Inspections, Compliance, Enforcement, and Criminal Investigations
William A. Gray, M.D. 16-Mar-05
Department of Health and Human Services
Public Health Service
Center for Devices and Radiological Health
Via Federal Express
William A. Gray, M.D.
Swedish Medical Center
Swedish Cardiovascular Research
1221 Madison Suite 1020s
Seattle, WA 98122
MAR 1 6 2005
Dear Dr. Gray:
The purpose of this Warning Letter is to inform you of the objectionable conditions found at your clinical site during a Food and Drug Administration (FDA) inspection conducted from July 13- August 15, 2004 by Ms. Nancy Saxenian Emmons, an investigator from the FDA Seattle District Office . This letter also discusses your written response dated October 21, 2004 to the noted violations and requests that you implement prompt corrective actions to the violations cited.
The purpose of the inspection was to determine if your activities and procedures relating to your participation in the following clinical studies complied with applicable federal regulations:
The products under investigation are devices as that term is defined in section 201(h) of the Federal Food, Drug, and Cosmetic Act, 21 U.S .C. 321(h) . The FDA conducted the inspection under a program designed to ensure that data and information contained in requests for Investigational Device Exemptions (IDE), Premarket Approval Applications (PMA), and Premarket Notifications [510(k)] are scientifically valid and accurate. The program also ensures 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 investigator revealed violations of the regulations governing clinical trials found in Title 21, Code of Federal Regulations (21 CFR), Part 812 - Investigational Device Exemptions. These deviations were listed on the Form FDA 483, "Inspectional Observations," that was presented to and discussed with you. These deviations and our subsequent review of the inspection report are discussed below:
In a non-emergency situation, deviations from the investigational plan that could have affected the rights, safety, or welfare of human subjects were initiated without prior approval of the changes from the IRB or sponsor. [21 CFR 812.150(a)(4)]
Pursuant to 21 CFR 812.150(a)(4), an investigator is responsible for notifying the sponsor and the reviewing IRB of any deviations from the investigational plan to protect the life or physical well-being of a subject in an emergency. Such notice shall be given as soon as possible, but no later than 5 working days after the emergency occurred . Except in such an emergency, prior approval by the sponsor is required for changes in or deviations from a plan. If theses changes or deviations affect the scientific soundness of the plan or rights, safety, or welfare of human subjects, FDA and IRB approval is required in accordance with 21 CFR 812.35(a).
You failed to secure IRB and sponsor approval of deviations from the investigational plan prior to treating the subjects in non-emergency situations . Examples of your failure to comply with applicable regulations include, but are not limited, to the following :
1) Subject [redacted] was enrolled in the study despite meeting the exclusion criteria for impaired renal function. This deviation from the protocol was not approved by the sponsor, IRB, or FDA prior to the subject's enrollment . The subject's medical history was significant for end stage renal disease since 2001, which required chronic dialysis . The protocol excludes enrollment of subjects with a serum creatinine level of > 3.0 mg/dj at the time of treatment. The subject was treated with the study stent [redacted] with a creatinine level of 5.2 mg/dl which is well above the exclusion level stated in the protocol . The subject experienced a myocardial infarction (MI) on 7/26/2001 (post procedure) with CK MB level of 7 times greater than normal reaching 39 ng/ml (normal 0-5ng/ml). On 8/12/2001 the subject was re-hospitalized for dyspnea and anginal chest pain. The subject expired on [redacted] from complications of gangrene.
1) The protocol excluded enrollment of subjects with acute myocardial infarction (MI), unstable angina, etc. within one month of the [redacted]. Less than one month prior to the study procedures (2/14/02) [redacted] developed vision changes, left arm numbness, and chest pain not relieved by nitroglycerine . She was hospitalized on 2/19/02 to rule out a suspected MI and Cerebral Vascular Accident (CVA). The study records for the subject did not clarify that these symptoms resolved or that the MI and/or CVA diagnoses were ruled out . The subject received the [redacted] on [redacted] which is less than one month of the noted event. This is a violation of the exclusion criteria and was not approved by the sponsor or IRB. The subject expired on 2/13/2003 from coronary artery atherosclerosis.
In your response, you note the nurse practitioner documented "R/O (rule out) CVA" during her initial patient assessment. A later cardiology progress note dated 2/19/02 notes "item # 2 ?CVA/TIAs/vision changes." This indicates this was not resolved .
2) A waiver from the sponsor allowed [redacted] to be enrolled with an abnormal White Blood Cell count (WBC) of 4..700 (exclusion critcria in the protocol is defined as WBC count <[redacted]). IRB approval was not obtained prior to treating the subject on 9/17/2003.
You obtained the sponsor's prior approval for this protocol deviation but did not obtain IRB approval as required by your IRB and the FDA regulations. In addition, the subject's history also noted a recent hospitalization due to symptoms of chest pain, eye changes, and left arm numbness and tingling. The subject was admitted to the hospital to R/O CVA/ Transient Ischemic Attack (TIA) and MI -- all of which are exclusion criteria. There are no records reflecting these issues were resolved.
In your response, you discuss your department's new policies that require documentation of verbal instruction, and that the staff now requests written verification of the sponsor's approval, if approval is obtained verbally . This new policy will assist in documenting the sponsor's approval for future requests . In addition to the sponsor's approval, IRB and FDA approvals are also required prior to deviations from the approved protocol in nonemergency situations where the deviations may affect the scientific soundness of the plan or the rights, safety, or welfare of human subjects . Your response does not address this requirement. Please supply copies of policies and/or procedures that are being developed and/or implemented and their implementation and training plan with expected completion dates to ensure that all approvals occur prior to initiating a protocol deviation in these situations.
Failure to conduct the investigation according to the signed agreement, the investigational plan, applicable FDA regulations, and any conditions of approval imposed by the IRB and FDA. [21 CFR 812.100, 21 CFR 812.110(b)]
Pursuant to 21 CFR 812.100 and 812.110 (b), clinical investigators are required to ensure that investigations are conducted according to the following: the signed agreement, the investigational plan, and applicable FDA regulations, as well as any conditions of approval imposed by the IRB or FDA. The study protocol is part of the investiuational plan 21 CFR 812.25(b) . Our investigation revealed several deviations from the signed agreement and investigational plan, including but not limited to the following:
1) [redacted] was enrolled without an echocardiogram at screening as required by the protocol, and an [redacted] hour post procedure neurological exam was performed outside of the required time frame.
1) [redacted] did not meet inclusion criteria but was enrolled in the study. The protocol required the baseline ultrasound and neurological exam be performed within 30 days of the [redacted] . Both the ultrasound and neurological exam were performed on 8/15/2001, which was more than 30 days before the [redacted].
You failed to submit complete and accurate reports to reviewing IRB and sponsor for unanticipated/serious adverse device effects that occurred during the investigation within the time constraints set forth by the reviewing IRB and stated in the investigational plan. 21 CFR 812.110(b). Examples of your failure to comply with applicable regulations include, but are not limited, to the following:
1) On 7/26/2001, [redacted] experienced a MACE event involving CK-MB levels greater than 7 times the normal range reaching 39 ng/ml (normal range 0-5 ng/ml). This was not reported to the sponsor and IRB until 8/20/2001.
2) Subject [redacted] underwent the [redacted] on 7/19/2001. On 5/8/2002, the subject was readmitted for insertion of a [redacted]. On 9/18/2002, the subject was noted to be in Congestive Heart Failure (CHF) with a pacemaker failure. A new pacemaker was implanted along with new ventricle leads. The IRB was not notified until 3/17/2003.
Also, on 1/30/2003 after fainting the subject was brought by ambulance to the [redacted] Hospital in [redacted]. On admission, diagnosis was wide complex ventricular tachycardiA with a CPK rise to 898 IU/L. The patient was diagnosed as having a MI. The subject was transferred to Swedish Medical Center on 1/31/2003 for additional evaluation and treatment. The subject [redacted] and implanted with an impIantable cardiac defibrillator (ICD); however, the IRB was not notified until 3/17/2003.
1) [redacted] was implanted with the [redacted]. Post procedure on 3/7/2002, the subject complained of chest pain on inspiration. The IRB was not notified until 6/12/2002 .
1) [redacted] developed blindness in the left eye due to a recurrent retinal detachment and a vitreous hemorrhage in the right eye. [redacted] Was admitted to the hospital on 2/3/2003. However, the IRB was not notified until 3/27/2003.
In response your written response, you claim that investigators will continue to work with management and staff to assure protocol adherence. Also, the department has installed new software that provides a check-list for study protocol required procedures . This change should assist you in ensuring study procedures are completed as outlined by the protocol.
Additionally, in your response you state that new management was hired in the fourth quarter of 2001. This new management instituted measures that emphasize the retraining of managers and investigators on the reporting of unanticipated/serious adverse device effects (AE) . However, adverse event deviations continue to occur despite implementation of these new training procedures . The training appears to be ineffective. Please provide documentation as to what additional steps have been taken to ensure timely reporting of AEs. Please supply copies of policies and/or procedures that are being developed and/or implemented and their implementation and training plan with expected completion dates to ensure timely reporting of AEs.
Lastly, your response does not address timely and accurate completion of case histories. You claim additional forms were developed by coordinators which were reviewed, signed, and dated by the investigator after reviewing all eligibility data and echocardiograms. For [redacted], the inclusionlexclusion form was signed by Dr. Gray but not dated. [redacted] had a coordinator's form but it does not match the inclusion/exclusion case report form (CRF) [redacted] inclusion/exclusion CRF and the coordinator's form are incomplete and [redacted] signed these incomplete CRFs. Despite the change in the form process, there continues to be incomplete and inconsistent forms. Please supply copies of policies and/or procedures that are being developed and/or implemented and their implementation and training plan with expected completion dates to ensure subject eligibility prior to enrollment.
Failure to maintain accurate, complete, and current case histories [21 CFR 812.140(a)(3)]
Pursuant to 21 CFR 812.140(a)(3), an investigator is responsible for maintaining accurate, current, and complete records of each subject's case history and exposure to the device, which includes the case report forms, and supporting data.
You failed to maintain complete and accurate case history files regarding study activities required by the study protocol . Examples of your failure to comply with applicable regulations include, but are not limited, to the following:
1) [redacted] did not meet exclusion criteria but was enrolled in the study. The CFR indicates that no baseline ultrasound was performed. In addition, the 2 year follow up CFR does not document that the subject was admitted and underwent extensive lower extremity peripheral vascular procedures . These procedures included multiple lower extremity angiographies with angioplasty and stenting of several peripheral vessels.
Additionally, for this subject there was no "confirmed" EKG on file for the 30 day follow up visit. The EKG in the subject's study records was labeled as "unconfirmed" and dated 09-Jan---..The only subject identifier is a hand written entry noted as [redacted]. In addition, this EKG has a hand written cross-out changing the date from 09 Jan . . . . to 10/29/2001 . A review of the source documents revealed the subject did not have an EKG performed on-site on 10/29/2001.
1) For subject [redacted] the NIH Stroke Scale assessment tool was not performed at the 1 month follow up visit.
2) Subject [redacted] had 2 screening CRFs with conflicting information. and neither was completed.
3) Subject [redacted] screening forms were noted to be incomplete.
In your written response, you claim that these are deficiencies that occurred and that investigators will continue to work with management and staff to ensure they will not
occur, in the future, however, this response does not address plans to ensure data will be recored accurately and completely . Please supply copies of policies and/or procedures that are being developed and/or implemented and their implementation and training plan with expected completion dates to ensure case histories are complete and accurate. It is recommended, at a minimum, that additional staff training be provided that includes retraining on Good Clinical Practice (GCP) guidelines with emphasis on safety.
Failure to document the dates of and reasons for each deviation from the protocol [21 CFR 812.140(a)(4)]
It is the investigator's responsibility to document dates of and reasons for each deviation from the protocol . Examples of your failure to comply with applicable regulations include, but are not limited, to the following:
No records were found documenting the reasons for deviations from the protocol which allowed for the inclusion of subject [redacted] into the study despite being diagnosed with end stage renal failure.
In your response you state, "Studies perform [redacted] investigators are reviewed by [redacted] so we follow the procedure set out by the [redacted] for reporting protocol deviations. [redacted] requires that unplanned protocol deviations be reported to [redacted] within ten (10) days of the investigator becoming aware of the deviation, if the variance could adversely affect the rights, safety, or welfare of subjects, or significantly impact the integrity of the research data. [redacted] also requires .investigators to obtain pre-approval from [redacted] for planned protocol deviations prior to proceeding with the study-related procedures." Your response describes the IRB procedure but does not assure that the aforementioned IRB requirement is met. Please supply copies of policies and/or procedures that are being developed and/or implemented and their implementation and training plan with expected completion dates to ensure IRB and sponsor approval.
Failure to maintain accurate, complete, and current records of device receipt, use or disposition [21 CFR 812.140(a)(2)]
Pursuant to 21 CFR 812.140(a)(2)(ii) and (iii), an investigator is responsible for maintaining records of the names of all persons who received, used, or disposed of each device, as well as records relating to why and how many units of the device have been returned to the sponsor, repaired, or otherwise disposed of. Examples of your failure to comply with applicable regulations include, but are not limited, to the following:
1) Device accountability records contain information for only 3 out of [redacted] subjects enrolled in the study.
In your response you note that a Product Accountability Policy has been developed and was reviewed with. staff on 9/3/2004. Please provide us with a copy of this policy.
This is not intended to be an all-inclusive list of deficiencies at your site. It is your responsibility to ensure that you follow FDA regulations. Within 15 working days after receiving this letter, please provide written documentation of the specific steps you have taken or will take to correct these violations and prevent the recurrence of similar violations in current and future studies. Any submitted corrective action plan must include projected completion dates for each action to be accomplished . In addition, please provide a list of your current investigational studies and include the name of the study sponsor and the date of IRB approval. Failure to respond to this letter and take appropriate corrective action could result in the FDA taking regulatory action, including initiation of disqualification procedures, without further notice.
Please respond in writing to:
Food and Drug Administration
Center for Devices and Radiological Health
Office of Compliance
Division of Bioresearch Monitoring
Program Enforcement Branch I (HFZ-311)
2094 Gaither Road
Rockville, Maryland 20850
Attention : Michael Marcarelli
We are also sending a copy of this letter to FDA's Seattle District Office . We request that a copy of your response also be sent to that office . If you have any questions, please contact Michael Marcarelli by phone at (240) 276-0125.
For further information concerning the Bioresearch Monitoring program, please visit our Internet homepage at http://www.fda.gov/cdrh/comp/bimo.html . Valuable links to related information are included at this site.
Timothy A. Ulatowski
Office of Compliance
Center for Devices and Radiological Health