The Pistoia Alliance is examining the challenges of the Faster Safe Companion Diagnostics (CDx) by Aligning Discovery & Clinical Data in the Regulatory Domain.
The slides discuss whether the data standards used in the research environment be aligned better with the data standards used in the regulated environment? If so, the time and cost of the development of NGS-based CDx could be reduced.
3. ŠPistoiaAlliance
Speaker Biographies
Keith Nangle: formerly Head, Genetic Data Sciences at
GlaxoSmithKline Inc. Keith has also served as European Community
Manager for the tranSMART Foundation before working with the Pistoia
Alliance on the use of NGS in regulated areas of drug development.
Mike Furness: is the MD and Founder of TheFirstNuomics and has
spent over 30 years working in genomics and bioinformatics, developing
and applying new technologies to understanding disease and drug R&D.
He has previously worked for Life Technologies, Cancer Research UK,
Pfizer, Incyte Genomics, DNAnexus and Congenica, as well as
consulting widely for pharmaceutical and technology companies and
investors.
Stephen Lee: 30 years experience of in vitro diagnostic medical
devices. Chair of European Commission's IVD Working Group.
Now focused on implementation of IVDR (2017/746): performance
evaluation; companion diagnostics; software / bioinformatics;
classification; health institution exemption; conformity assessment;
reference labs; etc.
A lifelong learner adapted to working in a constantly changing
environment. Chartered Scientist, Fellow of the Institute of Biomedical
Science.
4. ŠPistoiaAlliance
Overview
The growth and challenges of NGS in research and the
regulated domain
Keith Nangle (Pistoia Alliance)
An overview of the regulations around CDx and the new
changes coming
Stephen Lee (Senior Regulatory Policy Manager â IVD Devices Division
MHRA)
How can bringing together discovery and clinical data
standards reduce time and cost to generate safe CDx?
Mike Furness (Pistoia Alliance)
6. ŠPistoiaAlliance
Question 1
⢠How much experience have you had with NGS
for regulated purposes?
â None
â None but we expect to
â Some experience, but not in a regulatory submission
â We have successfully used NGS data in a regulatory
submission
26 March 2018
7. ŠPistoiaAlliance
Next Generation Sequencing (NGS)
⢠Refers to sequencing technology in which millions of short reads (100-
200 bases) are generated per sample, aligned to a reference genome,
and genetic variants identified with respect to that reference genome.
⢠While the technique is reliable and costs are low, the computational
complexities of QC, mapping, and variant calling makes it difficult to get
exact reproducible results.
⢠This is a challenge for use of NGS in a regulated environment, such as
diagnostic development, but the value of the technology makes it
important that we work with regulators to establish effective guidelines
and standards.
⢠Reproducibility is just one of several challenges that come together
during CDx development; others include the fact that many sequencing
efforts have been done on large heterogeneous populations for
purposes of discovery, and we would like to be able to use those data as
well.
8. ŠPistoiaAlliance
Cost of Sequencing
Wetterstrand KA. DNA Sequencing Costs: Data from the NHGRI Genome Sequencing Program (GSP) Available
at: www.genome.gov/sequencingcostsdata. Accessed 22-Feb-2018.
10. ŠPistoiaAlliance
From Research to Clinical
Genetic and Genomic tests, like other types of diagnostic tests, can be
evaluated and regulated on the following three criteria: *
Analytical Validity: Refers to how well the test predicts the presence or absence of a
particular gene or genetic change. Can the test consistently and accurately detect
whether a specific genetic variant is present or absent?
Clinical Validity: Refers to how well the genetic variant(s) being analyzed is related to
the presence, absence, or risk of a specific disease. Has having a specific genetic
variant been conclusively shown to increase the risk or likelihood of having a disease or
eventually developing a disease?
Clinical Utility: Refers to whether the test can provide information about diagnosis,
treatment, management, or prevention of a disease that will be helpful to patients and
their providers. Will use of the test lead to improved health outcomes?
ďś Definitions are adapted from the National Library of Medicine's Genetics Home Reference.
https://www.genome.gov/10002335/regulation-of-genetic-tests/
15. ŠPistoiaAlliance
Other regulatory guidance and resources
⢠ICH guideline E18 on genomic sampling and management of genomic data - First version
(Adopted Oct 2017)
⢠EMA Concept paper on development and lifecycle of personalised medicines and companion
diagnostics (Jul 2017)
⢠Overview of FDA Precision Medicine and NGS Guidance Documents (Feb 2018)
⢠EMA Guideline on good pharmacogenomic practice (Draft, Apr 2016)
⢠FDA Principles for Codevelopment of an In Vitro Companion Diagnostic Device with a Therapeutic
Product (Draft, Jul 2016)
⢠List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools) (Jan 2018)
⢠List of Nucleic Acid Based Tests (Nov 2017)
⢠IMI SAFE-T (Safer and Faster Evidence-based Translation)
17. ŠPistoiaAlliance
Technology/data initiatives and platforms
⢠PrecisionFDA
⢠NIH BD2K
⢠The Human Variome Project
⢠Global Alliance for Genomics and Health
⢠Global Biological Standards Institute
⢠The Common Workflow Language (CWL)
⢠BioCompute Objects
⢠Genome in a Bottle
⢠Platinum Genomes
⢠myExperiment.org
⢠BioSharing/FAIR Sharing
⢠Reproducible Bioinformatics Project
18. ŠPistoiaAlliance
An overview of the regulations
around CDx and the new
changes coming
Stephen Lee
Senior Regulatory Policy Manager â IVD Devices Division MHRA
20. ŠPistoiaAlliance
Overview of CDx regulation
⢠IVDR basics
⢠Clinical evidence requirements
⢠Development models
⢠Assessment of performance studies
21. ŠPistoiaAlliance
Health Warning!
These views on the interpretation of the
Regulations represent my own best judgement
based on the information currently available.
MHRA would always advise you to seek the
views of your own professional advisers.
22. ŠPistoiaAlliance
Question 2
⢠What quality system are you currently using
when analysing samples?
â GxP
â ISO 17025
â ISO 15189
â Something else?
â Whatâs a quality system?
26 March 2018
24. ŠPistoiaAlliance
The Regulations entered
into force on 25th May 2017.
However, most
requirements will not fully
apply until 26th May 2020
for Medical Devices, and
26th May 2022 for In Vitro
Diagnostic Medical Devices.
26. ŠPistoiaAlliance
Clinical evidence is âŚ
⢠based on performance studies
⢠used to demonstrate compliance with the regulations
⢠updated through the lifecycle of the product
29. ŠPistoiaAlliance
General requirements for all IVD
performance studies
⢠the health and safety of patients, users and other subjects
⢠the circumstances of the study
⢠rights, safety, dignity and well-being of the subjects in the
study
⢠studies involving left over samples
⢠data generated by the study
data generated are going to be
scientifically valid, reliable and robust
30. ŠPistoiaAlliance
Additional requirements may apply
⢠Prior authorisation by a Member State(s)
⢠Review by an independent ethics committee
⢠Protection of vulnerable subjects
⢠Management of risks and benefits to the subject
⢠Informed consent and not exerting undue influence
⢠Demonstrating analytical performance and scientific validity
⢠Qualifications of those involved in the study
⢠Study facilities
31. ŠPistoiaAlliance
'companion diagnostic'
⢠a device which is essential for the safe and effective use of a
corresponding medicinal product to:
⢠identify, before and/or during treatment, patients who are most likely to
benefit from the corresponding medicinal product; or
⢠identify, before and/or during treatment, patients likely to be at increased
risk of serious adverse reactions as a result of treatment with the
corresponding medicinal product
⢠*This includes devices used in clinical trials to stratify patients for
inclusion/exclusion in the trial or stratified to a cohort within a trial.
35. ŠPistoiaAlliance
Stage 1. Application and coordination Stage 2. Verification
Stage 3. Assessment
Stage 5. Performance study report
Stage 4. Running the trial
Application process for
Competent Authority
assessment of companion
diagnostic IVD performance
evaluation studies
1a Trial sponsor
notifies application
1b Commission
assigns SIN via
electronic system
2a Coordinating
member state
verifies application
2b
In scope and
complete?
2c Return to
sponsor
2d
In scope and
complete?
2e Rejected
2f Member State
appeals process
1d Trial sponsor
submits changes
3a
Member State
opinion
4c Substantial
modification
4d
Member State
opinion
4a Study begins
4b Study continues
(with modification
or corrective
measures - if
needed)
4e Refusal
4f Corrective
measures needed
4g
Sponsor
opinion
4i Authorisation
withdrawn
4h
Member state
opinion
5a Study ended,
suspended, or
terminated early
by sponsor
5b Performance
study report
submitted
5c Performance
study report
publicly accessible
1c Agree
coordinating
Member State and
inform sponsor
10 days from receipt
with clock stops
10 days
(extendable to 20+5 days)
Within 1 week of
the change
5 days from receipt of comments
(extendable by 5 days) with clock
stops
45 days (extendable by 20 days)
38 days (extendable by 7
days)
7 days
24 hours for early termination or suspension
15 days for end of study
3 months for early termination
1 year for end of study
Immediately (if study terminated early)
On registration (if study ended)
Within one year (if study ended but device not
registered)
6 days + 6 days
36. ŠPistoiaAlliance
Summary of CDx regulation
⢠IVDR basics
⢠Clinical evidence requirements
⢠Development models
⢠Assessment of performance studies
⢠Anything else to cover?
38. ŠPistoiaAlliance
How can bringing together discovery
and clinical data standards reduce
time and cost to generate safe CDx?
Mike Furness
Pistoia Alliance
39. ŠPistoiaAlliance
Question 3
⢠How much experience have you had with NGS
Companion Diagnostics?
â Worked, or working, on one or more companion
diagnostics brought successfully to market
â Worked, or working, on companion diagnostics in
development
â Planning to work with companion diagnostics
â Interested in finding out more about companion
diagnostics
26 March 2018
41. ŠPistoiaAlliance
ââŚ..in a survey by McKinsey in 2007 indicated that, on
average, 30 to 50 percent of drugs in development have an
associated biomarker program, and suggested this number
was likely to increaseâŚ. while the most aggressive players
have biomarker programs for 100 percent and companion
diagnostics for 30 percent or more of their compounds, the
average company has far fewer (30 to 50 percent and less
than 10 percent respectivelyâŚâ
Invention reinvented â McKinsey 2010
44. ŠPistoiaAlliance
Companion Diagnostics for Cancer
âŚâŚ. AstraZeneca has collaborated with Roche to develop the cobasÂŽ EGFR
Mutation Test v2 as the companion diagnostic for AZD9291.âŚ
âŚ.ZD9291 is an EGFR-TKI, a targeted cancer therapy, designed to inhibit both the
activating, sensitising mutations (EGFRm), and T790M, a genetic mutation responsible for
EGFR-TKI treatment resistance. Nearly two-thirds of NSCLC patients who are EGFR
mutation-positive and experience disease progression after being treated with an EGFR-TKI
develop the T790M resistance mutation, for which there have been limited treatment
optionsâŚ..
52. ŠPistoiaAlliance
References:
Companion diagnostics for targeted cancer drugs - clinical and regulatory aspects.
Olsen D, Jørgensen JT. - Front Oncol. 2014 May 16;4:105.
doi: 10.3389/fonc.2014.00105.
The current and future state of companion diagnostics.
Agarwal A, Ressler D, Snyder G. - Pharmgenomics Pers Med. 2015 Mar 31;8:99-110.
doi: 10.2147/PGPM.S49493
Frost & Sullivan - Precision Medicine- Growth Opportunities for Genomics Technologies
https://www.slideshare.net/SachaHenry3/precision-medicine-growth-opportunities-for-
genomics-technologies
Invention Reinvented: McKinsey perspectives on pharmaceutical R&D
https://www.mckinsey.com/~/media/mckinsey/dotcom/client_service/pharma%20and%20medic
al%20products/pmp%20new/pdfs/773771%20invention%20reinvented.ashx
Companion and Complementary Diagnostics: Clinical and Regulatory Perspectives.
Jørgensen JT. - Trends Cancer. 2016 Dec;2(12):706-712.
doi: 10.1016/j.trecan.2016.10.013
53. ŠPistoiaAlliance
11th April 2018 Workshop at Royal Soc Chemistry
Morning Session Afternoon Session
09:00 Registration and Coffee 14:00 Industry Regulatory â Perspectives
Challenges of NGS Companion Diagnostics
Development
(Stewart McWilliams, VP Quality & Regulatory Affairs, Almac)
10:00 Overview of the day and planned outcomes
(Pistoia Alliance)
14:30 Cross-Expertise Delegate Breakout Groups to discuss:
> What benefits could aligning the data
requirements and standards bring?
> What needs to be achieved to facilitate this?
> Identify possible next steps
10:30 Overview of current large-scale NGS data projects
(John Whittaker, VP Target Discovery, GSK)
11:00 Coffee 15:15 Coffee
11:30 What are CDx and the regulatory requirements around
them?
(Stephen Lee, Senior Regulatory Policy Manager â IVD
Devices Division, MHRA)
15:45 Plenary session: Collect ideas, identify next steps and
define targeted outcomes
12:00 How good is your next generation sequencing?
(Simon Patton, Director, European Molecular Genetics
Quality Network)
16:30 Networking Reception
12:30 Notified Body â Perspectives
(Elizabeth Harrison, Technical Team Manager - IVD, BSI
Group - tbc)
17:30 Close of Workshop
13:00 Lunch
Register for workshop at https://pistoia_alliance_cdx_workshop.eventbrite.co.uk/
54. ŠPistoiaAlliance
More information
Please see the problem statement on the Pistoia Alliance Interactive Project
Portfolio Platform at:
https://ip3.pistoiaalliance.org/subdomain/main/end/node/1852
To explore this challenge, the Pistoia Alliance has created a short questionnaire
that only takes a few minutes to complete. We would be very grateful if you
would complete the questionnaire. It can be found at:
https://www.surveymonkey.co.uk/r/YQ8L2H3
The Pistoia Alliance will also hold a workshop at the Royal Society of Chemistry,
Piccadilly, London on Wednesday 11th April 2018. To register your interest in
attending the workshop please follow the link:
https://pistoia_alliance_cdx_workshop.eventbrite.co.uk
Editor's Notes
Itâs likely that most of you know this, but for the sake of completeness:
Note that the term ânext-generationâ is as compared to âtraditionalâ Sanger sequencing and is now a bit stale; it is now the current generation of sequencing technology.
NGS approaches can range from the sequencing of targeted âpanelsâ of genes implicated in a particular disease, to whole-genomes, with whole-exome an intermediate approach between the two. Exome sequencing targets the 2% or so of the genome that actually codes for proteins.
This chart shows the dramatic decline in cost of sequencing (2001-2017) has fuelled the growth of both population-level efforts and clinical applications. Around 2016 we reached the milestone of the $1000 whole-genome.
This cost refers to the basic data generation and analysis process, but does not include costs associated with interpreting the data and making decisions based on it.
There are an ever-increasing number of genomics projects, and these are continually increasing in size.
As an example, I have shown examples of many of those looking at over 100,000 individuals.
Large genomics projects are a product of both reductions in speed and costs of the technology to generate the data and to analyse it.
Whilst all the initial large-scale projects were research-based, there has been a rapid growth in new large-scale projects applied to clinical samples for medical diagnostics, better understanding drug actions, and helping to generate so-called âpersonalised medicinesâ targeted to patients with specific phenotypes or genotypes.
NGS analyses need to satisfy criteria related to validity and utility in order to move from research to clinical use.
Welcome to precisionFDA, the community platform for NGS assay evaluation and regulatory science exploration.
One of the major challenges posed by NGS technology as compared to some other assay technologies, is the reproducibility of the analysis methods and pipelines that go from raw reads to variants and genotypes. NGS results depend as much on computation as on chemistry.
The PrecisionFDA Consistency Challenge was an attempt to evaluate various analysis pipelines for concordance with a well-established reference data set (GIAB), as well as the reproducibilty of the results from each pipeline. In a minute weâll see the reproducibility results.
Each step in this pipeline is the subject of many possible algorithms, and adds variability to the end results.
Navigating from âRaw Unmapped Reads to âUse in projectâ is an exercise in routefinding.
There is a lot of detail here, but focus on the columns at the right: when running the exact same data through the exact same analysis pipeline twice in succession, only 8 of 18 (accepted) challenge entries produced the same results (Deterministic). This does not include variability introduced by different sequencing platforms, laboratory procedures, personnel, etc.
The last entry in the table represents a difference of about 2.6% of variants detected
A couple of examples from the literature of efforts to standardize parts of the analysis and interpretation process; in the first case regarding the interpretation of variants (rather than the detection of variants from raw, which is more of a technical issue)
There are also technologies that are being developed to help with challenges of reproducibilty and data provenance and integrity.
One such effort is the BioCompute Object or BCO, being developed by the FDA and academic and industry partners. BCO builds on other established standards such as the Common Workflow Language and container technologies, to define a single referenceable object that contains the data, processing pipeline and parameters, and results of any analysis. These objects can then be submitted to a regulator and/or databased to be searched and reused by others.
The Global Alliance for Genomics and Health (GA4GH) is focused on technologies to support a set of real-world Driver Projects including for example the Clinical Genome Resource (ClinGen), Genomics England, and the NCI Genomic Data Commons.
This is a (not exhaustive) list of some of the data and technology-related efforts that try to address issues of standardization, reproducibility, and sharing of genomic and biomedical data.
There is no shortage of efforts in this area, but that can make it difficult to know which one(s) to follow.
Clarify/recap definitions of CDx
Growth in use of biomarkers
Growth in use of CDx
Add in slide with example of complementary diagnostic