Risk Analysis Reports and EU Clinical Trials

A Whitepaper by Nancy J Stark 
An e-Conference by Barry Sands
Wednesday, 4 August 2010; available OnDemand soon after.

If you are planning a clinical trial in Europe, now is the time to learn about risk management in clinical trials. Risk management plays a critical new role in ISO/FDIS 14155 "Investigation of medical devices in human subjects—good clinical practices". The standard is expected to be published in late 2010 or early 2011 and will be incorporated into the AIMD and MDD immediately; there will be no phase in period.

Compliance with risk management is required
The ISO 14971, "Medical devices—Application of risk management to medical devices" standard is a normative reference for ISO/FDIS 14155; meaning its implementation is indispensable for the conduct of clinical trials. In other words, in order to be compliant with ISO/FDIS 14155, the entire clinical trial process must also be compliant with ISO 14971.

Hazards, harms, and risks in clinical trials
It's simple: in risk management terms a hazard is a situation that could cause harm, a harm is an adverse event, a risk is the likelihood that the harm will occur. For example, a lose connection is a hazard, an unwanted electrical shock is a harm, the risk is the mathematical probability that the harm will occur. In a clinical trial you focus on subject-centric risks: what happens to the subject if the device's handle falls off? What happens to the subject if the procedure takes too long? Then you consider the probability that the adverse event will occur and the severity to the subject if it does occur.

Risk and its application to clinical trials
Applying risk management to making sound/informed decisions on clinical study initiation, suspension, modification, reinitiation and stoppage are among the most intense decisions your organization will make. These decisions affect patient safety, clinician/surgeon reputation/relationships, company reputations and product liability.

As clinical research professionals responsible for these studies you aren't unfamiliar with risk concepts, but you will have to learn a new language. For example, what is the difference between risk estimation, risk analysis, risk assessment, risk evaluation, risk control, residual risk, a risk analysis report, risk management, and a risk management file? Here is a partial list of some of the issues you will face with regard to risk management.

Clinical evaluation report
The ISO/FDIS 14155 (2010) takes a whole new strategy toward initiating a clinical trial. Before you start writing the protocol you review the scientific data to prepare a clinical evaluation report consistent with the principles of GHTF Study Group 5. CDG has written several whitepapers on how to prepare clinical evaluation reports and scientific literature reviews. One outcome of the clinical evaluation report is a justification for the design of your clinical study.

Risk analysis report
Another outcome of the clinical evaluation report is a Risk Analysis Report. "What's that?" you ask? It is a table of potential adverse events (i.e. harms) that may occur to the subject as a result of participation in the trial. The list includes all the adverse events that might occur from use error (say, perforating the bowel during a colonoscopy), device malfunction (a laser that over-delivers energy), or the procedure itself (tooth loss following radiation for head and neck cancer). Then the next columns of the table identify the frequency with which the event will occur, the severity of the event if it does occur, the risk (likelihood) that the event will occur, how you will mitigate the event (protect against occurrence or treat should it occur), and finally any residual risks left after mitigation. The table might look like this:

RISK ANALYSIS REPORT
POSSIBLE ADVERSE EVENT | FREQUENCY | SEVERITY | RISK | MITIGATION | RESIDUAL RISK

The standard is serious about risk management; any serious adverse event that occurs and is not identified in the Risk Analysis Report is considered unanticipated and is subject to expedited reporting.

There is a skill to writing Risk Analysis Reports. One colleague prepared a three page report on the risks of removing medical tape from your skin. Don't include so many minor harms that you obfuscate the important ones. Don't omit serious harms, even when they have only a slight chance of occuring. Update the Report and the Investigator's Brochure whenever there is a change in perceived risks.

Informed consent
It isn't enough to prepare a Risk Analysis Report; you have to share it with the subject as part of the informed consent.

Resulting decisions
You will decide whether or not to establish a data monitoring committee based on the findings in the Risk Analysis Report. You will decide whether or not to audit the study based on the Risk Analysis Report. You will determine the follow-up period based on the Report, the follow-up period should be long enough to asses whether or not a harm occurs. And the decision to suspend or terminate a study due to unacceptable risk to subjects will follow naturally from the Risk Analysis Report.

Final report
The conclusion section of the final report shall assess the risks and benefits of the investigational device and identify any groups of persons that are at particular risk.

Expertise in ISO/EN 14971
I've asked Barry Sands to walk us through ISO/FDIS 14155 and ISO/EN 14971 and examine all the ways in which risk and risk concepts are to be applied to clinical trials. Barry is experienced in both clinical research and risk management and we are lucky to have him. He will provide examples on how this process was and was not effectively applied to actual medical device clinical trials.

If you liked this whitepaper, take the e-conference
In this e-conference you will learn how to apply risk management concepts to the clinical research process. You will learn how risk management allows a manufacturer to make more objective and informed decisions about when to initiate, suspend, restart, modify or stop a clinical study. And you will learn how specific risk management tools can assist in these clinical study decisions. 

You will receive
[x] PowerPoint slides.
[x] An expert speaker who has worked for industry and FDA.
[x] Knowledge essential for ISO/FDIS 14155 compliance.
[x] Chance for Q&A.
[x] CEUs and certificate of attendance.
[x] Please purchase your own copy of ISO/DIS 14155 from DIN and ISO/EN 14971 at www.iso.org.

Who should attend?
[x] Anyone who's considering a device trial outside the United States.
[x] Anyone who monitors clinical trials outside the United States.
[x] Regulatory professionals who prepare documents for CE certification and marking.
[x] Regulatory professionals submitting foreign data to FDA.
[x] FDA personnel who review data from foreign trials.
[x] FDA inspectors who inspect foreign sites or sponsors.

Instructor
Mr. Barry Sands is a biomedical engineer with a chemical engineering concentration. He has seven years experience as a Biomedical Engineer and Sr. Scientific Reviewer at FDA/CDRH/ODE and FDA’s Boston District. This government experience was followed with seventeen (17) years in midlevel and executive regulatory/clinical/quality affairs management positions in small start-up and large multinational medical device companies. His firm provides support in the areas of regulatory submissions (510k, IDE, PMA, HUD/HDE, Design Dossiers), Clinical Study Design/Management, Risk Management, Quality System Design/Audits (FDA QSR and ISO 13485) and FDA Negotiation and Communication (QSR Audits, 483s, Warning Letters, Bioresearch Monitoring, Medical Device Reports, Recalls). He can be reached at barrysands@rqmis.com.

System requirements
[x] Personal computer.
[x] Internet Access.
[x] Telephone.

Date, time, registration
The 90-minute e-conference will be presented on Wednesday, 4 August 2010, at 11:00 am Central Time. Event materials will be distributed the day before the event. Sign up at registration.

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Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc