The 2009 Revision of ISO 14155: A True Worldwide Guidance for Medical Device Companies?
This article was originally published in RAJ Devices
ISO 14155, the international standard covering medical device clinical investigation, has had its controversies over the past two years. An immature revision was brought out in 2008 and was subsequently voted down by many European Union countries; when it emerged that it had attracted no fewer than 1,100 comments, it was clear that something was wrong.
Now another revision is close to being finalised. This article examines how the revision aims to improve the current version.
The current standard, ISO 14155 Part 1 and ISO 14155 Part 21,2, is well recognised by European regulatory bodies. However, it has not yet earned its credibility among many countries elsewhere in the world, with the result that the medical device industry is forced to rely upon other good clinical practice documents.
ISO 14155 does not intend to re-invent GCP. Rather, it seeks to provide strong medical device-oriented guidance to an industry where many start-up companies have limited resources and regulators rightfully impose an increasing demand for clinical data both in the premarket and postmarket phases. For many years, the industry has been trying painfully to adapt International Conference on Harmonisation guidance designed for pharmaceutical companies to medical device clinical investigations. Now, a second revision of ISO 14155 has been published – ISO/DIS 14155.23 – which has the unique aim of being a stand-alone document that will enable medical device companies to fulfil GCP worldwide requirements for clinical investigations.
Voting on the new document, which revises both Part 1 and Part 2 of the current standard, began on 22 October.
The current document
The existing standard contains all the main elements of GCP. However, it is considered to lack in-depth guidance and this has led to considerable differences in the way in which it has been interpreted4. This is far from ideal for an activity such as GCP that needs optimal precision and uniform understanding if it is to result in compliance with the relevant regulations, which require patient safety and scientific valid data.
Scope
The new draft, generally referred to as ISO 14155 DIS 2 (ie draft international standard, version 2), does not apply solely to premarket clinical investigations; it clearly indicates that it can also be applied to nonregulatory studies, meaning postmarket clinical investigations.
The document allows for the necessary flexibility in the area of postmarket studies – commercial documentation, for example, may replace the investigator brochure, or some investigations may not need such stringent accountability as is applied in a premarket investigation. Its applicability to all clinical investigations will hopefully clarify many situations in a postmarket phase as to what methodology to apply.
Adverse events/complaint reporting
There is considerable clarification in the many definitions that have been added to the document; there is, for example, a more worldwide approach concerning safety and the notion of unexpected serious adverse device effects has been added, with an emphasis on including consideration of events related to the procedure directly related to the use of the device.
Coupled with the adverse event definitions, the complaint definition has been introduced in the standard. Incidents that might have happened if circumstances had been less fortunate as defined in the current version of the standard have always been a grey area for most clinical professionals.
The notion that something might have happened is very often difficult to detect or identify. Moreover, if we consider primarily an adverse event as a “medical occurrence”, then it is difficult to include under this definition any events where there has not been a medical occurrence; such incidents are better considered as complaints that may have led to a medical occurrence. Although DIS 2 is open for comments, members of the working group are convinced that the introduction of the process of complaints will clarify many situations during clinical investigations and lead to a more comprehensive handling of the relevant data.
Ethical considerations
Although ethics committee or institutional review board processes have national requirements, it became obvious that, in order to have the document better accepted worldwide, more detailed guidance was needed concerning the ethics committee processes, both prior to starting and during the clinical investigation.
With emphasis on both what to submit to an ethics committee including notifications of amendments, safety reporting and reporting of serious deviations, and what to expect in the reply from the ethics committees, the document covers in a general manner all the requirements.
Many special circumstances for obtaining informed consent of subjects have been clarified in the revision. These include enrolment of subjects unable to read, vulnerable populations needing legally authorised representatives and subjects needing emergency treatment where either no time is available to obtain informed consent or subjects are unconscious at the time of enrolment.
Process layout
The layout of ISO 14155 DIS 2 has evolved to become more process-oriented. It now starts with activities necessary for the study setup. The need for a risk analysis – a process with which clinical professionals are very often unfamiliar – is emphasised; this is coupled with the justification for the design of the clinical investigation.
Although many of the members of the working group would have liked a more elaborate section on the justification for clinical investigations, regulators in general consider that such a regulatory requirement should not be defined in the standard.
There was extensive debate over whether the standard should continue to provide elaborate guidance on the literature review. In the end, the decision was taken to leave out the current Annex A and refer to other guidance documents available at a global level, namely the Global Harmonization Task Force Study Group 5 document on clinical evaluation5.
The current Part 2 on investigation plan requirements is merged in the document as an annex, and an additional annex was created to clarify the contents of the investigator brochure.
An important point in the process of the clinical investigation is also the monitoring. The DIS 2 document provides more elaborate guidance on the different monitoring activities at setup, during the investigation and at close down. Specific emphasis on device accountability, data handling, training and identification of all parties involved as well as the need for traceability at all times has been extensively outlined both in the process part of the document as well as in the sections on responsibilities of the sponsor, the monitor and the investigators.
In addition to covering more extensively monitoring activities, the standard also considers the need for additional verification methodologies such as a data monitoring board and auditing. Although strong arguments are provided to include these processes in a clinical investigation, the standard abstains from making these mandatory.
Annexes
Several valuable annexes have been added, including a checklist on essential documentation at the different stages of a clinical investigation as well as an adverse event decision tree chart, which, the working group that is revising the ISO 14155 standard is convinced, can be used as a basis for standard operating procedures.
Conclusion
Medical device clinical investigations are significantly different from those for pharmaceuticals and, thus, device companies need specific, detailed guidance. Furthermore, in the current regulatory climate where global clinical investigations are increasingly needed to optimise the manufacturer’s investment, a globally recognised standard would be a major advantage. Hence, it is hoped that the major changes made in the ISO/DIS 14155.2 will lead to a better acceptance of this important GCP guidance for medical device clinical investigations.
Timelines
Voting on the DIS 2 document began on 22 October. As the TC 194 WG4 members have unanimously elected to have a short voting period – two months compared with the more usual five months – voting will be over on 22 December 2009.
The goal is to tentatively bring out the final DIS by the end of the first quarter of 2010, as close as possible to the 21 March deadline for implementation of Directive 2007/47/EC, the amending directive that brings with it new requirements for companies in terms of clinical investigation, so it can be used in conjunction by the industry.
References
1. ISO 14155-1:2003 Clinical Investigation of Medical Devices for Human Subjects Part 1: General requirements, www.iso.org/iso/iso_catalogue/catalogue_tc/catalogue_detail.htm?csnumber=31723
2. ISO 14155-2: 2003 Clinical Investigation of Medical Devices for Human Subjects Part 2: Clinical investigation plans, www.iso.org/iso/iso_catalogue/catalogue_ics/catalogue_detail_ics.htm?csnumber=45557
3. Clinical investigation of medical devices for human subjects – Good clinical practice, ISO/DIS 14155.2, www.iso.org/iso/iso_catalogue/catalogue_ics/catalogue_detail_ics.htm?ics1=11&ics2=100&ics3=20&csnumber=45557
4. Giroud D, ISO 14155-1:2003 – Why the Newly Published Standard on Medical Device Clinical Investigations May Need Improving, The Regulatory Affairs Journal – Devices, 2003, 11(6), 324-325
5. GHTF final document, Clinical Evaluation, SG5/N2R8:2007, dated May 2007/posted 29 June 2007, www.ghtf.org/documents/sg5/sg5_n2r8_2007final.pdf
Danielle Giroud is founder of the World Medical Device Organisation (WMDO), a professional development organisation for the medical device sector based in Ecublens, Switzerland. Ms Giroud recently took on the convenorship of the TC 194 WG4, the working group that is revising the ISO 14155 standard. Email: [email protected].