Advertisement
Mayo Clinic Proceedings Home

Strength of Validation for Surrogate End Points Used in the US Food and Drug Administration's Approval of Oncology Drugs

  • Chul Kim
    Affiliations
    Medical Oncology Service, National Cancer Institute, National Institutes of Health, Bethesda, MD
    Search for articles by this author
  • Vinay Prasad
    Correspondence
    Correspondence: Address to Vinay Prasad, MD, MPH, Assistant Professor of Medicine, Division of Hematology Oncology/Knight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239.
    Affiliations
    Department of Medicine, Division of Hematology Oncology/Knight Cancer Institute, Oregon Health & Science University, Portland
    Search for articles by this author

      Abstract

      Objective

      To determine the strength of the surrogate-survival correlation for cancer drug approvals based on a surrogate.

      Participants and Methods

      We performed a retrospective study of the US Food and Drug Administration (FDA) database, with focused searches of MEDLINE and Google Scholar. Among cancer drugs approved based on a surrogate end point, we examined previous publications assessing the strength of the surrogate-survival correlation. Specifically, we identified the percentage of surrogate approvals lacking any formal analysis of the strength of the surrogate-survival correlation, and when conducted, the strength of such correlations.

      Results

      Between January 1, 2009, and December 31, 2014, the FDA approved marketing applications for 55 indications based on a surrogate, of which 25 were accelerated approvals and 30 were traditional approvals. We could not find any formal analyses of the strength of the surrogate-survival correlation in 14 out of 25 accelerated approvals (56%) and 11 out of 30 traditional approvals (37%). For accelerated approvals, just 4 approvals (16%) were made where a level 1 analysis (the most robust way to validate a surrogate) had been performed, with all 4 studies reporting low correlation (r≤0.7). For traditional approvals, a level 1 analysis had been performed for 15 approvals (50%): 8 (53%) reported low correlation (r≤0.7), 4 (27%) medium correlation (r>0.7 to r<0.85), and 3 (20%) high correlation (r≥0.85) with survival.

      Conclusions

      The use of surrogate end points for drug approval often lacks formal empirical verification of the strength of the surrogate-survival association.

      Abbreviations and Acronyms:

      AA (accelerated approval), ALL (acute lymphoblastic leukemia), CCyR (complete cytogenetic response), CLL (chronic lymphocytic lymphoma), CML (chronic myeloid leukemia), CRC (colorectal carcinoma), CR (complete response), CRi (complete response with incomplete blood count recovery), CRPC (castrate-resistant prostate cancer), CTCL (cutaneous T-cell lymphoma), DFS (disease-free survival), DOR (duration of response), FDA (Food and Drug Administration), GEJ (gastroesophageal junction), GIST (gastrointestinal stromal tumor), HER2 (human epidermal growth factor receptor 2), HR (hazard ratio), MaHR (major hematologic response), MCyR (major cytogenetic response), MMR (major molecular response), MRD (minimal residual disease), NET (neuroendrocine tumor), NSCLC (non-small cell lung cancer), OR (odds ratio), ORR (objective response rate), OS (overall survival), pCR (pathologic complete remission), PFS (progression-free survival), Ph (Philadelphia chromosome), PR (partial remission), PTCL (peripheral T-cell lymphoma), RCC (renal cell cancer), RR (response rate), SLL (small lymphocytic lymphoma), TA (traditional approval), TTP (time to progression)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Mayo Clinic Proceedings
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Hirschfeld S.
        • Pazdur R.
        Oncology drug development: United States Food and Drug Administration perspective.
        Crit Rev Oncol Hematol. 2002; 42: 137-143
        • Johnson J.R.
        • Williams G.
        • Pazdur R.
        End points and United States Food and Drug Administration approval of oncology drugs.
        J Clin Oncol. 2003; 21: 1404-1411
        • Pazdur R.
        Endpoints for assessing drug activity in clinical trials.
        Oncologist. 2008; 13: 19-21
        • Sridhara R.
        • Johnson J.R.
        • Justice R.
        • Keegan P.
        • Chakravarty A.
        • Pazdur R.
        Review of oncology and hematology drug product approvals at the US Food and Drug Administration between July 2005 and December 2007.
        J Natl Cancer Inst. 2010; 102: 230-243
        • Miller K.
        • Wang M.
        • Gralow J.
        • et al.
        Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer.
        N Engl J Med. 2007; 357: 2666-2676
        • Carpenter D.
        • Kesselheim A.S.
        • Joffe S.
        Reputation and precedent in the bevacizumab decision.
        N Engl J Med. 2011; 365: e3
        • Prasad V.
        • Kim C.
        • Burotto M.
        • Vandross A.
        The strength of association between surrogate end points and survival in oncology: a systematic review of trial-level meta-analyses.
        JAMA Intern Med. 2015; 175: 1389-1398
        • Buyse M.
        • Molenberghs G.
        • Burzykowski T.
        • Renard D.
        • Geys H.
        The validation of surrogate endpoints in meta-analyses of randomized experiments.
        Biostatistics. 2000; 1: 49-67
        • Freedman L.S.
        • Graubard B.I.
        • Schatzkin A.
        Statistical validation of intermediate endpoints for chronic diseases.
        Stat Med. 1992; 11: 167-178
        • Lassere M.N.
        • Johnson K.R.
        • Schiff M.
        • Rees D.
        Is blood pressure reduction a valid surrogate endpoint for stroke prevention? an analysis incorporating a systematic review of randomised controlled trials, a by-trial weighted errors-in-variables regression, the surrogate threshold effect (STE) and the Biomarker-Surrogacy (BioSurrogate) Evaluation Schema (BSES).
        BMC Med Res Methodol. 2012; 12: 27
        • Torri V.
        • Simon R.
        • Russek-Cohen E.
        • Midthune D.
        • Friedman M.
        Statistical model to determine the relationship of response and survival in patients with advanced ovarian cancer treated with chemotherapy.
        J Natl Cancer Inst. 1992; 84: 407-414
        • Weir C.J.
        • Walley R.J.
        Statistical evaluation of biomarkers as surrogate endpoints: a literature review.
        Stat Med. 2006; 25: 183-203
        • Taylor R.S.
        • Elston J.
        The use of surrogate outcomes in model-based cost-effectiveness analyses: a survey of UK Health Technology Assessment reports.
        Health Technol Assess. 2009; 13 (iii, ix-xi, 1-50)
        • Shi Q.
        • Sargent D.J.
        Meta-analysis for the evaluation of surrogate endpoints in cancer clinical trials.
        Int J Clin Oncol. 2009; 14: 102-111
      1. Institute for Quality and Efficiency in Health Care. Validity of surrogate endpoints in oncology: executive summary. https://www.iqwig.de/download/A10-05_Executive_Summary_v1-1_Surrogate_endpoints_in_oncology.pdf. Published 2011. Accessed July 23, 2015.

        • Kim C.
        • Prasad V.
        Cancer drugs approved on the basis of a surrogate end point and subsequent overall survival: an analysis of 5 years of us food and drug administration approvals.
        JAMA Intern Med. 2015; 175: 1992-1994
        • Gay F.
        • Larocca A.
        • Wijermans P.
        • et al.
        Complete response correlates with long-term progression-free and overall survival in elderly myeloma treated with novel agents: analysis of 1175 patients.
        Blood. 2011; 117: 3025-3031
        • Jaeckle K.
        • Wu W.
        • Kosel M.
        • Flynn P.
        • Buckner J.
        Correlation of response with survival endpoints in patients with newly diagnosed and recurrent glioblastoma (GBM) treated on prospective North Central Cancer Treatment Group (NCCTG) clinical trials.
        J Clin Oncol. 2008; 26: 2024
        • Jain P.
        • Kantarjian H.
        • Nazha A.
        • et al.
        Early responses predict better outcomes in patients with newly diagnosed chronic myeloid leukemia: results with four tyrosine kinase inhibitor modalities.
        Blood. 2013; 121: 4867-4874
        • Oriana C.
        • Martin H.
        • Toby P.
        • et al.
        Complete cytogenetic response and major molecular response as surrogate outcomes for overall survival in first-line treatment of chronic myelogenous leukemia: a case study for technology appraisal on the basis of surrogate outcomes evidence.
        Value Health. 2013; 16: 1081-1090
        • Rosti G.
        • Testoni N.
        • Martinelli G.
        • Baccarani M.
        The cytogenetic response as a surrogate marker of survival.
        Semin Hematol. 2003; 40: 56-61
        • van de Velde H.J.
        • Liu X.
        • Chen G.
        • Cakana A.
        • Deraedt W.
        • Bayssas M.
        Complete response correlates with long-term survival and progression-free survival in high-dose therapy in multiple myeloma.
        Haematologica. 2007; 92: 1399-1406
        • Kong X.
        • Moran M.S.
        • Zhang N.
        • Haffty B.
        • Yang Q.
        Meta-analysis confirms achieving pathological complete response after neoadjuvant chemotherapy predicts favourable prognosis for breast cancer patients.
        Eur J Cancer. 2011; 47: 2084-2090
        • Berruti A.
        • Amoroso V.
        • Gallo F.
        • et al.
        Pathologic complete response as a potential surrogate for the clinical outcome in patients with breast cancer after neoadjuvant therapy: a meta-regression of 29 randomized prospective studies.
        J Clin Oncol. 2014; 32: 3883-3891
        • Cortazar P.
        • Zhang L.
        • Untch M.
        • et al.
        Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis.
        Lancet. 2014; 384: 164-172
      2. Ciccarese M, Bria E, Cuppone F, et al. Disease-free survival (DFS) as surrogate end point for overall survival (OS) in adjuvant aromatase inhibitors (AIs) trials for breast cancer (BC): meta-analysis of 10 randomized clinical trials (RCTs) exploring the magnitude of the benefit. Paper presented at: American Society of Clinical Oncology (ASCO) 43rd Annual Meeting; June 1-5, 2007; Chicago, IL.

        • Matsubara Y.
        • Sakabayashi S.
        • Nishimura T.
        • et al.
        Surrogacy of tumor response and progression-free survival for overall survival in metastatic breast cancer resistant to both anthracyclines and taxanes.
        Int J Clin Oncol. 2011; 16: 623-629
        • Hackshaw A.
        • Knight A.
        • Barrett-Lee P.
        • Leonard R.
        Surrogate markers and survival in women receiving first-line combination anthracycline chemotherapy for advanced breast cancer.
        Br J Cancer. 2005; 93: 1215-1221
        • Burzykowski T.
        • Buyse M.
        • Piccart-Gebhart M.J.
        • et al.
        Evaluation of tumor response, disease control, progression-free survival, and time to progression as potential surrogate end points in metastatic breast cancer.
        J Clin Oncol. 2008; 26: 1987-1992
        • Miksad R.A.
        • Zietemann V.
        • Gothe R.
        • et al.
        Progression-free survival as a surrogate endpoint in advanced breast cancer.
        Int J Technol Assess Health Care. 2008; 24: 371-383
        • Ng R.
        • Pond G.R.
        • Tang P.A.
        • MacIntosh P.W.
        • Siu L.L.
        • Chen E.X.
        Correlation of changes between 2-year disease-free survival and 5-year overall survival in adjuvant breast cancer trials from 1966 to 2006.
        Ann Oncol. 2008; 19: 481-486
        • Sherrill B.
        • Amonkar M.
        • Wu Y.
        • et al.
        Relationship between effects on time-to-disease progression and overall survival in studies of metastatic breast cancer.
        Br J Cancer. 2008; 99: 1572-1578
        • Beauchemin C.
        • Cooper D.
        • Lapierre M.E.
        • Yelle L.
        • Lachaine J.
        Progression-free survival as a potential surrogate for overall survival in metastatic breast cancer.
        Onco Targets Ther. 2014; 7: 1101-1110
        • Splinter T.A.
        Response rate as criterium to evaluate chemotherapy in non-small cell lung cancer.
        Lung Cancer (Amsterdam, Netherlands). 1991; 7: 91-104
        • Paesmans M.
        • Sculier J.P.
        • Libert P.
        • et al.
        Response to chemotherapy has predictive value for further survival of patients with advanced non-small cell lung cancer: 10 years experience of the European Lung Cancer Working Party.
        Eur J Cancer. 1997; 33: 2326-2332
        • Sekine I.
        • Kubota K.
        • Nishiwaki Y.
        • Sasaki Y.
        • Tamura T.
        • Saijo N.
        Response rate as an endpoint for evaluating new cytotoxic agents in phase II trials of non-small-cell lung cancer.
        Ann Oncol. 1998; 9: 1079-1084
      3. Bruzzi P, Sormani M, Tiseo M, Boni L, Rosell R, Ardizzoni A. Tumor response to chemotherapy as a surrogate endpoint of survival in advanced non-small cell lung cancer (NSCLC): results of an individual patients data meta-analysis. Paper presented at: American Society of Clinical Oncology (ASCO) 43rd Annual Meeting; June 1-5, 2007; Chicago, IL.

        • Tsujino K.
        • Kawaguchi T.
        • Kubo A.
        • et al.
        Response rate is associated with prolonged survival in patients with advanced non-small cell lung cancer treated with gefitinib or erlotinib.
        J Thorac Oncol. 2009; 4: 994-1001
        • Mandrekar S.J.
        • Qi Y.
        • Hillman S.L.
        • et al.
        Endpoints in phase II trials for advanced non-small cell lung cancer.
        J Thorac Oncol. 2010; 5: 3-9
        • Li X.
        • Liu S.
        • Gu H.
        • Wang D.
        Surrogate end points for survival in the target treatment of advanced non-small-cell lung cancer with gefitinib or erlotinib.
        J Cancer Res Clin Oncol. 2012; 138: 1963-1969
        • Blumenthal G.M.
        • Karuri S.W.
        • Zhang H.
        • et al.
        Overall response rate, progression-free survival, and overall survival with targeted and standard therapies in advanced non-small-cell lung cancer: US Food and Drug Administration trial-level and patient-level analyses.
        J Clin Oncol. 2015; 33: 1008-1014
        • Johnson K.R.
        • Ringland C.
        • Stokes B.J.
        • et al.
        Response rate or time to progression as predictors of survival in trials of metastatic colorectal cancer or non-small-cell lung cancer: a meta-analysis.
        Lancet Oncol. 2006; 7: 741-746
        • Penel N.
        • Cousin S.
        • Duhamel A.
        • Kramar A.
        Activity endpoints reported in soft tissue sarcoma phase II trials: quality of reported endpoints and correlation with overall survival.
        Crit Rev Oncol Hematol. 2013; 88: 309-317
        • Rose P.G.
        • Tian C.
        • Bookman M.A.
        Assessment of tumor response as a surrogate endpoint of survival in recurrent/platinum-resistant ovarian carcinoma: a Gynecologic Oncology Group study.
        Gynecol Oncol. 2010; 117: 324-329
        • Singh S.
        • Wang X.
        • Law C.H.
        Association between time to disease progression end points and overall survival in patients with neuroendocrine tumors.
        Gastrointest Cancer Targets Ther. 2014; 4: 103-113
        • Flaherty K.T.
        • Hennig M.
        • Lee S.J.
        • et al.
        Surrogate endpoints for overall survival in metastatic melanoma: a meta-analysis of randomised controlled trials.
        Lancet Oncol. 2014; 15: 297-304
        • Hayashi H.
        • Okamoto I.
        • Morita S.
        • Taguri M.
        • Nakagawa K.
        Postprogression survival for first-line chemotherapy of patients with advanced non-small-cell lung cancer.
        Ann Oncol. 2012; 23: 1537-1541
        • Sekine I.
        • Tamura T.
        • Kunitoh H.
        • et al.
        Progressive disease rate as a surrogate endpoint of phase II trials for non-small-cell lung cancer.
        Ann Oncol. 1999; 10: 731-733
        • Suzuki H.
        • Hirashima T.
        • Okamoto N.
        • et al.
        Relationship between progression-free survival and overall survival in patients with advanced non-small cell lung cancer treated with anticancer agents after first-line treatment failure.
        Asia Pac J Clin Oncol. 2015; 11: 121-128
        • Hayashi H.
        • Okamoto I.
        • Taguri M.
        • Morita S.
        • Nakagawa K.
        Postprogression survival in patients with advanced non-small-cell lung cancer who receive second-line or third-line chemotherapy.
        Clin Lung Cancer. 2013; 14: 261-266
        • Hotta K.
        • Suzuki E.
        • Di Maio M.
        • et al.
        Progression-free survival and overall survival in phase III trials of molecular-targeted agents in advanced non-small-cell lung cancer.
        Lung Cancer. 2013; 79: 20-26
        • Mauguen A.
        • Pignon J.P.
        • Burdett S.
        • et al.
        Surrogate endpoints for overall survival in chemotherapy and radiotherapy trials in operable and locally advanced lung cancer: a re-analysis of meta-analyses of individual patients' data.
        Lancet Oncol. 2013; 14: 619-626
        • Hotta K.
        • Fujiwara Y.
        • Matsuo K.
        • et al.
        Time to progression as a surrogate marker for overall survival in patients with advanced non-small cell lung cancer.
        J Thorac Oncol. 2009; 4: 311-317
        • Halabi S.
        • Rini B.
        • Escudier B.
        • Stadler W.M.
        • Small E.J.
        Progression-free survival as a surrogate endpoint of overall survival in patients with metastatic renal cell carcinoma.
        Cancer. 2014; 120: 52-60
        • Heng D.Y.
        • Xie W.
        • Bjarnason G.A.
        • et al.
        Progression-free survival as a predictor of overall survival in metastatic renal cell carcinoma treated with contemporary targeted therapy.
        Cancer. 2011; 117: 2637-2642
        • Bria E.
        • Massari F.
        • Maines F.
        • et al.
        Progression-free survival as primary endpoint in randomized clinical trials of targeted agents for advanced renal cell carcinoma: correlation with overall survival, benchmarking and power analysis.
        Crit Rev Oncol Hematol. 2015; 93: 50-59
        • Johnson K.R.
        • Liauw W.
        • Lassere M.N.
        Evaluating surrogacy metrics and investigating approval decisions of progression-free survival (PFS) in metastatic renal cell cancer: a systematic review.
        Ann Oncol. 2015; 26: 485-496
        • Petrelli F.
        • Barni S.
        Surrogate end points and postprogression survival in renal cell carcinoma: an analysis of first-line trials with targeted therapies.
        Clin Genitourin Cancer. 2013; 11: 385-389
        • Delea T.E.
        • Khuu A.
        • Heng D.Y.
        • Haas T.
        • Soulieres D.
        Association between treatment effects on disease progression end points and overall survival in clinical studies of patients with metastatic renal cell carcinoma.
        Br J Cancer. 2012; 107: 1059-1068
        • Petrelli F.
        • Pietrantonio F.
        • Cremolini C.
        • et al.
        Early tumour shrinkage as a prognostic factor and surrogate end-point in colorectal cancer: a systematic review and pooled-analysis.
        Eur J Cancer. 2015; 51: 800-807
        • Kay A.
        • Higgins J.
        • Day A.G.
        • Meyer R.M.
        • Booth C.M.
        Randomized controlled trials in the era of molecular oncology: methodology, biomarkers, and end points.
        Ann Oncol. 2012; 23: 1646-1651
        • Sacher A.G.
        • Le L.W.
        • Leighl N.B.
        Shifting patterns in the interpretation of phase III clinical trial outcomes in advanced non-small-cell lung cancer: the bar is dropping.
        J Clin Oncol. 2014; 32: 1407-1411
        • Amir E.
        • Seruga B.
        • Martinez-Lopez J.
        • et al.
        Oncogenic targets, magnitude of benefit, and market pricing of antineoplastic drugs.
        J Clin Oncol. 2011; 29: 2543-2549
        • Bailar III, J.C.
        • Mosteller F.
        Guidelines for statistical reporting in articles for medical journals: amplifications and explanations.
        Ann Intern Med. 1988; 108: 266-273
        • Booth C.M.
        • Eisenhauer E.A.
        Progression-free survival: meaningful or simply measurable?.
        J Clin Oncol. 2012; 30: 1030-1033
        • Shao T.
        • Wang L.
        • Templeton A.J.
        • et al.
        Use and misuse of waterfall plots.
        J Natl Cancer Inst. 2014; 106
        • Ebos J.M.
        • Kerbel R.S.
        Antiangiogenic therapy: impact on invasion, disease progression, and metastasis.
        Nat Rev Clin Oncol. 2011; 8: 210-221
        • Iwamoto F.M.
        • Abrey L.E.
        • Beal K.
        • et al.
        Patterns of relapse and prognosis after bevacizumab failure in recurrent glioblastoma.
        Neurology. 2009; 73: 1200-1206
        • Miles D.
        • Harbeck N.
        • Escudier B.
        • et al.
        Disease course patterns after discontinuation of bevacizumab: pooled analysis of randomized phase III trials.
        J Clin Oncol. 2011; 29: 83-88
        • Moore T.J.
        • Furberg C.D.
        The safety risks of innovation: the FDA's Expedited Drug Development Pathway.
        JAMA. 2012; 308: 869-870
        • Prasad V.
        Double-crossed: why crossover in clinical trials may be distorting medical science.
        J Natl Compr Canc Netw. 2013; 11: 625-627
        • Prasad V.
        • Grady C.
        The misguided ethics of crossover trials.
        Contemp Clin Trials. 2014; 37: 167-169
        • Kantoff P.W.
        • Higano C.S.
        • Shore N.D.
        • et al.
        Sipuleucel-T immunotherapy for castration-resistant prostate cancer.
        N Engl J Med. 2010; 363: 411-422
        • Prasad V.
        • Vandross A.
        Characteristics of exceptional or super responders to cancer drugs.
        Mayo Clin Proc. 2015; 90: 1639-1649
      4. US Government Accountability Office. New drug apporval: FDA needs to enhance its oversight of drugs approved on the basis of surrogate endpoints. http://www.gao.gov/new.items/d09866.pdf. Published September 2009. Accessed July 25, 2015.