On 18 October 2007 a
Reflection Paper on Advice to Applicants / Sponsors / CROs was published by the GCP Inspectors Working Group. A Corrigendum was relased on 19 September 2008.
An overview of the document is given below:
A number of critical problems with verification of data available in Marketing Authorisation Application (MAA) dossiers for generic products (BE/BA studies) have been observed during the assessment of applications by the Competent Authorities, national GCP inspections, and have been published also in relation to WHO inspections.
The problems were manifold, diverse and observed in many aspects of the clinical trials. The findings have included:
Therefore, the decision was made to develop this advisory document to underline the responsibilities of the parties involved, clarify expectations, and reinforce the steps taken by the applicants, sponsors and CROs themselves to ensure the quality of bioequivalence trials submitted in marketing authorisation dossiers.
This document is addressed to sponsors, CROs and applicants, specifically in the field of generics. The aim of this document is to increase awareness with the responsible parties that the data submitted in a MA should be of high quality, safety and should be verifiable and to give guidance to the applicant on how to obtain more certainty on the trial data. This way, for the future studies similar problems may be prevented. […]
General requirements for clinical trials submitted in Marketing Authorisation Applications are set out in Annex I to Directive 2001/83/EC as amended by Directive 2003/63/EC. It should also be noted that all clinical trials conducted in third countries should be conducted to the ethical standards of Directive 2001/20/EC and the applicant will have to testify to this when submitting a marketing authorisation using the clinical trial.
In addition to the legal context, there are already a number of guidelines and documents available that are applicable to the clinical trial environment, including the CPMP/ICH/135/95 Note for guidance on Good Clinical Practice and the CPMP/EWP/QWP/1401/98 Note for guidance on the investigation of bioavailability and bioequivalence. This document will therefore only cover those aspects where additional information may be helpful.
Further aspects that need to be taken into account are:
The quality and safety issues related to the activities of the CRO and specialised laboratories have been described in the Annex 9 of the WHO Technical Report Series, No. 937, 2006, entitled “Additional guidance for organizations performing in vivo bioequivalence studies”, which is already very comprehensive for this environment. Therefore the present document refers CROs and laboratories participants to the WHO document, which is available on the WHO website.
The requirements and responsibilities of the sponsor and applicant have not been extensively described in the WHO document and therefore, the present document and advice is directed at aspects that may be verified by and activities that may be undertaken by the applicant and sponsor to ensure the quality of the clinical study data.
As many studies are either contracted to third parties or bought from other parties, close attention should be paid to the content of the contracts, to ensure that quality elements are clearly described.
Elements of the contracts should ensure guarantees for study quality, verification issues, access to the original data and processes, and archiving aspects.
Quality evaluation of the contract partner or of the acquisition of the dossiers should be a standard part of the negotiations for buying or contracting.
Processes and system used in the development of the clinical data should be clearly described and verifiable.
Quality Assurance processes such as monitoring and auditing of the study sites, processes and data should be evaluated.
There should be transparency of all transactions for the involved parties.
It seems wise to include in the transactions specific guarantees for GCP/GMP compliance and compliance with the relevant guidance (including applicable GLP principles) and legal obligations. This can be formalised by the statements issued by the parties conducting the studies and on the basis of audit and monitoring reports related to the quality of the site and data.
At the time of buying or developing an application dossier the applicant should consider the following activities:
At the time of contracting a study to a CRO, the sponsor should consider the following activities:
At the time the study is finalised by a CRO the following activities may be undertaken by the sponsor:
A quality system approach to the sponsoring, contracting, purchase of a dossier/product or applying for a marketing authorisation will give a good basis through which verification of a number of the above issues can be implemented. This approach will ensure that the chances for problematic quality in (BA/BE) study dossiers used in generic applications are lessened.
This document should be used as complementary to the legal requirements, existing guidelines, including the CPMP notes for guidance on GCP and on investigation of bioequivalence and the WHO publications.
End of consultation (deadline for comments) of the original document was 31 March 2008.
document date 2007-11-14 | last update 2019-03-14