BEBAC  Ing. Helmut Schütz

Reflection Paper on Advice to Applicants / Sponsors / CROs of BE Studies


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:

  1. Introduction

    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:

    • Study Subjects
      Participation not verifiable, informed consent and subject numbers not matching, subject list incomplete, ECGs not attributable to subjects, falsified or originals missing
    • Ethics
      Ethics committee not in operating in accordance with requirements, conflict of interest present, ethics approval not available, issues relating to the participation of CRO staff in trials
    • Bio-analytical data
      Verification not possible, no audit trails available, discrepant data sets all presented as source data, analytical methods not validated, biological samples not attributable, sample shipments not verifiable
    • IMP (reference and comparator)
      IMP quality not verifiable, counterfeit IMP, IMP administration not traceable, shipment and storage not verifiable, origin unclear, blinding during clinical and analytical conduct of the study not ensured
    • Facilities
      Number of beds inconsistent with number of subjects staying overnight, equipment and instruments not validated, operation and procedures not traceable,
    • Protocol
      Not followed, specifics not verifiable
    • Safety
      Adverse events not reported, no follow up of SAEs
    • Sponsor
      Contracts not available, no QC/QA system implemented
    • Study Report
      Reported data not consistent with the source data, study report not in accordance with requirements of protocol, statistical analysis not in conformity with requirements
    • Archives
      Incomplete, lost, access by inspectors not permitted

    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.

  2. Scope

    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. […]

  3. Legal Basis

    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.

  4. Points to consider
    1. Data Verification & Quality
      A number of guidance documents are available to enhance the quality and safety of clinical trials.
      • For the clinical part of the studies:
        CPMP/ICH/135/95, Declaration of Helsinki, other CHMP/ICH-Guidelines
      • For the bioanalytical part:
        CPMP/ICH/135/95, CPMP/EWP/QWP/1401/98, OECD-GLP
      • For the PK and statistical analysis:
        CPMP/ICH/135/95, CPMP/EWP/QWP/1401/98, GLP
        Reference should also be made to other applicable CHMP/ICH-Guidelines that may be applicable in that context.
    2. CRO, Sponsor, Applicant
      For evaluation of quality the following aspects are relevant:
      Type of organisation, activities, location/regulatory environment of the site(s) (EU/EEA, third countries), other MA dossiers developed, previous inspections etc…
    3. Investigational Medicinal Product
      In addition to the legal obligations a number of additional guidance documents is available that need to be followed to ensure optimal quality of the investigational product (reference and comparator).
      Quality of the IMP: Chapter III of the EUDRALEX Volume 10- Clinical trials (Information on the Quality of the Investigational Medicinal Product)

      Further aspects that need to be taken into account are:

      • Type of product (e.g. stability, PK and PK profiles, and analytical methods)
      • Production site (e.g. location, GMP license/inspection, QP activities)
      • Indication (e.g. vulnerable population, orphan population, population size, impact on market)
    4. Regulatory & Ethical Issues
      • Location of sponsor, CRO, laboratories (e.g. already well known region/regulatory environment)
      • Subjects (e.g. type, group, patients or volunteers)
      • Ethics Committee and Competent Authority (e.g. applicable local regulations and guidelines, national, international, trial type, specific local guidance)
  5. Specific Guidance

    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.

  6. Administrative Activities

    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.

  7. Specific Activities of the Applicant

    At the time of buying or developing an application dossier the applicant should consider the following activities:

    • Quality requirements detailed in contracts (safeguards to apply when purchasing a dossier)
    • Verification that the sponsor/CRO had adequate control of the quality of the study (performance and outcome of sponsor audits; evaluation of the activities of the sponsor)
    • General information on the CRO and their procedures
    • Verification of contracts between sponsor and CRO (details on quality, tasks and contracts)
    • Verification of IMP production certificates
    • Verification and guarantees of continued archiving and availability of source data
  8. Specific Activities of the Sponsor

    At the time of contracting a study to a CRO, the sponsor should consider the following activities:

    • Preferred vendor audits
    • Facilities and procedures of CRO
    • Evaluation of the responsibilities of the sponsor and the CRO
    • Quality and completeness of the protocol
    • Validation of analytical methods
    • Qualifications of personnel
    • Quality system of the CRO (monitoring/auditing)
    • Division of tasks in the contract
    • Validation of clinical activities
    • Qualifications of personnel (e.g. investigators, technicians, monitors)
    • Quality system (including monitoring and auditing) implemented by the CRO and the sponsor
    • Definition of responsibilities in contracts between CRO and sponsor
    • Performance of audits by the sponsor (pre-contracting, post-contracting); evaluation of audit results and improvement cycles
    • Verification of archiving of source data

    At the time the study is finalised by a CRO the following activities may be undertaken by the sponsor:

    • Verification of report, data listings, statistics and protocol
    • Effectiveness of contracted responsibilities
    • Performance of audits by sponsor (post-study); Evaluation of audit results and improvement cycles
    • Verification of (continued) archiving source data
  9. General Conclusion

    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.

  10. References


End of consultation (deadline for comments) of the original document was 31 March 2008.