CLINICAL TRIAL DEVIATIONS AND AMENDMENTS

A Whitepaper and Workshop presented by Dr. Nancy J Stark; available OnDemand.


DEVIATIONS, VIOLATIONS, and NON-COMPLIANCES
Even the definition of a deviation is arguable. The dictionary tells us that a deviation is a departure from some standard or norm, but what is the standard?

Most device companies consider deviations to be a departure from the IDE application (if a significant risk device) or from the protocol (if a non-significant risk device). Departures from other study documents also count. Departures from the regulations, which are incorporated by reference, count too.

And changes in device design count, too. This is an issue we don’t think about much. The configuration, manufacturing process, software version, or materials selection change more often during the course of a clinical study than most of us want to admit. A paper clip here, a little code there, surely we don’t have to amend the protocol for every little modification? We’ll see.

A violation is a serious deviation, one which jeopardizes subject safety or data integrity. Violations can stem from IRBs failing to perform annual reviews to investigators using old consent forms to sponsors neglecting to impose version control on their software. In other words, anyone can contribute to a violation.


AMENDMENTS
The only difference between an amendment and a deviation/violation is timing. In an amendment you ask permission from the FDA and/or IRB to make a change before you implement the change. If the change is ridiculous, “Can I use an old informed consent?” we would either never ask the question or promptly be told, “No.” In a deviation/violation, we implement the change first and ask permission later or not at all.


THE IRB’S PERSPECTIVE
But talk to an IRB and you'll get a totally different opinion. In their view of the world a deviation is a departure from the protocol and related documents only. A departure from the regulations is called a non-compliance. And deviations and non-compliances together make up violations. It’s a whole different categorization not dependent on seriousness.

But even government agencies don't agree with each other on the lexicon. Consider the NIH guidance* to IRB's in which they supply a memo template** for IRBs to use in sending notices to investigators or others. Here a deviation from the protocol is a departure that does not have a major impact on subject safety or data integrity, while a violation is a protocol departure that does.

BiMo uses the words deviation and violation to mean an increase in seriousness in the impact of patient safety and data integrity, however the inspectors do not use the words consistently.

In the long run it probably doesn't matter what you call them, the pivotal issue is whether subject safety or data integrity are seriously affected.


FDA 2009 WARNING LETTERS
The Agency's thinking is what concerns most device manufacturers and warning letters issued by CDRH are a valuable resource for getting into their heads.

I reviewed the twelve device warning letters from 2009 that related to device clinical studies; they were sent to only three sponsors, five investigators, and four IRBs. Then I identified the major types of deviations or non-compliances cited. Here is a summary:

[1] Failure to do a study to validate device design
[2] Failure to monitor adequately
[3] Failure to secure protocol compliance
[4] No protocol approval
[5] No IRB approval
[6] No informed consent, missing elements, or wrong consent form
[7] Unauthorized person signed informed consent form
[8] Consent made positive statements about device
[9] No FDA approval for change to eligibility criteria
[10] Inadequate device accountability
[11] No investigator agreements
[12] No progress reports to IRB or sponsor
[13] No DSMB meetings
[14] No financial disclosure by investigators
[15] Implantation before consent signed
[16] Study staff dated consent
[17] No device accountability records for receipt
[18] No device accountability records for disposition
[19] No case histories or records of device exposure
[20] IRB approved study retroactively

You get the idea, pretty much any record-keeping or reporting task that could be avoided or overlooked was, by someone. But that’s what I take from this list: most deviations and non-compliances and violations involve record-keeping and reporting tasks.


REPORTING TO IRBs
IRBs each write their own procedures and hence, have their own unique take on deviations, violations, and non-compliance.

It is a happy thing for sponsors that investigators carry the primary responsibility of reporting to IRBs. Let the investigator decide if what sponsors call a deviation or a violation is a non-compliance in the IRB's view.

REPORTING TO FDA
Reporting deviations and violations to FDA will be paramount in the sponsor's mind. A large study might have several thousand deviations if we count everything.

For example, a test might be run at 25 minutes instead of 30 minutes, a subject might come in at 9 days instead of 7 days, common examples of protocol deviations.

Source files have been lost (in one case shredded by the janitor), an example of departing from the regulations because investigators are required to keep records of device exposure.

Monitoring procedures might change or not be met, an example of departing from the regulations because sponsors are required to meet the monitoring procedures they set forth in the IDE.

Engineers might select a material from a different vendor, never thinking of it as a significant change, and cause a situation where the device performs differently during a trial.

Sponsors are looking for guidance on how to report departures to FDA, and when.


FDA GUIDANCE
FDA recognizes that protocol designs and device designs may need to change over the course of a clinical study, such changes may be in the best safety interest of the subjects or allow you get obtain higher quality data without changing the risk to subjects. The two guidance documents “Changes or Modifications during the Conduct of a Clinical Investigation,” *** and “Deciding When to Submit a 510(k) for a Change to an Existing Device,” **** provide detailed insight into FDA’s current thinking on sponsor reporting responsibilities.

Of course, we must recognize that as 510k requirements change, FDA’s thinking about resubmissions may also change.


DEPARTURE MANAGEMENT STRATEGY
Management should have in place a strategy for managing departures before they occur. You need clear definitions of deviations, violations, non-compliances and amendment requirements that are appropriate for your company and product line, and everyone involved in product development must understand them.

Monitors should be trained to identify departures in the field, note them in the monitoring report, and report them to management. Every departure should be assessed with regard to its impact on subject safety and data integrity and appropriate action taken. Appropriate action might include reversing the action, assuring the investigator reports to the IRB, the sponsor reports to FDA, and documentation be placed in the sponsor’s study file.

Identifying and reporting departures are a part of every study, significant risk or non-significant risk.

REGISTER FOR THE WORKSHOP
If you found this white paper helpful, you should register for CDG's Deviations and Amendments Workshop, OnDemand. There you'll find the back-up documentation for this well-researched event so your company can develop the deviation management strategy best suited for your types of products.


YOU WILL RECEIVE
[x] PowerPoint slides.
[x] An expert speaker.
[x] A chance for questions and answers.
[x] 2009 Warning Letters with deviations highlighted.
[x] OHRP Guidance [to IRBs] on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events (Jan 2007).
[x] FDA Information Sheet Guidance for IRBs, Clinical Investigators, and Sponsors – FDA IRB Inspections (Jan 2006).
[x] FDA guidance: Changes or Modifications during the Conduct of a Clinical Investigation (May 2001).
[x] FDA guidance: Deciding when to submit a 510k for a Change to an Existing Device (Jan 1997).
[x] A 30-minute quiz.
[x] 0.45 CEUs and certificate of attendance.


WHO SHOULD ATTEND
[x] Anyone who's sponsoring a device trial.
[x] Anyone who's an investigator for a device trial.
[x] Regulatory professionals who submit final reports to FDA.
[x] FDA personnel who inspect investigational sites.
[x] Marketers or managers who select investigators.


PRESENTER
Dr. Nancy J Stark, PhD and President of Clinical Device Group can be reached at www.nancystark.com.


SYSTEM REQUIREMENTS
[x] Personal computer.
[x] Internet Access.
[x] Telephone.


DATE, TIME, REGISTRATION
The 4-hour workshop is available OnDemand.

Sign up at https://www.clinicaldevice.com/mall/Workshops.aspx#Deviations.  


Nancy J Stark, PhD, President

Clinical Device Group Inc
2128 W. Evergreen Ave.
Chicago, IL 60622
Phone: 773-489-5706
eMail:cdginc@clinicaldevice.com


REFERENCES
* http://www.genome.gov/Pages/Research/Intramural/IRB/Deviation_Violation_examples8-07.pdf
** http://www.genome.gov/Pages/Research/Intramural/IRB/Deviation_Memo_Template)8-07.doc
*** http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm082158.pdf
**** http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM080243.pdf
or http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm080235.htm


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