- Lazzaro, Marc, 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
JUL 9, 2015
VIA UNITED PARCEL SERVICE
Marc Lazzaro, MD
Froedtert Memorial Lutheran Hospital
9200 W. Wisconsin Avenue
Milwaukee, WI 53226-3522
Dear Dr. Lazzaro:
This Warning Letter is to inform you of objectionable conditions observed during the Food and Drug Administration (FDA) inspection of your clinical site from February 24, 2015, to March 23, 2015, by an investigator from the FDA Minneapolis District Office. This inspection was conducted to determine whether your activities and procedures related to your participation as a clinical investigator (CI) in the significant risk clinical study, “(b)(4)", Investigational Device Exemption (IDE) (b)(4) complied with applicable federal regulations. This inspection was expanded to include IDE (b)(4), titled "(b)(4).” The (b)(4) and the (b)(4) are devices as those terms are 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 April 10, 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, 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 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 in accordance with the signed agreement, the investigational plan, applicable FDA regulations, and any conditions of approval imposed by the Institutional Review Board (IRB) or FDA [21 CFR 812.110(b)].
A Clinical Investigator is responsible for ensuring that an investigation is conducted according to the investigational plan and applicable FDA regulations. You failed to follow exclusion criteria. Examples include the following:
a. Subjects enrolled in the (b)(4) studies met exclusion criteria after the IRB audit, for example:
1) Section 3.4.2 (v. 9/25/12) of the (b)(4) study protocol states to exclude subjects with multiple cerebral aneurysms or extradural ones. At least one subject (006) was identified as having this medical condition at the time of pre-implant evaluation and then inappropriately enrolled.
2) The (b)(4) study protocol, section 2.3, and case report form # 2, describe exclusion criteria including a Modified Rankin Score. Subjects 009 and 010 showed Modified Rankin Scores greater than or equal to one but were then enrolled, an exclusion criteria.
According to the study protocol, the risks associated with the study include but are not limited to intracerebral/intracranial hemorrhage,aneurysm rupture, emergent neurosurgery and death. Your enrollment of subjects who met the exclusion criteria may have increased their risk of developing these and other study related complications.
In your response, you agree with this observation and accept responsibility for this violation. You also acknowledge that you did not ensure that research staff (sub-investigators and other staff) had a clear understanding of the protocol. As a CI, it is your responsibility to ensure that the protocol is followed as written.
Also in your response, you explain that you plan to conduct early internal review, continuing review, staff training, and review of CI responsibilities. Your response is inadequate because it does not provide documentation of these preventive measures. Please provide documentation of your procedures for early internal and continuing review, training of staff, list of names and dates trained. In addition, provide a list of training you received in the conduct of human research, including content and completion date(s).
2. Failure to ensure that informed consent was obtained in accordance with 21 CFR Part 50. [21 CFR 812.100, 21 CFR 50.20, 21 CFR 50.25, 21 CFR 50.27].
An investigator is responsible for obtaining and documenting informed consent from a subject using a consent form approved by the Institutional Review Board (IRB) prior to involving the subject in the clinical investigation. You failed to ensure that informed consent was obtained from subjects and documented in accordance with federal regulations. Examples of these failures include, but are not limited to, the following:
a. In the (b)(4) study, Subject (ID (b)(6)) signed an incorrect version of the Informed Consent Document (9/10/12). The CI signature was cut and pasted onto the 5/13/13 version of the document.
b. In the (b)(4) study, Subject 006 signed the informed consent document on 7/22/13. A study coordinator cut and pasted a copy of Dr. Lazzaro’s signature on the document and sent it to the sponsor on 7/29/13.
c. In the (b)(4) study, on (b)(4), an intervention was conducted emergently because subject 003 suffered a stroke. The subject was unable to sign, and the neurology nurse signed the informed consent for the subject. The subject died on (b)(6). Her husband and a sub-CI signed the consent form after her death on 2/22/13.
A valid informed consent process ensures that research subjects have a clear understanding of risks of participation in a research protocol, have sufficient opportunity to consider whether to participate in the study, and make an informed decision if they decided to participate. The Clinical Investigator is responsible for ensuring that study subjects were made aware of these risks prior to study enrollment. Their acceptance of these risks must be documented through a signed informed consent document with these risks are clearly listed.
Your response, that you do not dispute the findings in this observation and accept responsibility for this violation, includes your recognition that you failed to provide adequate oversight of the study. In addition you acknowledge a lack of understanding of the differences between clinical practice and research activities. As CI, it is your responsibility to ensure that informed consent is obtained and reviewed through the course of the research.
As part of your corrective measures you state that you plan to provide frequent and detailed review of the consenting documents and closely review and double check research staff to ensure CI signature is completed in a timely manner. Also you state that you plan to be included in all communications between the sponsor and research staff in future, and provide training for staff. Your response is inadequate because it does not explain how this will be done and document these corrective measures.
Please provide documentation of your plan for ensuring effective communication between you and the sponsor and between you and your staff. Also, provide documentation of your plan to sign and date informed consent documents in a timely manner. Furthermore, provide documentation of any training for staff to ensure adequate audit of consent documents is conducted with regularity. Please include content, names of attendees and dates of staff training for all involved with the informed consent process.
3. Failure to maintain accurate, complete, and current records of each subject’s case history and exposure to the device [21 CFR 812.140(a)(3)].
A Clinical Investigator is required to maintain subject records and assure their accuracy and completeness. This requirement includes records concerning previous medical history, condition of subjects upon entering the investigation, during the course of the investigation, and all the diagnostic test results. You failed to fulfill this requirement because study related records and files at your site were found to be incomplete and inadequate. Examples include the following:
a. In the (b)(4) study, Subject 006’s procedure date was (b)(4). The pre-implant Case Report Form (CRF) was not completed until nearly 6 months later (12/20/13) and there was no source documentation available to support this data. The staff used lab values from a sample that was collected on (b)(4) (nine days after the procedure) as the two-month follow-up labs.
b. Data on the electronic CRF for (b)(4) Subject 001’s 12-month follow-up visit does not match the source CRF.
c. The (b)(4) study Case Report Form for Subject 005 had the clot type left blank two years after the procedure.
The missing data includes clinically significant information regarding case histories, test results, clinical assessments, and follow-up visits. This information is required to ensure that subjects are receiving necessary study procedures and are not experiencing medical complications that may be device related. Accurate, complete, and current research records also help ensure the validity of the data collected from your site. The failure to maintain accurate, complete and current records relating to the investigation may undermine the validity of the data and lead to errors in subject management with potentially serious health consequences.
In your response, you plan to perform an in-depth early review of study files, communicate with research staff and replace research staff. This response is inadequate because it does not provide documentation of these corrective measures. Please provide documentation of the above, including any training records or revised procedures demonstrating that you have implemented the corrective and preventive actions.
Furthermore, many of the deviations identified during the inspection, such as those described above, were not reported to the IRB. Specifically, the continuing review of the protocol failed to include any documentation of protocol deviations. You state in your response that you plan to meet with staff weekly and maintain a spreadsheet to track events. This response is inadequate because it does not provide documentation of the corrective measures. Please provide a timeline of actions you plan to take or have taken, a copy of the tracking spreadsheet and your plan for training staff, including agenda, names of attendees and dates.
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.
Within 15 working days of receiving this letter, please provide documentation of thecorrective 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 # (b)(4) and be sent to:
Attention: Adam Donat, MS
Food and Drug Administration
Center for Devices and Radiological Health
Office of Compliance
Division of Bioresearch Monitoring
10903 New Hampshire Avenue
Building 66, Room 3450
Silver Spring, Maryland 20993-0002.
A copy of this letter has been sent to FDA’s Minneapolis District Office, Food and Drug Administration, 250 Marquette Avenue, Suite 600, Minneapolis, MN 55401.Att: Michael Dutcher, DVM, District Director. Please send a copy of your response to that office.
The Division of Bioresearch Monitoring has developed training modules about FDA-regulated device clinical research practices. You may find them helpful for you and your staff. These modules are located at the following website address: http://www.fda.gov/Training/CDRHLearn/default.htm
Jan B. Welch, MHS, MT (ASCP) SBB
Office of Compliance
Center for Devices and