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Is it time to abandon complete blinded independent central radiological evaluation of progression in registration trials?

  • Francesco Pignatti
    Correspondence
    Corresponding author: Address: 7 Westferry Circus, Canary Wharf, London E14 4HB, United Kingdom. Tel.: +44 20 7523 7031, mobile: +44 78 8426 5946; fax: +44 20 7418 8613.
    Affiliations
    The European Medicines Agency (EMA), London, United Kingdom
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  • Author Footnotes
    d EMA Committee for Medicinal Products for Human Use (CHMP) Member, Chairperson of the CHMP Scientific Advice Working Party.
    Rob Hemmings
    Footnotes
    d EMA Committee for Medicinal Products for Human Use (CHMP) Member, Chairperson of the CHMP Scientific Advice Working Party.
    Affiliations
    Medicines and Healthcare Products Regulatory Agency (MHRA), London, United Kingdom
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  • Author Footnotes
    e Chairperson of the CHMP Oncology Working Party.
    Bertil Jonsson
    Footnotes
    e Chairperson of the CHMP Oncology Working Party.
    Affiliations
    Läkemedelsverket, Uppsala, Sweden
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  • Author Footnotes
    d EMA Committee for Medicinal Products for Human Use (CHMP) Member, Chairperson of the CHMP Scientific Advice Working Party.
    e Chairperson of the CHMP Oncology Working Party.
      Few subjects have generated as much regulatory discussion as the choice of primary endpoints in phase III trials in the advanced or metastatic cancer setting. Acknowledging that overall survival (OS) remains the most objective and clinically convincing endpoint to support a favourable decision on the benefit-risk balance and to change clinical practice, progression-free survival (PFS) has also been proposed as the primary endpoint to support drug approval. Although the interplay between PFS and OS remains unknown for most agents, and particularly for new ones, a primary rationale for using PFS is that this endpoint could be considered as a clinical benefit endpoint in itself, provided the treatment effect is sufficiently large. From the perspective of drug developers, the interest in PFS is because of the expectation that treatment effect will be numerically larger and quicker to observe, compared to OS. Furthermore, determination of PFS is not confounded by subsequent therapy and the increased interest in PFS as a primary endpoint likely reflects the fact that more active treatments have become available, making the OS comparison more complex due to the difficulty to control for the effect of subsequent therapies on OS. Regulators have recognised wider acceptance of PFS as the primary endpoint in registration trials, as evidenced by emerging guidance documents.

      Guideline on the evaluation of anticancer medicinal products in man; 2006. Available from: http://www.ema.europa.eu/ema/pages/includes/document/open_document.jsp?webContentId=WC500017748.

      Guidance for industry, clinical trial endpoints for the approval of cancer drugs and biologics; 2007. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071590.pdf.

      Nevertheless, the general acceptance of PFS as a primary endpoint from a regulatory perspective is still controversial because the clinical relevance of this endpoint is often debated, even in indications where the conventional response criteria (RECIST) are deemed appropriate.
      • Eisenhauer E.A.
      • Therasse P.
      • Bogaerts J.
      • et al.
      New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
      • Tuma R.
      Progression-free survival remains debatable endpoint in cancer trials.
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      References

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      2. Guidance for industry, clinical trial endpoints for the approval of cancer drugs and biologics; 2007. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071590.pdf.

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