FDA Warning Letters - Medical Device Studies

Frequently Asked Questions

All letters issued by FDA's Center for Biologics Evaluation and Research during 2005 involved medical devices [except Hostoffer , which was a drug] and are flagged as "CBER Warning Letter" in this list.

Dr. Ritch  12-4-2006 Warning Letter
Started a device study before all approvals had been obtained and made a change in research without IRB approval.

Aqueous Biomedical 11-15-2006 Warning Letter
There were other problems; however, you should note that FedEx receipts, pages from your personal calendar, and e-mails pertaining to device shipments are not considered accurate device accountability records. You are going to need a chart which reflects the required information.

Dr. Bartholomew 11-8-2006 Warning Letter
There were multiiple problems with this study but nothing new or unusual.

Dr. Morgan 10-3-2006 Warning Letter
Dr. Morgan used an approved device for an unapproved use. This would be OK if it was simply an "off-label" use; however, Dr. Morgan was conducting a clinical study with a protocol and multiple subjects were involved. An IDE is required for this type of research.

Dr. Wolf 9-28-2006 Warning Letter
There were multiple problems with the study. Dr. Wolf's response was "I am not, nor ever have been involved with any data collection or entry in any study. If my life depended on it, I could not access data. I do not know how. I do not know which patients are enrolled in the current FDA study."

Medelle Corporation 8-2-2006 Warning Letter
This is Medelle's second warning letter for GCP violations. The first was 2-1-2005. Multiple violations will only focus FDA on future IDE submissions; clinical study sponsors do not need this kind of attention.

Dr. Stachniw 7-6-2006 Warning Letter
Dr. Stachniw is with Galesburg Orthopedic Services, Ltd. There was a Warning Letter sent to the Galesburg IRB during May 2006.

Dr. DeVinney 4-21-2006 Warning Letter
In this case, the study sponsor advised Dr. DeVinney that certain devices could be used in the study but FDA says they were not approved for such use. Dr. DeVinney should have been able to rely on the sponsor's info.

Dr. Brown 3-27-2006 Warning Letter
FDA said: The IRB-approved consent form required the signature of a witness yet the informed consent forms did not have the signature of the person who witnessed the signing of the consent form; i.e. the dates of the subject and witness signature were different. This could be a simple date problem. If the witness was present during the discussion of the study and can attest to the subject's agreement to become enrolled in the study, then the witness may have signed the forms at a later date. If so, the IRB's requirement for a "witness" was met. FDA's Information sheet says "The intended purpose is to have the witness present during the entire consent interview and to attest to the accuracy of the presentation and the apparent understanding of the subject."

This case involves a misunderstanding of the approvals needed for emergency and/or compassionate use of a medical device in subjects who are not enrolled in a study. The study sponsor has world-wide experience and should have provided better assistance with this use. No device accountability records? The study monitor should have fixed this problem.

Dr. Greenhalgh 3-6-2006 Warning Letter
It's unusual for an investigator to modify a study protocol and that's what caused the problems in this case. Although there was a claim that the changes had been discussed with the sponsor, there was no record of the discussions or IRB approval for the changes.

Dr. Gross 2-24-2006 Warning Letter
In this case, the sponsor was apparently remiss in it's obligations to provide FDA approved device components and detect and correct problems during the monitoring of the study. In addition, the sponsor authorized deviations from the protocol without amending it and getting IRB approval.

Dr. Soo 2-21-2006 Warning Letter
In addition to protocol deviations and adverse event reporting issues, the FDA investigator observed that subject 11's consent document had the date the subject signed the document covered with "white-out" and a new date written over the "white-out". "White-out" should never be used to correct any source document. Although the letter said "In review of the CV's of you and your study team there is no documented training which focuses on the conduct of investigational device studies", there was no 21 CFR 812 violation cited regarding the lack of staff training.

Dr. Williams 2-7-2006 Warning Letter
There is good information in this case about treatment with a device without informed consent.

Dr. Dore    12-21-2005 Warning Letter
A lot of the problems could have been prevented if the study sponsor and study monitor had done a better job of finding and correcting the study issues.

Corin USA 11-25-2005 Warning Letter
There is good information in this case about 510(k) clearance, PMA approval and IDE requirements. Note: Corin shipped devices to sales representatives [21 CFR 812.43(b)]. They also can't be shipped to participating study subjects according to another Warning Letter.

Pursuant to 21 CFR 812.43(c), a sponsor shall obtain Form FDA 3454 - Financial Disclosure form from each participating investigator prior to initiation of any studies. Under 21 CFR 812.150(b)(4), every 6 months, a sponsor must submit a list of the current investigators to FDA.

Under 21 CFR 812.150(b)(5), a sponsor of a study of a significant risk device must submit a complete and accurate annual progress report to the IRB and FDA.

Under 21 CFR 812.150(b)(8), a sponsor must submit a copy of a report by an investigator of the use of a device without informed consent within 5 days of notice of such use. FDA highly recommends that any subjects who were implanted with investigational devices but did not sign an informed consent, be notified of the devices investigational status; asked to sign a patient permission document, and continue with follow-up visits per the study protocol. The patient permission document allows Corin USA and federal agencies to inspect, copy, and review their medical records and other source documents. In addition, send the letter and permission document to the reviewing IRBs for approval prior to having the clinical investigators contact the subjects.

OASIS Medical, Inc. 11-3-2005 Warning Letter
Device shipment prior to obtaining investigator agreements. Evidence of protocol non-compliance but no OASIS reaction. Device accountability issues.

Dr. Wholey    10-21-2005 Notice of Intent to Disqualify
This investigator will be disqualified. He repeatedly [multiple times] and deliberately [with disregard for regulatory requirements] failed to meet his responsibilities. FDA will not accept a claim that he relied on subordinates who failed to comply with regulatory requirements.

Dr. Weese-Mayer 10-14-2005 Warning Letter
Twenty-three out of forty-one study subjects were seen for four and five-year postoperative follow-up examinations without signing an amended approved ICF that included these visits. If ALL follow-up examinations are not in the original ICF, an amended ICF approved by the IRB is needed.

Dr. Rowen 10-11-2005 Warning Letter
Twenty-three out of forty-one study subjects were seen for four and five-year postoperative follow-up examinations without signing an amended approved ICF that included these visits. All examinations need to be in the original ICF or an amended ICF and IRB approval is needed.

Dr. Mulingtapang 10-7-2005 Warning Letter
Under the circumstances you describe, the subject files should have documentation of the efforts made to obtain consent, the subjects' refusals, and your subsequent steps to ensure that they were terminated from the study."

Dr. Ross 10-3-2005 Warning Letter
The consent form approved by the IRB for use at your site required you, the CI, to sign each consent form at the time of consent. You failed to sign consent forms for at least fifteen subjects.

The consent form approved by the IRB for use at your site required each form to be signed by a witness at the time of consent. Many of the witness signatures observed on the consent forms could not be identified as true witnesses, and could not be verified as clinic or study personnel.

Try to negotiate with the IRB to not require unnecessary signatures; the CI's signature and generally, a witness's signature, are not required by 21 CFR Part 50. ICH does require the signature of the person providing consent information; however, ICH requirements do not have to be met at US study sites. The problem here was non-compliance with IRB requirements, not 21 CFR Part 50 or ICH.

Dr. Parent 9-29-2005 Warning Letter
Nothing unusual in this case.

ReGen 9-16-2005 Warning Letter
The investigator's termination was by the IRB and the IRB was responsible for reporting to FDA; ReGen also [21 CFR 812.150] because it was an IRB "termination". With respect to drug studies, a sponsor's termination of an investigation is reportable to FDA only if it was for non-compliance, not lack of enrollment, etc. I don't see a device regs requirement that the sponsor advise FDA of THEIR temination of an investigator's study for non-compliance [21 CFR 812.150(b)]. There are some subtle differences between the drug and device regulations. Read regulatory requirements carefully ... if they do not say something is required, it's not a requirement even if, logically, it should be. A good example is the blood bank regulations which require SOPs but there is no requirement "that SOPs be followed". CBER has resorted to citing the 21 CFR 211 requirement that SOPs "be followed" however, Part 211 applies only to finished pharmaceuticals.

Efoora, Inc. 8-25-2005 CBER Warning Letter
FDA's inspection disclosed violations so numerous and pervasive that they demonstrate that you failed to properly monitor the study. All of the study sites and principal investigators were not identified in IDE submissions.

Saliva Diagnostic Systems, Inc. 8-25-2005 CBER Warning Letter
This case is almost identical to Efoora, Inc. and the letters have the same date.

Dr. Gottlieb     8-23-2005 Warning Letter and Response
Many of the issues dealt with protocol adherence. The protocol deviations were generally of little significance; the protocol was unnecessarily restrictive. Enrollment of subjects on Sunday is OK but causes FDA to suspect that something fishy was going on; that's why they asked for the Sunday enrollment details.

Lifestream Medical Corporation 8-15-2005 Warning Letter
You shipped investigational devices (components /replacement parts) to individuals who were not approved clinical investigators. From October 1999 to March 2005, you sent approximately 125 shipments of investigational devices directly to subjects. You failed to document accountability for all devices and components prior to 10/1999 and failed to document accountability for "loaner devices" as well as those shipped back to consignees following repairs

Uroplasty, Inc 7-19-2005 Warning Letter
Unlike the letter to ReGen, there is good information in the Uroplasty letter regarding corrective actions considered acceptable to FDA.

Dr. Mighell     7-6-2005 Warning Letter
Six patients were implanted with components that, at the time of the implantations, were not part of the approved study.

Dr. Frankle 7-6-2005 Warning Letter
This case involves custom devices and compassionate use of devices.

Orthometrix, Inc 7-6-2005 Warning Letter
There was investigator non-compliance and a lack of sponsor action to address this problem.

Dr. Khoury     6-23-2005 Warning Letter
There is information in this case regarding Emergency Use and Compassionate Use

Dr. Coutts     6-13-2005 Warning Letter
It appears that the consent form for implant surgery was approved by an IRB but not the IRB associated with the implanting institution. This is not a 21 CFR Part 50 violation; the consent form had IRB approval
[21 CFR 56.111 - 114]. Federal regulations do not require that the physician sign the consent form, the source documents which support CRF data entries or the CRFs themselves. FDA's Center for Devices and Radiological Health [CDRH] was encouraging IRB rule adherence which is a federal regulatory requirement.

Dr. Jones     6-10-2005 CBER Warning Letter
In this case, part of the problem was the wording of the IRB approved consent form. The form required a "doctor's" signature but a person who was not a doctor, signed the forms. The IRB could have helped prevent these problems.

Dr. Constantine     5-26-2005 CBER Warning Letter
Do not use pre-filled checklists to prospectively evaluate the eligibility of subjects; the data may be accurate but it is meaningless since it was not contemporaneously recorded at the time of the event(s) and could easily represent false information. It could be false even if contemporaneously recorded; however, in that case it's FDA's burden to prove that it's false.

Dr. Koppes     5-16-2005 CBER Warning Letter
He enrolled 202 subjects in the study but only 68 of those subjects had medical records on site documenting a medical history. It is unclear how he concluded they met study inclusion criterion.

The letter also says "Protocol section 10.0 directs that "Samples will be shipped to the [redacted] daily." Review of the specimen shipping forms shows that you failed to ship at least 77 samples to the central laboratory on the day they were obtained. Delays in shipping ranged from one to four days." It would help if FDA would identify why this "protocol deviation" is significant. It's no wonder the most often cited 21 CFR violation is non-compliance with the protocol. Sponsors can help with this problem by not making protocols specific unless truly necessary.

Dr. Cohen     5-16-2005 Warning Letter
Unlike the Gottlieb case, the protocol deviations in this case appear to be significant.

Dr. Lowther     5-13-2005 CBER Warning Letter
Subjects outside the age range were enrolled. She asked one subject to return for a second visit and repeated both the finger stick and venipuncture without obtaining informed consent.

The issue of site personnel training is an example of protocol compliance. There are no examples of anything done wrong by untrained personnel. That's probably why this violation was not included on the Form FDA 483; the FDA investigator did not consider it significant.

Dr. Winters 5-1-2005 Warning Letter
The violations in this case are clear and significant. The sponsor should have detected these and corrected them prior to the FDA inspection.

Dr. Rosenthal 4-11-2005 Warning Letter
This case cites violations brought to the investigator's attention in a previous letter.

Dr. Grubbs     4-11-2005 Warning Letter
In this case, the clinical study records had been inadvertently destroyed and were not available for inspection by FDA. The required period of 2 years for retaining the documents after study termination had passed before the records were put in storage. Dr. Grubbs was not cited for a records retention violation. FDA cited Dr. Grubbs for not notifying the agency of the record custody transfer [21 CFR 812.140(e)]. This citation was inappropriate [see Dr. Singleton] since the obligation to notify FDA exists only during the 2 year period specified in 21 CFR 812.140(d). If Dr. Grubbs had complied with the protocol, record retention responsibility would have transferred to the sponsor.

The sponsor re-opened the study nearly 2 years after termination but did so only by letter which Dr. Grubbs apparently did not see. The letter should have included a response deadline. If not met, Dr. Grubbs should have been called to verify record availability.

The other issue was the lack of financial information at the study site. The citation in the warning letter was
21 CFR 54.4(b) which requires this information be submitted to the sponsor, not that it must be available at the study site. The sponsor is responsible for retention of the information [21 CFR 54.6]. The 21 CFR 54.4 citation was inappropriate; 21 CFR 812.140(a)(1) should have been used. [see Dr. Singleton]

Dr. Yadav 4-11-2005 Warning Letter
AE reporting; lack of IRB approval for protocol deviations

Dr. Weil 3-29-2005 Warning Letter
Basic consent and protocol exclusion problems

Dr. Gray 3-16-2005 Warning Letter
A waiver from the sponsor allowed a subject to be enrolled with an abnormal White Blood Cell count. IRB approval was not obtained prior to treating the subject. In non-emergencies, IRB approval is needed. A list of things needing IRB prior approval and required reports would help.

Dr. Nichols 2-24-2005 Warning Letter and Response
Re "Study subjects were not provided with a copy of the informed consent form": subjects must be provided with a copy of the IRB approved consent form but it does not need to be the copy they signed. The signed copy is universally used and is a good business practice.

Dr. Tennant 2-15-2005 Warning Letter
Approval of the informed consent form was not specifically documented in any of the IRB correspondence documents. Re the warning letter statement "The informed consent form used did not have an IRB approval signature or date printed on the document."; this is a good idea but not a requirement. There needs to be documentation of IRB approval.

Medelle Corporation 2-1-2005 Warning Letter
No written monitoring procedures; Monitoring reports were inaccurate; Monitoring reports indicated that investigators were not compliant with the protocol by enrolling ineligible patients, but there was no documentation of any actions taken by Medelle to secure compliance. Medelle failed to use monitors qualified by training and experience

Dr. Marcum 1-27-2005 Warning Letter
There were nine subjects in the study who developed serious infections that were not reported to the IRB within five days. Also there were four deaths that were not reported to the IRB within 24 hours. Dr. Marcum had no records to indicate the date, the amount, or lot number of devices received.