Skip to main content

Advertisement

SpringerLink
Log in

A comparison between the assessments of progression-free survival by local investigators versus blinded independent central reviews in phase III oncology trials

  • Clinical Trial
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

In this study, we compared the assessments of progression-free survival (PFS) carried out by the local investigator or by a blinded independent central review in the framework of phase III registration randomized controlled trials (RCT) in oncology.

Methods

We carried out a search in the clinicatrials.gov database, looking at the RCTs reporting the results of both independently assessed and investigator-assessed PFS. The hazard ratios (HRs) of investigator-assessed PFS and independently assessed PFS were recorded, and a discrepancy index was obtained by calculating the ratio of their respective HRs. Moreover, we investigated possible factors of discrepancy by analyzing the trials in different groups (by year, by tumor type, by drug type, by study design).

Results

We analyzed 28 RCTs meeting the search criteria. The estimated mean discrepancy index was 0.98 (confidence interval 0.927–1.032 (n = 32)). Subgroup analysis showed that the confidence intervals in all cases included the value 1, except in the subgroup of studies started in the period 2003–2006.

Conclusion

In phase III oncology trials, we found no significant differences between the hazard ratios estimated by local investigators and those estimated by blinded independent central reviews. A relatively higher variability, in terms of large CI, was found in trials with biological agents.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Day SJ, Altman DG (2000) Statistics notes: blinding in clinical trials and other studies. BMJ 321:504. https://doi.org/10.1136/bmj.321.7259.504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Schulz KF, Grimes DA (2002) Blinding in randomised trials: hiding who got what. Lancet 359:696–700

    Article  PubMed  Google Scholar 

  3. Dodd LE, Korn EL, Freidlin B, Jaffe CC, Rubinstein LV, Dancey J, Mooney MM (2008) Blinded independent central review of progression-free survival in phase III clinical trials: important design element or unnecessary expense? J Clin Oncol 26:3791–3796

    Article  PubMed  PubMed Central  Google Scholar 

  4. 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.

  5. 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

  6. Pignatti F, Hemmings R, Jonsson B (2011) Is it time to abandon complete blinded independent central radiological evaluation of progression in registration trials? Eur J Cancer 47:1759–1762

    Article  PubMed  Google Scholar 

  7. Zhang J, Zhang Y, Tang S, Liang H, Chen D, Jiang L, He Q, Huang Y, Wang X, Deng K, Jiang S, Zhou J, Xu J, Chen X, Liang W, He J (2017) Evaluation bias in objective response rate and disease control rate between blinded independent central review and local assessment: a study-level pooled analysis of phase III randomized control trials in the past seven years. Ann Transl Med 5(24):481

    Article  PubMed  PubMed Central  Google Scholar 

  8. Zhang J, Zhang Y, Tang S, Jiang L, He Q, Hamblin LT, He J, Xu Z, Wu J, Chen Y, Liang H, Chen D, Huang Y, Wang X, Deng K, Jiang S, Zhou J, Xu J, Chen X, Liang W, He J (2018) Systematic bias between blinded independent central review and local assessment: literature review and analyses of 76 phase III randomised controlled trials in 45 688 patients with advanced solid tumour. BMJ Open 8(9):e017240

    Article  PubMed  PubMed Central  Google Scholar 

  9. Amit O, Mannino F, Stone AM, Bushnell W, Denne J, Helterbrand J, Burger HU (2011) Blinded independent central review of progression in cancer clinical trials: results from a meta-analysis. Eur J Cancer 47:1772–1778

    Article  CAS  PubMed  Google Scholar 

  10. Gyawali B, Parsad S, Feinberg BA, Nabhan C (2017) Real-world evidence and randomized studies in the precision oncology era: the right balance. https://doi.org/10.1200/PO.17.00132, JCO Precision Oncology - published online October 30, 2017.

  11. Rothenberg ML, Cox JV, Butts C, Navarro M, Bang Y-J, Goel R et al (2008) Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX-4) as second-line therapy in metastatic colorectal cancer: a randomized phase III noninferiority study. Annals of Oncology 19:1720–1726

    Article  CAS  PubMed  Google Scholar 

  12. Di Leo A, Gomez HL, Aziz Z, Zvirbule Z, Bines J, Arbushites MC et al (2008) Phase III, double-blind, randomized study comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line treatment for metastatic breast cancer. J Clin Oncol 26:5544–5552

    Article  PubMed  PubMed Central  Google Scholar 

  13. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115–124

    Article  CAS  PubMed  Google Scholar 

  14. Iwata H, Masuda N, Ohno S, Rai Y, Sato Y, Ohsumi S, Hashigaki S, Nishizawa Y, Hiraoka M, Morimoto T, Sasano H, Saeki T, Noguchi S (2013) A randomized, double-blind, controlled study of exemestane versus anastrozole for the first-line treatment of postmenopausal Japanese women with hormone-receptor-positive advanced breast cancer. Breast Cancer Res Treat 139:441–451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ravaud A, Motzer RJ, Pandha HS, George DJ, Pantuck AJ, Patel A, S-TRAC Investigators et al (2016) Adjuvant Sunitinib In High-Risk Renal-Cell Carcinoma After Nephrectomy. N Engl J Med 375:2246–2254

    Article  CAS  PubMed  Google Scholar 

  16. Reichardt P, Blay JY, Gelderblom H, Schlemmer M, Demetri GD, Bui-Nguyen B, McArthur GA, Yazji S, Hsu Y, Galetic I, Rutkowski P (2012) Phase III study of nilotinib versus best supportive care with or without a TKI in patients with gastrointestinal stromal tumors resistant to or intolerant of imatinib and sunitinib. Ann Oncol 23:1680–1687

    Article  CAS  PubMed  Google Scholar 

  17. Hutson TE, Escudier B, Esteban E, Bjarnason GA, Lim HY, Pittman KB, Senico P, Niethammer A, Lu DR, Hariharan S, Motzer RJ (2014) Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol 32:760–767

    Article  CAS  PubMed  Google Scholar 

  18. Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM, CLEOPATRA Study Group (2012) CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366:109–119

    Article  CAS  PubMed  Google Scholar 

  19. Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, CLEOPATRA Study Group et al (2015) Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 372:724–734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yao JC, Guthrie KA, Moran C, Strosberg JR, Kulke MH, Chan JA, LoConte N, McWilliams RR, Wolin EM, Mattar B, McDonough S, Chen H, Blanke CD, Hochster HS (2017) Phase III prospective randomized comparison trial of depot octreotide plus interferon Alfa-2b versus depot octreotide plus bevacizumab in patients with advanced carcinoid tumors: SWOG S0518. J Clin Oncol 35:1695–1703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rini BI, Bellmunt J, Clancy J, Wang K, Niethammer AG, Hariharan S, Escudier B (2014) Randomized phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial. J Clin Oncol 32:752–759

    Article  CAS  PubMed  Google Scholar 

  22. Stupp R, Hegi ME, Gorlia T, Erridge SC, Perry J, Hong YK, Aldape KD, Lhermitte B, Pietsch T, Grujicic D, Steinbach JP, Wick W, Tarnawski R, Nam DH, Hau P, Weyerbrock A, Taphoorn MJ, Shen CC, Rao N, Thurzo L, Herrlinger U, Gupta T, Kortmann RD, Adamska K, McBain C, Brandes AA, Tonn JC, Schnell O, Wiegel T, Kim CY, Nabors LB, Reardon DA, van den Bent M, Hicking C, Markivskyy A, Picard M, Weller M, European Organisation for Research and Treatment of Cancer (EORTC), Canadian Brain Tumor Consortium, CENTRIC study team (2014) CENTRIC study team. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 15:1100–1108

    Article  CAS  PubMed  Google Scholar 

  23. Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch AR, Cavo M, FIRST Trial Team et al (2014) Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med 371:906–917

    Article  CAS  PubMed  Google Scholar 

  24. Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C (2012) Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol 13:247–255

    Article  CAS  PubMed  Google Scholar 

  25. Hersh EM, Del Vecchio M, Brown MP, Kefford R, Loquai C, Testori A et al (2015) A randomized, controlled phase III trial of nab-Paclitaxel versus dacarbazine in chemotherapy-naïve patients with metastatic melanoma. Ann Oncol 26:2267–2274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Urruticoechea A, Rizwanullah M, Im SA, Ruiz ACS, Láng I, Tomasello G, Douthwaite H, Badovinac Crnjevic T, Heeson S, Eng-Wong J, Muñoz M (2017) Randomized phase III trial of trastuzumab plus capecitabine with or without pertuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who experienced disease progression during or after trastuzumab-based therapy. J Clin Oncol 35:3030–3038

    Article  CAS  PubMed  Google Scholar 

  27. van Oers MH, Kuliczkowski K, Smolej L, Petrini M, Offner F, Grosicki S, Levin MD, Gupta I, Phillips J, Williams V, Manson S, Lisby S, Geisler C, PROLONG study investigators PROLONG study investigators (2015) Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised phase 3 study. Lancet Oncol 16:1370-1379.

  28. van Oers MH, Smolej L, Petrini M, Offner F, Grosicki S, Levin MD, et al. PROLONG study investigators (2018 Role of ofatumumab (OFA) maintenance treatment in relapsed chronic lymphocytic leukemia (CLL): final analysis of PROLONG study. https://doi.org/10.1200/JCO.2018.36.15_suppl.7517, Journal of Clinical Oncology 36, no. 15_suppl (May 20 2018) 7517-7517.

  29. Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P, Martin M, Pienkowski T, Pivot X, Burris HA, Petersen JA, Stanzel S, Strasak A, Patre M, Ellis P (2017) Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2-positive, advanced breast cancer: primary results from the phase III MARIANNE study. J Clin Oncol 35:141–148

    Article  CAS  PubMed  Google Scholar 

  30. Motzer RJ, Porta C, Vogelzang NJ, Sternberg CN, Szczylik C, Zolnierek J, Kollmannsberger C, Rha SY, Bjarnason GA, Melichar B, de Giorgi U, Grünwald V, Davis ID, Lee JL, Esteban E, Urbanowitz G, Cai C, Squires M, Marker M, Shi MM, Escudier B (2014) Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial. Lancet Oncol 15:286–296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, METRIC Study Group et al (2012) Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 367:107–114

    Article  CAS  PubMed  Google Scholar 

  32. Vitolo U, Trněný M, Belada D, Burke JM, Carella AM, Chua N, Abrisqueta P, Demeter J, Flinn I, Hong X, Kim WS, Pinto A, Shi YK, Tatsumi Y, Oestergaard MZ, Wenger M, Fingerle-Rowson G, Catalani O, Nielsen T, Martelli M, Sehn LH (2017) Obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated diffuse large B-cell lymphoma. J Clin Oncol 35:3529–3537

    Article  CAS  PubMed  Google Scholar 

  33. Hiddemann W, Barbui AM, Canales MA, Cannell PK, Collins GP, Dürig J, Forstpointner R, Herold M, Hertzberg M, Klanova M, Radford J, Seymour JF, Tobinai K, Trotman J, Burciu A, Fingerle-Rowson G, Wolbers M, Nielsen T, Marcus RE (2018) Immunochemotherapy with obinutuzumab or rituximab for previously untreated follicular lymphoma in the GALLIUM study: influence of chemotherapy on efficacy and safety. J Clin Oncol 36:2395–2404

    Article  CAS  PubMed  Google Scholar 

  34. Marcus R, Davies A, Ando K, Klapper W, Opat S, Owen C, Phillips E, Sangha R, Schlag R, Seymour JF, Townsend W, Trněný M, Wenger M, Fingerle-Rowson G, Rufibach K, Moore T, Herold M, Hiddemann W (2017) Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med 377:1331–1334

    Article  CAS  PubMed  Google Scholar 

  35. Ramalingam SS, Jänne PA, Mok T, O'Byrne K, Boyer MJ, Von Pawel J et al (2014) Dacomitinib versus erlotinib in patients with advanced-stage, previously treated non-small-cell lung cancer (ARCHER 1009): a randomised, double-blind, phase 3 trial. Lancet Oncol 15:1369–1378

    Article  CAS  PubMed  Google Scholar 

  36. Kurzeder C, Bover I, Marmé F, Rau J, Pautier P, Colombo N, Lorusso D, Ottevanger P, Bjurberg M, Marth C, Barretina-Ginesta P, Vergote I, Floquet A, del Campo JM, Mahner S, Bastière-Truchot L, Martin N, Oestergaard MZ, Kiermaier A, Schade-Brittinger C, Polleis S, du Bois A, Gonzalez-Martin A (2016) Double-blind, placebo-controlled, randomized phase III trial evaluating pertuzumab combined with chemotherapy for low tumor human epidermal growth factor receptor 3 mRNA-expressing platinum-resistant ovarian cancer (PENELOPE). J Clin Oncol 34:2516–2525

    Article  CAS  PubMed  Google Scholar 

  37. Wu YL, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, Tsuji F, Linke R, Rosell R, Corral J, Migliorino MR, Pluzanski A, Sbar EI, Wang T, White JL, Nadanaciva S, Sandin R, Mok TS (2017) Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol 18:1454–1466

    Article  CAS  PubMed  Google Scholar 

  38. Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim DW, ALEX Trial Investigators et al (2017) Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med 377:829–838

    Article  CAS  PubMed  Google Scholar 

  39. Shitara K, Özgüroğlu M, Bang YJ, Di Bartolomeo M, Mandalà M, Ryu MH, et al. KEYNOTE-061 investigators (2018) Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet 392:123-133.

  40. Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA et al (2018) Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol 36:2465–2472

    Article  CAS  PubMed  Google Scholar 

  41. Novello S, Mazières J, Oh IJ, de Castro J, Migliorino MR, Helland Å, Dziadziuszko R, Griesinger F, Kotb A, Zeaiter A, Cardona A, Balas B, Johannsdottir HK, Das-Gupta A, Wolf J (2018) Alectinib versus chemotherapy in crizotinib-pretreated anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer: results from the phase III ALUR study. Ann Oncol 29:1409–1416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, Lin NU, Litière S, Dancey J, Chen A, Hodi FS, Therasse P, Hoekstra OS, Shankar LK, Wolchok JD, Ballinger M, Caramella C, de Vries EGE, RECIST working group RECIST working group (2017) iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol 18:e143-e152.

  43. Borcoman E, Kanjanapan Y, Champiat S, Kato S, Servois V, Kurzrock R, Goel S, Bedard P, le Tourneau C (2019) Novel patterns of response under immunotherapy. Ann Oncol 30:385–396. https://doi.org/10.1093/annonc/mdz003

    Article  CAS  PubMed  Google Scholar 

Download references

Contributions

Conception and design of the study: Pierluigi Navarra, Cinzia Dello Russo

Acquisition of data: Natalia Cappoli, Cinzia Dello Russo

Analysis and interpretation of data: Pierluigi Navarra, Cinzia Dello Russo

Drafting the article: Pierluigi Navarra

Critically revising the article: Cinzia Dello Russo

Final approval: Cinzia Dello Russo, Natalia Cappoli, Pierluigi Navarra

Author information

Authors and Affiliations

  1. Institute of Pharmacology, Catholic University Medical School, Largo F. Vito 1, 00168, Rome, Italy

    Cinzia Dello Russo, Natalia Cappoli & Pierluigi Navarra

  2. Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy

    Cinzia Dello Russo & Pierluigi Navarra

Authors
  1. Cinzia Dello Russo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Natalia Cappoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pierluigi Navarra
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pierluigi Navarra.

Ethics declarations

Ethical approval was not required for this study

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dello Russo, C., Cappoli, N. & Navarra, P. A comparison between the assessments of progression-free survival by local investigators versus blinded independent central reviews in phase III oncology trials. Eur J Clin Pharmacol 76, 1083–1092 (2020). https://doi.org/10.1007/s00228-020-02895-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-020-02895-z

Keywords

Search

Navigation