The Critical Role of Risk Analyses in Clinical Investigations

A Whitepaper by Nancy J Stark about ISO/FDIS 14155 (2010)
An e-Conference by Barry Sands, Wednesday, 4 August 2010; available OnDemand soon after.

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Risk management plays a critical new role in ISO/FDIS 14155 "Investigation of medical devices in human subjects—good clinical practices". The word "risk" appears 50 times in the revised standard, as opposed to only 21 times in Part 812 (excluding the phrase significant risk device.) Clinical trial sponsors, monitors, investigators, and study staff will have to learn a raft of new risk terms, rewrite their standard procedures, and figure out how to incorporate new risk management processes into the daily implementation of clinical investigations.

Risk is a "normative reference"
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.

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What's risk, anyway?
Risk is an interesting concept, a mathematical concept really. It is a function of: a) the probability that a harm (risk lingo for an adverse event) will occur and, b) the severity of that harm. We could say that Risk = (Probability) x (Severity), but we can also say that Risk = (Probability) + (Severity) . Or we are free to add modifiers to the formula, such as Risk = (Probability) + 4(Severity).

To identify a risk, we must first make a list of potential harms, i.e., potential adverse events that might occur in the clinical trial. The list of harms should be subject-centric: what happens to the subject if the device's handle falls off? What happens to the subject if the procedure takes too long? Then we 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 the most intense decisions an organization can make. They affect patient safety, clinician/surgeon reputation/relationships, company reputations and product liability. Clinical research professionals responsible for these studies aren't unfamiliar with risk concepts, but we 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? 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. Examples on how this process was and was not effectively applied to medical devices will be provided.

For example, here is a partial list of some of the risk issues that Mr. Sands will discuss, identified by the ISO/FDIS section it comes from:
3.42 - an unanticipated serious adverse device effect is one not identified in the current risk analysis report.
4.7.4.b.1-2 - risks, residual risks, and risks associated with the clinical procedures must be informed to the subject; but how do we identify residual medical risks?
4.7.4.d.1 - the risks and benefits of of alternative procedures must be informed to the subject.
5.2 - risks associated with the investigational device shall be estimated in accordance with ISO 14971. How is this estimation process implemented and documented?
5.2 - the risk analysis shall include ... a review of ... scientific data. Is this a clinical evaluation report?
5.5 - the Investigator's Brochure shall be updated if there is a significant change in risk.
5.11 - the decision to establish a data monitoring committee shall be guided by the risk analysis.
6.11.e - the audit plan and procedure shall be guided by the ... level of risk to the subjects.
7.1.1 - the suspicion of unacceptable risk to subjects ... shall cause the sponsor to terminate the clinical trial until the level of risk is confirmed.
7.1.1.b.NOTE - the principal investigator shall ... inform enrolled subjects ... of a change in perceived risks.
8.2.5.f - in multi-center investigations ... other principal investigators ... shall be informed of a change in perceived risks.
8.2.5.h - when does the risk analysis need to be updated?
A.4.c - the protocol shall list residual risks as identified in the risk analysis report.
A.4.d - the protocol shall list risks associated with [the subject's] participation in the clinical trial.
A.4.f - the protocol shall list steps taken to mitigate the risks.
A.4.g - the protocol shall contain a risk/benefit rationale.
A.5.d - the protocol shall list the risks and anticipated adverse device effects to be assessed.
A.6.4.c - the follow-up period shall be long enough to assess any risks associated with the device.
B.5.a - the investigator's brochure shall summarize the risk analysis.
B.5.b - the investigator's brochure shall have a risk assessment.
B.5.c - anticipated risks shall be identified in the investigator's brochure.
D.8.b - the clinical investigation report (final report) conclusions shall assess the risks and benefits.
D.8.d - the final report shall identify any at-risk groups.

Learning objective
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 with many years experience.
[x] Knowledge essential for ISO/FDIS 14155 compliance.
[x] Chance for Q&A.
[x] CEUs and certificate of attendance.
[x] Please purchase your own copies of ISO/DIS 14155 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 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.

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