Reporting Study Deviations: US and ISO

A Whitepaper and Workshop by Nancy J Stark, PhD Wednesday, 30 July 2010, 11 AM Central; or OnDemand soon after. Reading someone else's copy? Opt-in for whitepapers to get your own. In this whitepaper I want to discuss the concepts of study deviations, violations, non-compliances, and amendments; and to compare the US and ISO positions with regard to reporting. When I say ISO, I mean ISO/FDIS 14155 "Clinical investigation of medical devices for human subjects—good clinical practice" (2010) which may be purchased from the International Standards Organization in Geneva. When I say US, I mean 21 CFR Part 812 plus a collection of FDA guidances and IRB voluntary standards. A poll—how many deviations do your colleagues make? Maybe you'd like to compare your perceptions to your colleague's. Answer poll question 18, "How many total deviations do you think will occur in a typical device study of 100 subjects, 50 case report forms per subject, and 5 investigative sites?" and then see what your colleagues had to say. The one hundredth person to answer the poll will receive an Adverse Event Notepad. Who deviates? Who amends? Investigators deviate, sponsors amend. It is the nature of 'sponsored' research: the firm paying the bills gets to design the study the way they want within the limits of regulatory and ethical boundaries. The difference between an amendment and a deviation is timing: did the investigator get permission prior to making the change, or did they make the change and then go to confession.   Sponsors may, themselves, contribute to deviations. Sponsors do incredible things such as: 1) writing protocols with such tight specifications they cannot be reasonably followed, 2) authorizing changes verbally, but not following up in writing, 3) approving changes they have no authority to approve, 4) inadequately training the study staff, 5) not insisting on IRB or EC approval or notification, 6) not insisting on FDA approval or notification, or 7) changing the device—such as it's configuration, formulation, materials, or software—without prior approval or notification, 8) selling devices without FDA clearance (tantamount to conducting a study without approval), 9) trying an unapproved device on a few patients to see if the design is right, or 10) a host of other things I haven't thought of yet. Regulatory definitions ISO/FDIS 14155 is clear on what it means by a deviation. Section 3.14 defines a deviation as an "instance(s) of failure to follow, intentionally or unintentionally, the requirements of the [protocol]." A violation is not defined. And the only reference to a non-compliance is in regard to subjects not complying with requirements stated in the informed consent (Section 8.2.4.5.q—Routine on-site monitoring visits.) ISO/FDIS 14155 has no definition for amendment, but it can be deduced that it means any intentional change made to the investigator's brochure, protocol, case report forms, informed consent form, or other study documents; that the change must have the approval of the sponsor and investigator, and be noticed to the EC and regulatory authorities. (Section 6.5.1.) Part 812 has no definition of deviation, but it does say that the investigator is responsible to keep a log of deviations from the protocol (Part 812.140(a)(4)). Emergency deviations taken to protect a subject are reportable to the sponsor and reviewing IRB within 5 working days (Part 812.150(a)(4)). All other deviations require prior approval by the sponsor and possibly the IRB and FDA, and we usually consider these to be amendments. The only reference to a noncompliance is in regard to good laboratory practices. The IRB's view It's useful for sponsors to understand the IRB's point of view, because we are so concerned with our investigator's compliance to their requirements. It's mostly that their use of words is different. They think in terms of unanticipated problems, where a problem can be anything from a shortage of test tubes to malfunctioning equipment. In the short term, they want to know about everything that is unanticipated; the anticipated events can go in the annual report.   The IRB doesn't think in terms of deviations so much as unanticipated problems. And they merge the issue of adverse events with problems that are anticipated or unanticipated; in other words an adverse event is one more type of problem. Industry definitions It really isn't that hard. The ultimate goal is that no one gets to act independently, or make changes to the study plan, i.e., the protocol, investigator's brochure, case report forms, informed consent form, and any other critical study documents, without everyone else's approval. Here are definitions the industry has come to use: [ ] Deviation—a failure to follow the study plan. A deviation that occurs repeatedly should probably become an amendment. [ ] Violation—a failure to follow the study plan in such a way that subject safety was in jeopardy. [ ] Non-compliance—a failure to follow a regulation or IRB requirement. [ ] Amendment—a change to the study plan after obtaining the necessary permissions. [ ] Unanticipated—not identified in the study plan.

And what about reporting Only deviations and violations (and adverse device effects) have to be reported, since amendments already have approval. Time frames differ depending on IRB, country, the event's effect on subject safety and data integrity, and what you said in the protocol. The protocol is king, it governs your study. A wise monitor once said to me: "You can do anything, if you put it in the protocol." For ISO: The monitor is expected to identify deviations, discuss them with the investigator, and list them in the monitoring report (Section 7.2.4.5.a.) The sponsor is expected to list the deviations in progress reports as requested by reviewing ECs and regulatory authorities (Section 8.2.3.f). Investigators that cannot be compliant may need to be excused from the study (Section 7.1.1.) For FDA: The US is different from the rest of the world in that we have a risk classification system for clinical studies. The rules are different for non-significant risk and significant risk studies, and this system is unique in the international community. For significant risk studies, the investigator is expected to keep a deviation log (Part 812.140(a)(4) and report deviations to the sponsor (Part 812.150(a)(4)). The sponsor is expected to take steps to bring the investigator into compliance either by withholding shipment of additional devices or by reporting the investigator to FDA. These requirements do not apply to non-significant risk studies. For US IRBs: The rules vary from IRB to IRB, but if the board follows the OHRP guidance, unanticipated problems should be reported in the short term (my phrase) and anticipated problems in the annual progress report. Workshop learning objective The objective of the workshop is to explore the US and ISO definitions and reporting requirements in more detail, using practical examples to apply the rules, and reviewing warning letters to see how we have all gotten into trouble. You will receive [x] PowerPoint slides. [x] By popular demand, a three-hour course. [x] Office of Human Research Protections (OHRP) "Guidance on reviewing and reporting unanticipated problems involving risks to subjects or others and adverse events" (Jan07). [x] FDA "Information sheet guidance for IRBs, clinical investigators, and sponsors; FDA Institutional Review Board Inspections" (Jan06). [x] FDA "Changes or modifications during the conduct of a clinical investigation; final guidance for industry and CDRH staff" (May01). [x] FDA "Deciding when to submit a 510(k) for a change to an existing device" (Jan97). [x] A 30-minute quiz to reinforce your learning experience. [x] CEUs and certificate of attendance. Who should attend [x] Anyone monitoring a device trial. [x] Anyone sponsoring a device trial. [x] Investigators for device trials. [x] Regulatory professionals who prepare submissions to FDA. [x] Managers who sign-off on clinical trials. [x] Executives who are planning the future of their companies. Presenter Dr. Nancy J Stark is President and Founder of Clinical Device Group, a CRO and consulting firm that has been in business since 1990. Her curriculum vitae can be found at www.nancystark.com. System requirements [x] Personal computer. [x] Internet Access. [x] Telephone. Date, time, registration The three-hour workshop will be presented on Wednesday, 30 June 2010, at 11:00 Central Time. Event materials will be distributed the day before the workshop. Sign up at registration. Best Regards, Nancy J Stark, PhD President, Clinical Device Group Inc