regulatory record of IRB correspondence and reviews. Also, you state that you plan to have a second person verify the dates and documentation of important information on forms and that you will conduct periodic quality assurance audits of the (b)(4) entries. You will focus on the informed consent process and the importance of data integrity and documentation during the in-person training by the (b)(4).
Your response is inadequate because you did not submit documentation of your communication with Shared Medical Technology, Inc., and the IRB. Also, you did not submit documentation related to the correction of subjects 715 and 720’s records. Moreover, you did not provide documentation of training from all research staff involved in the conduct of these studies.
In addition to the violations described above, the FDA Investigator also cited violations related to your conduct as sponsor for the study “(b)(4),”IDE (b)(4).
4) 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. However, there is no documentation indicating that monitoring was done since the start of the (b)(4) study in which you enrolled 144 subjects. Proper monitoring helps ensure that the safety, rights, and well-being of the subjects are protected and that the data are 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.
You acknowledged in your response that monitoring was not performed during Stage 1 of the study (b)(4) after the study monitor left the Medical College of Wisconsin due to budget cuts. Your response is inadequate because it does not identify any corrective or preventive actions. Please describe in detail the actions you plan to take to correct this observation and prevent any recurrence. Please include documentation of how you plan to provide training with expected completion date to Sub-Investigators to ensure adequate monitoring for future studies.
We acknowledge your other plans to address the deficiencies and comply with applicable federal regulations governing human subjects’ research:
- You will hire a new study team member to ensure you stay in compliance with human subjects regulations and the University of Wisconsin-Madison (UW-Madison) policies;
- You will use the Office of Clinical Trials regulatory services to prepare submissions;
- All personnel will take the Collaborative Institutional Training Initiative (CTTI) Program’s Good Clinical Practice (GCP) training; and
- The (b)(4) will provide in-person training for the current study team.
In addition to your written response to the above violations, FDA received three letters dated August 28, 2014, September 15, 2014, and October 16, 2014, from Dr. Dan Uhlrich, the Associate Vice-Chancellor for Research Policy, UW-Madison. Dr. Uhlrich notified us that the Health Sciences IRB has suspended the (b)(4) study and the (b)(4) study, and has reported the suspension to the Office of Human Research Protection and the FDA. Also, the IRB will review all noncompliance that occurred and will work with you to ensure adequate corrective actions are put in place. Moreover, the ICTR has launched an IND/IDE Consultation Service to ensure that all UW-Madison investigators register with the consultation service and are aware of their additional responsibilities as sponsor-investigators. We are unable to verify the adequacy of the UW-Madison (b)(4) recently launched IND/IDE Consultation Service without supporting documentation.
We believe that a teleconference with you and Shared Medical Technology, Inc., may be helpful to further clarify the responsibilities of a sponsor and discuss corrective and preventive actions. We ask that you contact CDR Isatu Bah at (301) 796 – 5655 or Isatu.Bah@fda.hhs.gov
within two weeks of receiving this letter to propose several dates and times.
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 sponsor and clinical investigator to ensure compliance with the Act and applicable regulations.
Within 15 working days of receiving this letter, please provide documentation of the additional corrective and preventive 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. 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 # (b)(4)” 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 Minneapolis District Office, 250 Marquette Avenue, Suite 600, Minneapolis, MN 55401. 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/
Steven D. Silverman
Office of Compliance
Center for Devices and