From a new guidance on inspections to a bid to help the EU regain its R&D prowess, the Agency is busy.
Hardly had this column provided an overview of the European Union's Innovative Medicines Initiative (IMI) in the May issue of Applied Clinical Trials when the European Medicines Agency announced it was going to bid to become one of the players in the game. The Agency is planning to lead a consortium in an application to win one of the first calls: on strengthening the monitoring of benefit–risk. In what is a curious development for a regulatory authority of any sort (and all the more curious in that it is an EU regulatory body tendering to join an EU organized program), it is inviting interested parties to declare their interest in working with it as a member of the consortium it is putting together—still more curious, since many of the natural partners are likely to be the companies whose products the Agency is responsible for evaluating when it is doing its day job.
But don't all rush at once. The Agency has attached its own health warning: "As much as we appreciate interest in this important initiative, please understand that it is possible that not everyone who expresses an interest will be invited to join the consortium at an initial stage. As consortium leaders, we have to ensure and demonstrate to the peer review body that we have a balanced and manageable consortium capable of covering all aspects of this call."
The Agency sees a clear role for itself not just in this project but also in other IMI activities. As it explains, many of these activities are expected to foster drug development and to bring drugs to the market faster, so "many IMI-sponsored research projects will comprise at least some regulatory aspects."
Turning Aspirations into Leadership
The Agency is consequently anticipating that it may be asked to participate in expressions of interest in other projects by other consortia. If the invitation meets certain conditions, the Agency says, it "may be willing and able to participate in select projects." It does, however, accept that it may face constraints not just in resources, since some projects will be labor intensive, but also in terms of potential conflicts of interest since some projects—such as developing drug development methodologies like biomarkers or novel approaches to analysis of clinical trials—may well, at a later stage, become part of a marketing authorization dossier or a scientific advice procedure presented to the Agency for evaluation.
If you have ever wondered what else the European Medicines Agency gets up to when it isn't evaluating new medicines, the latest edition of its annual report provides plenty of indications of its gamekeeping activities. "In light of the growing complexity of evaluation procedures, and the advent of emerging therapies and new technologies," it says, the Agency "continued to extend the involvement of scientific experts and stakeholders in its work," and held workshops and conferences to address critical scientific areas such as first-in-man clinical trials, adaptive design in confirmatory clinical trials, and cell- and tissue-engineered products.
Avid readers of this column may also recall that the Agency—as it records it—"successfully organized a conference with a wide range of stakeholders to examine the operation of the clinical trials directive after three years of operation and published a report on the outcome." The conference certainly took place and was successful in giving critics of the directive a chance to indicate their concerns, but the Agency's annual report (rather like the report it published on the outcome) gives little indication of the unresolved controversies over this legislation.
The annual report also reveals that 56% of the requests it received for scientific advice (under its complemen-tary function of early guidance to drug developers) related to clinical trials, compared to 28% relating to preclinical research and just 16% to quality.
Some of the Agency's most intensive work now relates to pharmaco-vigilance. It received 381,990 adverse drug reaction reports in 2007, an increase of more than 25% from 2006. It also received 63,393 reports concerning investigational medicines' adverse drug reactions observed during clinical trials, an increase of 18% compared to 2006.
But closest to home for many readers of this magazine, the Agency coordinates the verification of compliance with the principles of good manufacturing practice (GMP), good clinical practice (GCP), good laboratory practice, and with certain aspects of the supervision of authorized medicinal products in use in the EU. It does this through inspections requested by its own scientific committee in connection with the assessment of marketing authorization applications or when specific product related problems have been referred to the committee.
In 2007, the report says, the total number of GMP inspections (145) was higher than expected, up from 110 in 2006. The Agency's explanation in part refers to the increasing number of authorized products requiring re-inspection and increasing numbers of variations. GCP and pharmacovigilance inspection figures "were also significantly over forecast," it says, with more than double the number of inspections requested in 2006. "This reflects an increase in the number of routine inspection requests in line with the policy on GCP inspections adopted in 2006, as well as in increasing focus on inspections in countries where there is little European experience."
Talking of inspections, the EU has just published a range of guidance documents on GCP inspections. In another step toward the goal of harmonization, the guidance contains common provisions for the authorities of the member states on how they should conduct inspections. It is an extensive range of guidance,1 covering the communication of findings, provisions for inspections at investigator sites and at clinical laboratories, checks on computer systems, and inspections of sponsors and contract research organizations. It also provides guidance for the preparation of GCP inspections and for the preparation of inspection reports.
For instance, at investigator sites inspectors should identify (and verify) the independent ethics committee (IEC) and check whether it provides a statement that the site is organized and operates according to GCP and applicable laws and regulations. They should determine whether IEC approval was obtained before starting the trial and clearly identifies the trial, the investigator, the documents reviewed, and all versions of them. And they should determine whether the coordinating investigator or sponsor has maintained copies of all reports submitted to the IEC when the trial was initiated.
Inspectors should also check on monitoring and follow-up by the sponsor in terms of number of visits at the site, scope, dates of the visits, and content of the monitoring visit reports. Similarly, they should assess arrangements for obtaining informed consent from subjects and should check by source data verification whether the investigator team conducted the clinical trial according to the approved protocol and its amendments.
In assessing whether the sponsor or CRO is providing quality assurance and quality control systems for its clinical trials, inspectors should check if clinical research activities are staffed with sufficient qualified and trained personnel for each area. They should review the organizational charts that identify the key personnel in each area, the independence of the quality assurance unit, and the job description, qualifications, and training of the individuals involved at any stage of the clinical trial process. Inspectors should also check the audit system and whether it includes audits of key clinical trial processes, audits of contractors and subcontractors, processes for communicating and addressing audit findings, and procedures for dealing with serious or persistent noncompliance.
For all inspections, an inspection plan should be established during the preparation period. The emphasis of the inspection may vary depending on whether or not the inspection is related to the assessment of a marketing authorization application, to the routine surveillance of clinical trials performed in the member states or to other purposes. But before every inspection, an opening meeting should introduce the inspectors to the organization being inspected and explain the regulatory framework for the conduct of the inspection. The inspectors should use this meeting to identify the distribution of duties for the conduct of the trial in the organization being inspected, and to review the scope and the objectives of the inspection with the staff. The names and titles of persons interviewed or present during the inspection meetings and the details of the inspected organization should be documented.
If access to records or copying of documents is refused for any reason or there is any withholding of documents or denial of access to areas to which the inspectors are legally entitled to access, these refusals should be documented and included in the inspection observations. At the end of the inspection, the inspectors should hold a closing meeting with the staff of the organization inspected and present their findings. They should ensure that the results of the inspection are clearly understood and that there are no misunderstandings. Issues to be followed up should be addressed, including any additional documents that may need to be sent to the inspection team. The guidance also sets out how and when GCP inspectors should make their reports available to other member states, ethics committees, and the European Medicines Agency.
The guidance specifically for the preparation of good clinical practice inspection reports indicates that certain "basic" items should be recorded. This list includes "administrative information on what was inspected, where, when, and who was present; reference texts and documents for the inspection; handling and reporting of data, analyses, and inclusion and exclusions of data; documents reviewed during the inspection, including a summary of the source document verification conducted; compliance/noncompliance with national regulations, applicable EU legislation, and the principles of GCP; an indication of any opportunity given to the inspectee or other involved party (e.g., investigator, sponsor, applicant) to comment, if and when comments were received, and whether these were accepted or not."
And just to give everyone sleepless nights, the guidance grades findings, with the most serious being "critical." It explains that "observations classified as critical may include a pattern of deviations classified as major, bad quality of the data, and/or absence of source documents. Fraud belongs to this group." The faults include "conditions, practices or processes that adversely affect the rights, safety or well being of the subjects and/or the quality and integrity of data." Critical observations "are considered totally unacceptable." The possible consequences include "rejection of data and/or legal action." You have been warned!
Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.
1. EU Guidance, Recommendations on Good Clinical Practice Inspections, available at: www.ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol10_en.htm#chap_iv.