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Voluntary exploratory data submissions to the US FDA and the EMA: experience and impact

Nature Reviews Drug Discovery volume 9, pages 435–445 (2010)Cite this article

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Abstract

Heterogeneity in the underlying mechanisms of disease processes and inter-patient variability in drug responses are major challenges in drug development. To address these challenges, biomarker strategies based on a range of platforms, such as microarray gene-expression technologies, are increasingly being applied to elucidate these sources of variability and thereby potentially increase drug development success rates. With the aim of enhancing understanding of the regulatory significance of such biomarker data by regulators and sponsors, the US Food and Drug Administration initiated a programme in 2004 to allow sponsors to submit exploratory genomic data voluntarily, without immediate regulatory impact. In this article, a selection of case studies from the first 5 years of this programme — which is now known as the voluntary exploratory data submission programme, and also involves collaboration with the European Medicines Agency — are discussed, and general lessons are highlighted.

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Figure 1: Biomarkers for renal cell carcinoma.
Figure 2: Dihydropyrimidine dehydoxygenase structure and variants used in a study of the toxicity of 5-fluorouracil.
Figure 3: Anonymized data flow for genomic data in the prasugrel studies.
Figure 4: Hepatoxicity of ximelagatran.
Figure 5: Differentially expressed genes associated with renal allograft interstitial fibrosis/tubular atrophy (IF/TA).
Figure 6: Genotoxic stress-response markers.

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References

  1. Lesko, L. J. & Woodcock, J. Pharmacogenomic-guided drug development: regulatory perspective. Pharmacogenomics J. 2, 20–24 (2002).

    Article  CAS  Google Scholar 

  2. Translation of pharmacogenomics and pharmacogenetics: a regulatory perspective. Nature Rev. Drug. Discov. 3, 763–769 (2004).

  3. Goodsaid, F. & Frueh, F. W. Implementing the U. S. FDA guidance on pharmacogenomic data submissions. Environ. Mol. Mutagen. 48, 354–358 (2007).

    Article  CAS  Google Scholar 

  4. Orr, M. S., Goodsaid, F., Amur, S., Rudman, A. & Frueh, F. W. The experience with voluntary genomic data submissions at the FDA and a vision for the future of the voluntary data submission program. Clin. Pharmacol. Ther. 81, 294–297 (2007).

    Article  CAS  Google Scholar 

  5. US Food and Drug Administration, European Medicines Agency. Guiding principles processing joint FDA EMEA voluntary genomic data submissions (VGDSs) within the framework of the confidentiality arrangement. EMA website [online], (2006).

  6. European Medicines Agency, Committee for Human Medicinal Products. Final report on the pilot EMEA/FDA VXDS experience on qualification of nephrotoxicity biomarkers. EMA website [online], (2008).

  7. Hudes, G. et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N. Engl. J. Med. 356, 2271–2281 (2007).

    Article  CAS  Google Scholar 

  8. Twine, N. C. et al. Disease-associated expression profiles in peripheral blood mononuclear cells from patients with advanced renal cell carcinoma. Cancer Res. 63, 6069–6075 (2003).

    CAS  PubMed  Google Scholar 

  9. Boni, J. et al. Population pharmacokinetics of CCI-779: correlations to safety and pharmacogenomic responses in patients with advanced renal cancer. Clin. Pharmacol. Ther. 77, 76–89 (2005).

    Article  CAS  Google Scholar 

  10. Burczynski, M. E. et al. Transcriptional profiles in peripheral blood mononuclear cells prognostic of clinical outcomes in patients with advanced renal cell carcinoma. Clin. Cancer Res. 11, 1181–1189 (2005).

    CAS  PubMed  Google Scholar 

  11. Burczynski, M. E. & Dorner, A. J. Transcriptional profiling of peripheral blood cells in clinical pharmacogenomic studies. Pharmacogenomics 7, 187–202 (2006).

    Article  CAS  Google Scholar 

  12. Atkins, M. B. et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J. Clin. Oncol. 22, 909–918 (2004).

    Article  CAS  Google Scholar 

  13. Golub T. R. et al. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 286, 531–537 (1999).

    Article  CAS  Google Scholar 

  14. Shippy, R. et al. Using RNA sample titrations to assess microarray platform performance and normalization techniques. Nature Biotech. 24, 1123–1131 (2006).

    Article  CAS  Google Scholar 

  15. Hill, A. A. et al. Evaluation of normalization procedures for oligonucleotide array data based on spiked cRNA controls. Genome Biol. 2, research0055.1–0055.13 (2001).

  16. Canales, R. D. et al. Evaluation of DNA microarray results with quantitative gene expression platforms. Nature Biotech. 24, 1115–1122 (2006).

    Article  CAS  Google Scholar 

  17. Sellar, G. et al. Opportunities posed by novel patient selection biomarker approaches in oncology drug development: going beyond the cytotoxics. Biomarkers Med. 2, 147–153 (2008).

    Article  CAS  Google Scholar 

  18. Lavallie, E. R., Dorner, A. J., Burczynski, M. E. Use of ex vivo systems for biomarker discovery. Curr. Opin. Pharmacol. 8, 647–653 (2008).

    Article  CAS  Google Scholar 

  19. DiBlasio-Smith, E. A. et al. Discovery and implementation of transcriptional biomarkers of synthetic LXR agonists in peripheral blood cells. J. Transl. Med. 6, 59 (2008).

    Article  Google Scholar 

  20. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, National Center for Toxicological Research, Center for Biologics Evaluation and Research, Center for Devices and Radiological Health. Guidance for Industry. Pharmacogenomic data submissions — companion guidance (draft guidance). FDA website [online], (2007).

  21. Heggie, G. D., Sommadossi, J. P., Cross, D. S., Huster, W. J. & Diasio, R. B. Clinical pharmacokinetics of 5-fluorouracil and its metabolites in plasma, urine, and bile. Cancer Res. 47, 2203–2206 (1987).

    CAS  PubMed  Google Scholar 

  22. Lu, Z., Zhang, R., Carpenter, J. T. & Diasio, R. B. Decreased dihydropyrimidine dehydrogenase activity in a population of patients with breast cancer: implication for 5-fluorouracil-based chemotherapy. Clin. Cancer Res. 4, 325–329 (1998).

    CAS  PubMed  Google Scholar 

  23. Ezzeldin, H. H. & Diasio, R. B. Predicting fluorouracil toxicity: can we finally do it? J. Clin. Oncol. 26, 2080–2082 (2008).

    Article  Google Scholar 

  24. van Kuilenburg, A. B. Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil. Eur. J. Cancer 40, 939–950 (2004).

    Article  CAS  Google Scholar 

  25. Wiviott, S. D. et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N. Engl. J. Med. 357, 2001–2015 (2007).

    Article  CAS  Google Scholar 

  26. Daly, T. M. et al. Multiplex assay for comprehensive genotyping of genes involved in drug metabolism, excretion, and transport. Clin. Chem. 53, 1222–1230 (2007).

    Article  CAS  Google Scholar 

  27. Dumaual, C. et al. Comprehensive assessment of metabolic enzyme and transporter genes using the affymetrix targeted genotyping system. Pharmacogenomics 8, 293–305 (2007).

    Article  CAS  Google Scholar 

  28. Mega, J. L. et al. Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes. Circulation 119, 2553–2560 (2009).

    Article  CAS  Google Scholar 

  29. Mega, J. L. et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N. Engl. J. Med. 360, 354–362 (2009).

    Article  CAS  Google Scholar 

  30. Varenhorst, C. et al. Genetic variation of CYP2C19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel in aspirin-treated patients with coronary artery disease. Eur. Heart J. 30, 1744–1752 (2009).

    Article  CAS  Google Scholar 

  31. Lee, W. M. et al. Hepatic findings in long-term clinical trials of ximelagatran. Drug Saf. 28, 351–370 (2005).

    Article  CAS  Google Scholar 

  32. Harenberg, J., Jörg, I. & Weiss, C. Observations of alanine aminotransferase and aspartate aminotransferase in THRIVE studies treated orally with ximelagatran. Intl J. Toxicol. 25, 165–169 (2006).

    Article  CAS  Google Scholar 

  33. AstraZeneca. AstraZeneca decides to withdraw Exanta. AstraZeneca website [online], (2006).

  34. Kenne, K. et al. Prediction of drug-induced liver injury in humans by using in vitro methods: the case of ximelagatran. Toxicol. In Vitro 22, 730–746 (2008).

    Article  CAS  Google Scholar 

  35. Kindmark, A. et al. Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis. Pharmacogenomics J. 8, 186–195 (2008).

    Article  CAS  Google Scholar 

  36. Andersson, U. et al. A systems biology approach to understanding elevated serum alanine transaminase levels in a clinical trial with ximelagatran. Biomarkers 14, 572–586 (2009).

    Article  CAS  Google Scholar 

  37. Burckart, G. J. et al. Qualification of biomarkers for drug development in organ transplantation. Am. J. Transplant. 8, 267–270 (2008).

    Article  Google Scholar 

  38. Jevnikar, A. M. & Mannon, R. B. Late kidney allograft loss: what we know about it, and what we can do about it. Clin. J. Am. Soc. Nephrol. 3, S56–S67 (2008).

    Article  Google Scholar 

  39. Nankivell, B. J. & Chapman, J. R. Chronic allograft nephropathy: current concepts and future directions. Transplantation 81, 643–654 (2006).

    Article  Google Scholar 

  40. Seron, D. & Moreso, F. Protocol biopsies in renal transplantation: prognostic value of structural monitoring. Kidney Int. 72, 690–697 (2007).

    Article  CAS  Google Scholar 

  41. Cosio, F. et al. Kidney allograft fibrosis and atrophy early after living donor transplantation. Am. J. Transplant. 5, 1130–1136 (2005).

    Article  Google Scholar 

  42. Scherer, A. et al. Early prognosis of the development of renal chronic allograft rejection by gene expression profiling of human protocol biopsies. Transplantation 75, 1323–1330 (2003).

    Article  CAS  Google Scholar 

  43. US Department of Health and Human Services, Food and Drug Administration, Center for Devices and Radiological Health, Office of In Vitro Diagnostic Device Evaluation and Safety, Center for Biologic Evaluation and Research. Draft Guidance for Industry, Clinical Laboratories, and FDA Staff. In vitro diagnostic multivariate index assays. FDA website [online], (2007).

  44. US Department of Health and Human Services, Food and Drug Administration, Center for Devices and Radiological Health, Office of In Vitro Diagnostic Device Evaluation and Safety, Division of Immunology and Hematology Devices. Guidance for Industry and FDA Staff. Class II special controls guidance document: gene expression profiling test system for breast cancer prognosis. FDA website [online], (2007).

  45. Snyder, R. D. & Green, J. W. A review of the genotoxicity of marketed pharmaceuticals. Mutat. Res. 488, 151–169 (2001).

    Article  CAS  Google Scholar 

  46. Aubrecht, J. & Caba, E. Gene expression profile analysis: an emerging approach to investigate mechanisms of genotoxicity. Pharmacogenomics 6, 419–428 (2005).

    Article  CAS  Google Scholar 

  47. Guyton, K. Z. et al. Improving prediction of chemical carcinogenicity by considering multiple mechanisms and applying toxicogenomic approaches. Mutat. Res. 681, 230–240 (2009).

    Article  CAS  Google Scholar 

  48. Amundson, S. A. et al. Stress-specific signatures: expression profiling of p53 wild-type and -null human cells. Oncogene 24, 4572–4579 (2005).

    Article  CAS  Google Scholar 

  49. Henderson, L., Albertini, S. & Aardema, M. Thresholds in genotoxicity responses. Mutat. Res. 464, 123–128 (2000).

    Article  CAS  Google Scholar 

  50. Kirsch-Volders, M., Vanhauwaert, A., Eichenlaub-Ritter, U. & Decordier, I. Indirect mechanisms of genotoxicity. Toxicol. Lett. 140–141, 63–74 (2003).

    Article  Google Scholar 

  51. Food and Drug Administration. Guidance for Industry and Review Staff. Approaches to integration of genetic toxicology study results. FDA website [online], (2006).

  52. Weinstein, D., Mauer, I., Katz, M. L. & Kazmer, S. The effect of methylxanthines on chromosomes of human lymphocytes in culture. Mutat. Res. 31, 57–61 (1975).

    Article  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Federico M. Goodsaid, Shashi Amur, Rosane Charlab, Li Zhang and Issam Zineh are at the Genomics Group, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US FDA, Building 51, 10903 New Hampshire Avenue, Silver Spring, Maryland 20903-002, USA.,

    Federico M. Goodsaid, Shashi Amur, Rosane Charlab, Li Zhang & Issam Zineh

  2. Jiri Aubrecht and and Sharada L. Truter are at Pfizer Global R&D, Eastern Point Road, Groton, Connecticut 06340-8012, USA.,

    Jiri Aubrecht & Sharada L. Truter

  3. Michael E. Burczynski, John Roth and Jacky Vonderscher are at F. Hoffmann-La Roche, 340 Kingsland Street, Nutley, New Jersey 07110-1199, USA.,

    Michael E. Burczynski, John Roth & Jacky Vonderscher

  4. Jennifer Catalano is at the Division of Cell And Gene Therapies, Office Of Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation and Research, US FDA, 1401 Rockville Pike Suite 200N/HFM-47, Rockville, Maryland 20852-1448, USA.,

    Jennifer Catalano

  5. Kevin Carl and Lois Hinman are at Novartis Pharmaceutical Corporation, One Health Plaza, East Hanover, New Jersey 07936, USA.,

    Kevin Carl & Lois Hinman

  6. Sandra Close and Peter Morrow are at Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.,

    Sandra Close & Peter Morrow

  7. Catherine Cornu-Artis and David Laurie are at Novartis Pharma, Rheinstrasse, 4133 Basel, Switzerland.,

    Catherine Cornu-Artis & David Laurie

  8. Laurent Essioux and Olivia Spleiss are at F. Hoffmann-La Roche, Grenzacherstrasse 124, 4070 Basel, Switzerland.,

    Laurent Essioux & Olivia Spleiss

  9. Albert J. Fornace Jr and Heng-Hong Li are at the Department of Biochemistry and Molecular and Cellular Biology and at the Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, USA.,

    Albert J. Fornace Jr & Heng-Hong Li

  10. Huixiao Hong, Leming Shi and Weida Tong are at the National Center for Toxicological Research (NCTR), US FDA, 3900 NCTR Road, Jefferson, Arkansas 72079, USA.,

    Huixiao Hong, Leming Shi & Weida Tong

  11. Ian Hunt, Ansar Jawaid and Ina Schuppe-Koistinen are at AstraZeneca R&D Sweden, UK and USA, respectively.,

    Ian Hunt, Ansar Jawaid & Ina Schuppe-Koistinen

  12. David Jacobson-Kram is at the Office of New Drugs, Center for Drug Evaluation and Research, US FDA, Silver Spring, Maryland, USA.,

    David Jacobson-Kram

  13. Lawrence Lesko is at the Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US FDA, Silver Spring, Maryland, USA.,

    Lawrence Lesko

  14. Klaus Lindpaintner is at Strategic Diagnostics Inc., 111 Pencader Drive, Newark, Delaware 19702, USA.,

    Klaus Lindpaintner

  15. James Mayne is at Worldwide Regulatory Strategy and Policy, Pfizer Global Research and Development, Groton, Connecticut, USA.,

    James Mayne

  16. Marisa Papaluca-Amati is at the European Medicines Agency Pre-Authorisation Unit Sector for Safety and Efficacy of Medicines, 7 Westferry Circus, London E14 4HB, UK.,

    Marisa Papaluca-Amati

  17. Timothy W. Robison is at the Division of Pulmonary and Allergy Products, Office of New Drugs, Center for Drug Evaluation and Research, US FDA, Silver Spring, Maryland, USA.,

    Timothy W. Robison

  18. Agnes Westelinck is at GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA.,

    Agnes Westelinck

Authors
  1. Federico M. Goodsaid
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  28. Olivia Spleiss
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  32. Agnes Westelinck
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  33. Li Zhang
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  34. Issam Zineh
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Corresponding author

Correspondence to Federico M. Goodsaid.

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Competing interests

Federico M. Goodsaid, Shashi Amur, Jiri Aubrecht, Jennifer Catalano, Rosane Charlab, Albert J. Fornace Jr, Huixiao Hong, David Jacobson-Kram, Ansar Jawaid, Lawrence Lesko, Heng-Hong Li, Klaus Lindpainter, Marisa Papaluca-Amati, Timothy W. Robison, Ina Schuppe-Koistinen, Leming Shi, Weida Tong, Li Zhang, and Issam Zineh declare no competing financial interests.

Michael E. Burczynski has none beyond previous employment by Wyeth and current employment by F. Hoffmann-La Roche.

Kevin Carl is an employee and shareholder of Novartis Pharmaceuticals Corporation.

Sandra Close is an employee and shareholder of Eli Lilly and Company.

Catherine Cornu-Artis is a full-time employee of Novartis Pharma AG, Switzerland.

Laurent Essioux is a full-time employee of F. Hoffmann-La Roche.

Lois Hinman is an employee of Novartis and shareholder of Novartis stock.

Ian Hunt is an employee of AstraZeneca.

David Laurie is a full-time employee of Novartis Pharma AG, Switzerland and a holder of shares in Novartis.

James Mayne has stocks in Pfizer, which participates in business activities that are regulated by the US FDA and the EMA.

Peter Morrow is an employee and shareholder of Eli Lilly and Company.

John Roth is a full-time employee of F. Hoffmann-La Roche.

Olivia Spleiss is a full-time employee of F. Hoffmann-La Roche.

Sharada L. Truter is a full-time employee and shareholder of Pfizer.

Jacky Vonderscher is a full-time employee and shareholder of F. Hoffmann-La Roche and also a shareholder of Novartis.

Agnes Westelinck has none beyond previous employment by F. Hoffmann-La Roche and current employment by GlaxoSmithKline.

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Disclaimer: Opinions, ideas and statements in this paper are presented at the sole discretion of the authors and do not necessarily represent those from each of the companies or agencies for which these authors work. No official endorsement or policy is intended nor should be inferred.

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DATABASES

OMIM

CYP1A2

CYP2B6

CYP2C9

CYP2C19

CYP3A4

CYP3A5

DPD

renal cell carcinoma

FURTHER INFORMATION

Interdisciplinary Pharmacogenomics Review Group

Pharmacogenomics Working Party

Table of valid genomic biomarkers in the context of approved drug labels

US FDA's Critical Path Initiative

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Goodsaid, F., Amur, S., Aubrecht, J. et al. Voluntary exploratory data submissions to the US FDA and the EMA: experience and impact. Nat Rev Drug Discov 9, 435–445 (2010). https://doi.org/10.1038/nrd3116

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