Applied Clinical Trials
Guidance for auditing quality systems of independent ethics committees throughout Europe.
Standards for Independent Ethics Committees (IECs) have been under discussion by many groups for several years, including the European Forum for Good Clinical Practice (EFGCP). The EFGCP survey published in 2007 shows there is enormous variation among IECs in Europe.1 One of the questions asked in this survey was, "Is there an ongoing quality assurance process (e.g., audits, inspections, and internal standard operating procedures) for research ethics committees," which produced an almost universal answer of "No." The areas of most striking difference related to quality assurance, training, collection of safety data, and consent from vulnerable subjects.
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As one of the steps to help standardize IECs in Europe, a subgroup of the Ethics Working party of EFGCP developed a guidance document to assist with the establishment of a quality assurance program. This was published on the EGFCP Web site, http://www.efgcp.be, in October 2008.
The authors would like to point out that EFGCP has no regulatory/official status, the document is not an official guidance document issued by a standard body such as ICH, EMA or European Commission. However, EFGCP membership is diverse and does include members of IECs and competent authorities.
The values and principles of medical ethics are generally considered to be similar across Europe. The differences occur in the practices related to the decision-making process.2
The EFGCP Ethics Working party found enormous differences in standards between IECs. The landmark 2001/20/EC Directive and subsequent directives and guidelines have given us the possibility of harmonization, but they have not gone far enough in certain areas, including the regulation of IECs across Europe. The procedures for ethical review defined in the Directives are very few: Each member state must provide a single opinion and the timeline for initial review is 60 days, with 35 days for substantial amendments.
The EU rules that have intended to provide the framework for harmonization have fallen short and have failed to provide the regulations to bring together these divergent groups. IECs still operate at a national level. Another factor to consider over the past few years is the fact that the EU has enlarged considerably and is constantly changing. New member states have had to adapt quickly to this evolving environment. IECs have been allowed to operate with their previous levels of bureaucracy in this continuing fragmented European climate with the lack of an imposed obligation to harmonize.
Ethics review of clinical research is mandatory per regulations. However, in Europe there has been no review of those organizations that have been doing this vital work. IECs in Europe are rarely, if ever, audited by sponsors/CROs and many have no internal mechanisms in place to assess their quality processes.
Accreditation would be a valuable next step for IECs if introduced at the governmental level. This would ensure that processes and standards are of the highest quality for ethical review and would also lead to homogeneity throughout Europe. An audit program may well form part of an accreditation process. There are, however, very few countries in Europe that have an established accreditation process in place or that is currently being developed.
ICH GCP (CPMP/ICH/135/95) defines an audit as a "systematic and independent examination of trial related activities and documents." The key words defining the process of an audit are "systematic" and "independent." Before the EFGCP Guideline was developed there were no established guidelines or recommendations in operation within Europe to assist IECs in establishing their quality systems. Our current guidance document builds on the EFGCP 2002 document, "European Guideline for Auditing Independent Ethics Committees."3
We acknowledge that some steps have been taken to introduce quality systems in IECs. A written constitution, SOPs, and training programs for members are now well developed in many member states. However, as a next step, the introduction of a quality system within an IEC to assure quality will assist in raising the quality of the ethical review process further and thereby provide greater protection for human subjects who take part in biomedical research. Auditing of the system will provide the assurance that the processes introduced work effectively.
In terms of details, the "Guidance for Auditing Quality Systems of Independent Ethics Committees in Europe 2008" outlines the audit approach and the minimum standards that are required when auditing a European Ethics Committee's quality system.4 A useful glossary defines the words and phrases used within the document. This includes a description of phrases such as "appointing body," "conflict of interest," and "community" that have no equivalent description in ICH GCP or similar documents. The table of contents for this document has been listed in Table 1.
Table 1. The table of contents from the Guidance for Auditing Quality Systems of Independent Ethics Committees in Europe 2008.
Our document provides a step-by-step approach to quality system review, commencing with how auditors should be assigned, qualifications, and training requirements. When we describe auditor experience and education, many of the requirements may be desirable, but there were some we felt were mandatory. For example, auditors must have training in auditing techniques and up to date records on qualifications, training, and experience must be maintained.
The importance of the independent role of the auditor has also been stressed in this section. Auditors "must report at the highest level to the body that has sponsored the audit, usually the appointing body." If auditors are assigned from external sources we recommend they sign a statement provided by the IEC to show they have no conflict of interest. The auditor should also sign a confidentiality agreement to be allowed full access to all relevant documents.
The following sections of the document describe audit planning, the steps involved in conducting an audit, and the follow-up process. The most descriptive and detailed section of the document outlines audit conduct, commencing with the opening meeting through the actual review process to the closing meeting. Some documents can of course be reviewed prior to the actual audit, but issues involving confidentiality and privacy will need to be considered. For a summary of the types of documents that can be reviewed during the audit, refer to Table 2.
Table 2. A summarized list of the types of documents that can be reviewed during an audit.
Interviews with relevant staff, a tour of the facilities, and a review of the storage and archiving of documents are also conducted as part of the audit. At the end of the audit, a closing meeting should be conducted to present the findings to the auditee(s) to ensure that they are clearly understood and that there is no misunderstanding by either the auditee(s) or the auditor.
Section 6 outlines the requirements of the audit report. Audit reports are strictly confidential and need to be retained securely and only shared with the auditor(s), auditee(s), and the appointing body. In some cases (SOP dependent), the Institutional Review Board may be required to destroy the report once all-corrective and preventative actions (CAPAs) have been put in place. Audit follow-up forms the final section of the document.
In order to derive the greatest benefit from an audit, it is necessary for the auditees (with the help of others) to:
Such implementation of a CAPA will increase the quality of the operations of an IEC and will provide assurance to regulatory bodies.
Implementing a quality system takes time and expertise. One suggestion to help with the implementation of this guidance document or any similar document would be to run a system of audits across several IECs with the same independent auditor. This would increase dialogue across IECs and again assist with the standardization process. Quality systems could be perceived to add complexity, but by introducing these types of audits, processes would become streamlined and increase transparency of the review process. Introducing quality activities would in no way effect the independence of the IEC.
Another area of concern may be the perceived threat felt by members of IECs being audited. Members are volunteers who work without remuneration and for the general public good. Introduction of such a system may lead to resentment with what may be seen as another imposition. As with any scheme, the advantages need to be communicated and any negativity dispelled.
Europe still functions independently despite many attempts to regulate the individual European countries. It cannot be considered the "United States of Europe." Separate identities and cultures have been developed over hundreds of years and are important to be maintained as part of our heritage. However, until IECs are obligated by regulations to work in a more harmonized way, documents such as this can assist by providing guidance.
The introduction of a quality system and audits will make a valuable contribution to the quality of the ethics review process. This would encourage IECs to develop standardized policies and procedures that promote the consistent application of ethical principles across studies.
Clinical research is often conducted by multinational companies/organizations working in many different countries, and consequently would benefit greatly from a more universal approach from IECs. There is still a great deal to be done to achieve harmonization. As part of the ongoing work of the Ethics Working Party at EFGCP, we are looking into producing a checklist document to assist IECs when they review local sites. IECs do rely on local expertise. They need to ensure that trial centers and site staff are adequate. It is hoped that this future document will enhance a standardized approach.
Nicky Dodsworth* is Senior Director, Global Quality Assurance, at Premier Research, email: firstname.lastname@example.org. Mary O'Flaherty is Principal at Global GXP Compliance at Biogen Idec. Colin Wilsher, is Associate Director, Quality Assurance, at Pfizer Medical.
*To whom all correspondence should be addressed.
1. The Procedure for the Ethical Review of Protocols for Clinical Research Projects in the European Union, 2007 (European Forum for Good Clinical Practice Ethics Working Party), Wolters Kluwer Health/Adis International ISSN 1364-9027, http://www.efgcp.be, The International Journal of Pharmaceutical Medicine, 21 (1) 1-113 (2007).
2. F.P. Crawley, "Diversity in Medical Ethics in Europe," CRFocus, 18 (6) 16-18 (2007).
3. European Guideline for Auditing Independent Ethics Committees, 2002 (European Forum for Good Clinical Practice), http:// www.efgcp.be.
4. Guidance for Auditing Quality Systems of Independent Ethics Committees in Europe, 2008 (European Forum for Good Clinical Practice, Ethics Working Party), http://www.efgcp.be.