ISO/FDIS 14155 "Clinical Investigations of Medical Devices in human subjects—good clinical practices" (2010)

New Rules for International Device Trials
A Whitepaper and Workshop by Nancy J Stark, PhD
Wednesday, 22 September 2010, 11 AM Central; or OnDemand soon after. 

Sweeping changes to ISO 14155
The international standard for medical device clinical research is about to undergo sweeping changes. The first and most evident change is the change in title; the standard is now known as ISO/FDIS 14155 " Clinical investigations of medical devices in human subjects—good clinical practices". Harmonized with the ICH-GCPs, 'Good clinical practices' was added to the title to signal to the world the Working Group's intention that this is now the standard to be followed for international medical device investigations.

There are other significant changes as well. The mechanical, physical, and engineering nature of devices are taken into account with the integration of the normative reference ISO 14971 "Application of Risk Management to Medical Devices". The contents of Investigator's Brochures looks like a document that reflects a mechanical device rather than a chemical drug, while the requirements for recording and reporting device deficiencies alongside adverse events complements the essential requirements of the MDD and AIMD.

All studies are created equal
Possibly the hardest thing for Americans to grasp is that there is no risk-based categorization of clinical trials in the standard. The concept of non-significant risk studies versus significant risk studies does not exist—all the rules apply equally to all clinical investigations.

An international standard written by international experts
The new standard was written by a team of experts from the US, Europe, and Japan. The team consisted of industry representatives, consultants, and regulators to assure that it was achievable, consistent with country regulations, and in keeping with accepted ethical and organizational practices. It did not come easily; the working group and editing committee met fourteen times, with a dozen or so teleconferences sprinkled in between the meetings.

One result is a standard that will be an an economic leveler—it will be neither easier nor more difficult to conduct a trial in one country over another. Another result is a standard that will be an ethical leveler—it will be neither easier nor more difficult to conduct trials in developing countries than developed countries.

Format and approach
The Part 1 and Part 2 standards from 2003 are now combined into single, comprehensive, 65-page document. The strategy was to approach clinical investigations from a project management perspective. A look at the layout gives an idea of the breadth and depth of the standard.

First, there are four administrative sections:
[1] Scope.
[2] Normative references.
[3] Terms and definitions.
[4] Ethical considerations.
The scope tells us that "the principles ...apply to all other clinical investigations...." The statement has no legal precedence but was clearly important to the Europeans. The scope also makes it clear that the standard does not apply to in vitro diagnostic devices.

"Normative" is ISO-speak for required. It is the one, small sentence under normative references that elevates ISO 14971 to importance. Being listed as a normative reference means that the sponsor is, de facto, non-compliant with ISO 14155 if they are not compliant with ISO 14971. Scattered throughout the document are the many ways in which Risk Analysis Reports are integrated into clinical investigations.

These are followed by three project planning sections:
[5] Clinical investigation planning.
[6] Clinical investigation conduct.
[7] Suspension, termination, and close-out.
It is not that there is anything new in the project management sections, but there is so much more detail and instructive language. If you have never done a clinical study before, you will find these sections to be a welcome reference.

The need for a Clinical Evaluation Report performed according to the principles of GHTF Study Group 5 to justify the design of the clinical protocol is another example of a requirement included to meet the essential requirements of EU Directive 93/42/EEC on medical devices (MDD) and EU Directive 90/385/EEC on active implantable medical devices (AIMD).

These are followed by two responsibilities sections:
[8] Responsibilities of the sponsor.
[9] Responsibilities of the principal investigator.
Sponsor and principal investigator responsibilities follow closely with FDA's new guidance "Investigator Responsibilities—Protecting the Rights, Safety, and Welfare of Study Subjects" and the ICH-GCPs. Principal investigators (aka "investigators" in the States) are still required to sign final reports under ISO, but investigators (aka "co-investigators" or "sub-investigators" in the States) are off the hook.

While much of the detail is laid out in five annexes:
Annex A (normative)—Clinical investigation plan.
Annex B (normative)—Investigator's Brochure.
Annex C (informative)—Case report forms.
Annex D (informative)—Clinical investigation report.
Annex E (informative)—Essential clinical investigation documents.
Annex F (informative)—Adverse event classification decision tree.
Annexes A and B on Clinical Investigation Plans (i.e. protocols) and Investigator's Brochures are required for compliance, the remaining annexes are for the reader's information. They contain extremely valuable information on organizing case report forms, writing a final report, and understanding the relationships between adverse events and effects.

Other extensive changes
Each section was expanded to include sufficient narrative to teach a new sponsor how to conduct a clinical investigation. This controversial move is meant to educate as well as to set a performance bar. Some notable examples of additions or changes include:
[1] Clearer definitions of adverse events, adverse device effects, and unanticipated device effects.
[2] A new definition, recording, and reporting requirements for device deficiencies.
[3] Requirements for recording and reporting adverse device effects in persons other than subjects.
[4] Implied requirement for a clinical research quality management system.
[5] Requirement for Risk Analysis Report.
[6] Requirement for a Clinical Evaluation Report to justify the study design.
[7] Required content for a protocol (clinical investigation plan).
[8] Required content for an Investigator's Brochure.
[9] Suggested content and organization for case report forms.
[10] Discussion of data monitoring committees.
[11] Requirements for document and data control.
[12] Requirements for electronic data systems.
[13] Auditing recommendations.
[14] Procedures for suspension or premature termination of a trial.
[15] Procedures for working with vulnerable populations.
[17] An extensive list of the documents essential for a clinical trial.
[18] Omission of the annex discussing how to do a literature review.
[19] And, very importantly, two differing attempts at adverse event classification.

The publication plan
FDIS stands for 'final draft international standard'. While the document is in the final draft stage it is being translated into French and German. Once this is complete the FDIS will be presented to the ISO members (Standards Bodies from each member country) for a final vote, but the only changes allowed at this stage will be spelling, punctuation, or grammar. After publication by ISO in 2011, each member Standards Body will adopt the standard into its own system; so in the US the standard will be re-issued as an ANSI (American National Standards Institute) standard of the same number.

Oddly enough, a member Standards Body is free to modify the standard, before issuing it under its own name if it wishes. So buyer beware, the French version may be different from the British version or from the US version!

If you liked the whitepaper, take the workshop
The learning objective of this five-hour workshop is to review the changes from the old, 2003 standards to the new, 2010 FDIS. The recording is available by OnDemand or CD at http://www.clinicaldevice.com/mall/Workshops.aspx.

You will receive, we will discuss
[x] PowerPoint slides.
[x] A 5 hour presentation.
[x] Hints for writing Clinical Evaluation Reports and their role in clinical investigations.
[x] Hints for writing Risk Analysis Reports and their role in clinical investigations.
[x] The required contents of clinical investigation plans (i.e. protocols).
[x] The required contents of investigator's brochures.
[x] Steps in planning clinical investigations.
[x] Steps in implementing clinical investigations.
[x] Steps in closing-out clinical investigations.
[x] The monitor's role in clinical investigations.
[x] Responsibilities of sponsors and investigators.
[x] A 30-minute quiz to reinforce your learning experience.
[x] CEUs and certificate of attendance.

Who should attend
[x] Clinical research professionals who estimate study costs.
[x] Project managers who want better planning and reporting from their group.
[x] CROs who want to improve their proposal skills.
[x] Executives who are planning the future of their company.

Presenter
Dr. Nancy J Stark has been a member of Working Group 4 since 2001 and was an active participant in shaping the coming ISO 14155 standard. She 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 5 hour workshop will be presented on Wednesday, 22 September 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