Project description

Summary

On-site monitoring is an essential part of quality assurance of clinical studies. As specified in the guidelines of Good Clinical Practice (GCP), the objective is to ensure protection of patients and their rights and guarantee the credibility of data and results. The adequate amount of monitoring is an open question.

In industrially sponsored clinical trials, intensive on-site monitoring is usually performed (frequent site visits and verification at least of all the efficacy and safety parameters for all study subjects). In non-commercial, investigator-initiated studies, varying monitoring strategies are employed, the scope of which is often scaled according to available resources. The impact of the amount of monitoring on patient safety and data quality is unclear. The ADAMON project addresses the following question:

Is a focused, reduced monitoring strategy that is adapted to the design and objectives of the clinical trial and implemented by monitors specifically trained for the study sufficient to ensure achievement of the objectives of good clinical practice?

The ADAMON project prospectively investigated whether a trial-specific, risk-adapted, reduced on-site monitoring strategy (as proposed in [1]) is as effective as an intensive monitoring strategy.

ADAMON is a cluster randomised study involving eleven different clinical trials. Within each trial, the trial sites were randomised to a monitoring strategy either according to a risk-adapted approach or to an intensive monitoring strategy with frequent visits and 100% source data verification.

The main endpoint is the proportion of patients with at least one serious or critical finding with respect to patient safety, patient rights, or reliability of the data. This endpoint was determined by an independent ADAMON audit of each trial site. ADAMON results will be published in peer-reviewed journals and additionally disseminated through TMF e.V.

Funding period: December 1, 2008 - June 30, 2016
Funding amount: € 2,343,090
Funded project: "Instrument and Method Developments for Patient-Oriented Medical Research" of the German Federal Ministry for Education and Research (BMBF)
Funding code: 01EZ0876
Project leader: Dr. Oana Brosteanu, ZKS Leipzig

Background

The ICH Guidelines for "Good Clinical Practice" (ICH-GCP) pursue two main objectives:

To ensure the protection, safety and well-being of trial subjects
To ensure the credibility and validity of data obtained

In order to ensure that these objectives are achieved the ICH-GCP Guidelines require quality assurance measures – like monitoring, for example – in all areas of the clinical trial. The on-site monitoring requirement is very clearly formulated in the GCP Guidelines. However, it is not specified to what extent and with what strategies the required monitoring must be performed in order to achieve the objectives of GCP.

Generally speaking, in the industrially sponsored clinical trials, especially in phases I-III registration-relevant studies, highly intensive on-site monitoring is performed (frequent site visits, 100% source data verification at least of all the efficacy and safety parameters in 100% of patients). The result of this is that monitoring represents one of the major cost factors in the budget planning of registration-relevant studies.

In non-commercial clinical trials as well the need for quality assurance measures is undisputed. The establishment of structures such as Competence Networks in Medicine and Coordination Centers for Clinical Studies has contributed to this in Germany. It was accompanied by extensive public debate that began prior to implementation of EU Directive 2001/20/EC and was intensified when the 12th amendment to the German Pharmaceuticals Act (AMG) came into force in 2004. The scope of quality assurance measures required, especially of on-site monitoring, remains an unresolved debate issue. This applies not only to Germany but also to other EU countries in a similar way.

There is consequently a need to develop and validate a tool with which a rational quality assurance strategy adapted to the conditions of the specific clinical trial can be derived, especially for on-site monitoring. Such a strategy must be characterized by the fact that it ensures compliance with GCP objectives, at the same time optimizing the resources required.

Initial situation

Against this background two projects were implemented from 2005 - 2007 within the TMF umbrella organization. The projects integrated a broad scientific community, and presented the following results as a starting point for filing the application for the ADAMON project:

A proposal for risk-adapted monitoring in non-commercial clinical studies. It is comprised of
(1) a detailed procedure for risk analysis in clinical trials with respect to the required on-site monitoring,
(2) based on that, a classification of the clinical trial, and
(3) risk-adapted, reduced monitoring strategies for the different risk categories.
A full investigation protocol for the prospective randomized comparison of risk-adapted, reduced monitoring with extensive "full" monitoring.

Objectives

Primary objective:

To investigate whether the reduced on-site monitoring strategy developed within the scope of two TMF projects and adapted on a study-specific basis is equivalent to extensive "full" monitoring according to commercial standards with regard to the occurrence of serious or critical findings (as detected by a final audit).

Secondary objectives:

To compare the two monitoring strategies with regard to the occurrence of serious or critical findings (revealed by a final audit) that were not discovered by monitoring.
To compare the two monitoring strategies with regard to the different types of serious or critical findings (as detected by a final audit)

Procedure

For the investigation, cooperation agreements were concluded with 11 clinical trials (8 to AMG, 3 non-AMG / non-MPG, as of February 2014). They are trial of the phases II - IV, randomized, and multi-site with standardized data management. Within each participating clinical trial each participating trial site is randomised as to whether the site will be monitored on site using specifically adapted monitoring or intensive "full" on-site monitoring. A final audit is planned for each trial site. The audit results are crucial for a comparison of the two monitoring strategies.

The primary endpoint of ADAMON is the occurrence of a serious or critical violation of GCP that is detected during the final audit, defined as the occurrence of at least one of the following findings:

Patient consent was obtained either with gross negligence or not at all
Safety-relevant or efficacy-relevant inclusion and exclusion criteria were disregarded without prior agreement with the coordinating investigator
A serious adverse event (SAE) was reported too late, inadequately, with gross negligence, or not at all
The primary endpoint of the clinical trial was avoidably assessed with negligence, inadequately, or not at all
There was a significant deviation from the protocol-specified treatment or protocol-specified follow-up observation, without any compelling medical reasons

The following parameters are investigated as secondary endpoints in ADAMON:

Frequency of serious or critical violations of GCP that were not identified by monitoring. This endpoint allows statements to be made regarding the reliability of error detection when comparing the two monitoring strategies
Frequency of serious or critical violations of GCP, individually by category

In addition, other exploratory parameters are investigated, measures are taken to avoid bias, and compliance with biometric requirements is ensured.

Various management and dissemination measures are planned in order to ensure smooth project procedure or to be able to respond to unforeseen circumstances beyond the influence of this project and achieve a high level of attention in the national and international scientific community, as well as maximum dissemination of results.