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Surrogate end points in the design of immunotherapy trials: emerging lessons from type 1 diabetes

Nature Reviews Immunology volume 10, pages 145–152 (2010)Cite this article

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Abstract

Approximately 5% of people in developed countries suffer from 1 of ∼80 classified autoimmune diseases. The sheer scale of the clinical problem captures the interests of health policy makers, academics, funding bodies and pharmaceutical companies in equal measure. In recent decades, immunologists have gained a good understanding of disease pathogenesis, which has led to the development of various potential therapies. The next challenge is to establish which therapies have superior efficacy, sustainability and safety. Therapeutic trials that depend on clinical end points are long lasting and expensive. In this Opinion article we offer a perspective on the future of clinical trial design in which the process is significantly shortened by making greater use of laboratory measures to determine therapeutic outcome.

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Figure 1: The main immune components involved in the multi-step process that leads to β-cell destruction in type 1 diabetes.
Figure 2: A stepwise approach to the development of biomarkers of the autoimmune process of type 1 diabetes and surrogate end points of successful immune intervention.
Figure 3: Proposed extended deployment of surrogates in the design and conduct of immunotherapeutic trials for type 1 diabetes.

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Acknowledgements

B.O.R. is a recipient of a Vici award from The Netherlands Organization for Health Research and Development (ZonMW) and is supported by the Dutch Diabetes Research Foundation. M.P. acknowledges financial support from the Department of Health through the National Institute for Health Research comprehensive Biomedical Research Centre award to Guy's & St Thomas' National Health Service Foundation Trust in partnership with King's College London and from the Juvenile Diabetes Research Foundation. Both B.O.R. and M.P. receive funding from the European Union 7th Framework Programme Large-scale Focused Collaborative Research Project on Natural Immunomodulators as Novel Immunotherapies for Type 1 Diabetes.

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  1. National Diabetes Expert Center and Department of Immunohaematology and Blood Transfusion, Bart O. Roep is at the Leiden University Medical Center, Leiden N2-2300RC, The Netherlands. boroep@lumc.nl,

    Bart O. Roep

  2. Department of Immunobiology and National Institute for Health Research Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust, Mark Peakman is at King's College London, London SE1 9RT, UK. mark.peakman@kcl.ac.uk,

    Mark Peakman

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M.P. has no competing financial interests. B.O.R. is a member of the Medical Advisory Boards of Diamyd Medical and Andromeda Biotech.

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FURTHER INFORMATION

Mark Peakman's homepage

Immune Tolerance Network homepage

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Diabetes TrialNet homepage

Glossary

Biomarker

A substance or objective measurement that relates to a biological status. It indicates a specific disease state, risk of the disease, amelioration of disease on treatment or susceptibility to disease amelioration by a specific treatment. A biomarker can be an analyte measured in the blood, a cellular activity, a gene polymorphism or a radiographic feature. For example, multiple islet cell-specific autoantibodies are biomarkers that predict type 1 diabetes risk.

Humanized mouse

A mouse carrying functioning human genes, cells, tissues or organs that are introduced by transgenesis, injection or transplantation. For example, an immune-deficient mouse transgenically expressing susceptibility genes for type 1 diabetes and reconstituted with T cells from a patient with the disease and human islets of Langerhans can be used to study relevant autoimmune processes.

Surrogate end point

A biomarker that, when altered by treatment, indicates a clinical benefit. It is typically an analyte in the blood, such as could be represented by reduction in relevant effector T cell activation or the appearance of regulatory T cells.

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Roep, B., Peakman, M. Surrogate end points in the design of immunotherapy trials: emerging lessons from type 1 diabetes. Nat Rev Immunol 10, 145–152 (2010). https://doi.org/10.1038/nri2705

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