Sequencing


data generated for research purposes must be col- lected and managed to the same regulatory stan- dards as clinical trials data.


Government, academic and industry initiatives


Government, academic and industry players are heavily involved in efforts to provide the infras- tructure, databases, standards and regulatory over- sight necessary to support use of NGS in clinical development. Among the examples are:


ELIXIR: An EU-sponsored programme to develop interoperable data, computational and training resources for life science research. ELIXIR is a leader in the promotion of the FAIR principles, that biomedical data must be Findable, Accessible, Interoperable and Reusable. Precision Medicine Initiative: An initiative of the US National Institutes of Health, established in 2015. The goal of the PMI is to develop the scien- tific evidence needed to move the concept of preci- sion medicine into clinical practice. The Association of Molecular Pathology and the College of American Pathologists have recently published a joint set of standards and guidelines for validating NGS bioinformatics pipelines. Global Alliance for Genomics and Health (GA4GH): An alliance whose goal is to enable the interoperability of systems and processes used to process clinical and genomic data, and thereby enhance the sharing process. One of the primary deliverables is a set of standard application pro- gramming interfaces (APIs) that support the dis- covery and interchange of genomic data. The alliance has more than 500 institutional members and individuals can be members as well. Pistoia Alliance: The mission of the Pistoia Alliance is to lower the barriers to innovation in life sci- ences R&D through pre-competitive collaboration. Among the projects in its portfolio is Faster CDx by Aligning Discovery & Clinical Data in the Regulatory Domain, which aims to address many of the issues described in this article.


Table 3 Conventional diagnostic Low/medium resolution technology


Detect a finite number of analytes (usually one)


One test – one disease


Clinical evidence from clinical studies – research separate from practice


Drug Discovery World Winter 2017/18 Precision diagnostic


High resolution technology (‘omics’) Undefined (millions?)


One test – many diseases


Clinical evidence from learning health systems – merging of research and practice


69


Regulatory guidance


In its presentations and workshops on regulatory oversight of NGS-based tests, the FDA recognises some key differences between ‘conventional’ and ‘precision’ diagnostics (Table 3.)


The agency clearly recognises that these tech- nologies require a different, more adaptive approach to regulation as compared with earlier technologies, and they are keen not to stifle inno- vation that will lead to real benefit for patients. Both EU and US regulatory agencies have issued draft guidelines to address the challenges of using NGS technologies in drug development. Examples include:


l ‘Use of Standards in FDA Regulatory Oversight of Next Generation Sequencing (NGS)-Based In Vitro Diagnostics (IVDs) Used for Diagnosing Germline Diseases’. l ‘Use of Public Human Genetic Variant Databases to Support Clinical Validity for Next Generation Sequencing (NGS)-Based In Vitro Diagnostics’. l Guideline on good pharmacogenomic practice (Draft). l Guidelines for diagnostic next-generation sequencing.


What next ?


In this article we have reviewed some of the chal- lenges posed by NGS technology in clinical devel- opment, including:


l Rapidly changing sequencing and analysis tech- nology. l Complex data processing pipelines and infras- tructure requirements. l Non-deterministic algorithms, with variable per- formance across the genome. l Use of a variety of public annotation sources to help establish clinical validity of results. Each of the topics discussed above is a ‘work in progress’, and the examples shown for each catego- ry are by no means exhaustive. Neither regulators


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