Written evidence submitted by the Department of Health (GEN0059)

The life sciences industry is critical to the UK economy and UK health - with over 5,600 companies, 220,000 employees and over £60 billion turnover in 2015, it provides products which the NHS and over 60 million UK patients rely on every day. The UK has shown global leadership in life sciences and is world-leading in genomics also being an early adopter of gene editing technologies.

A new Life Sciences Strategy will be launched in Spring 2017 and will outline what the life sciences industry can deliver for the UK economy and for UK patients, and set out what actions Government proposed to take to set the framework for success. It is anticipated that genomics will be a key part of the new Life Sciences Strategy which will be closely aligned with the Department for Exiting the EU (DExEU) work on negotiating priorities and the cross-Government Industrial Strategy. 

The Department of Health remains at the forefront of developing genomics as it relates to human health. A wide ranging review of this topic is timely and provides an opportunity to illustrate how this technology is likely to have a significant impact on the delivery of healthcare. It is less than 15 years since the completion of the Human Genome Project but the pace and scope of technological development has been remarkable. The Government and the Department of Health have recognised the potential of genomic technology and it is one of the key priorities in research and the in the NHS. Genomics has been identified together with synthetic biology and life sciences as one of the great eight technologies where the UK has the potential to develop a world-leading industry.

Genomics and human health

Genetic changes are responsible for a significant subset of human disease including approximately 75% of all rare diseases and genetic change also underlies the process of tumour (cancer) formation. The identification and characterisation of genetic changes is essential to accurate diagnosis and appropriate treatments being chosen. The accessibility of rapid whole genome sequencing and increasingly sophisticated bioinformatics analysis mean that genomic approaches are more likely to become used as the primary method of diagnosis or disease detection. The same technologies can also be used to improve the diagnosis of infectious disease and the control of infections and outbreaks.

The 100,000 Genomes Project has been the single highest profile project in this area with over £500 million invested by the Department, National Institute of Health Research (NIHR), the NHS, research funders and industry. It is being delivered by Genomics England, a company wholly owned by the Secretary of State for Health. It is working in partnership with NHS England, NHS Digital, Health Education England, Public Health England, the sequencing company Illumina and a range of external partners including the Wellcome Trust, Cancer Research UK and the Medical Research Council.

Rare disease patients are a primary beneficiary of the 100,000 Genomes Project. Rare Diseases are increasingly featured in healthcare policy development at a global level, from both a health and growth perspective. Over the past 3-4 years, the UK, through the Department of Health, has been working to promote better engagement on rare diseases policy internationally, especially at an EU level. The UK is a world leader in rare diseases and a natural first choice partner for research, innovation and technology development.

A rare disease is a life-threatening or chronically debilitating disease that affects 5 people or fewer in 10,000 and requires special, combined efforts to enable patients to be diagnosed and treated effectively. 1 in 17 people will suffer from a rare disease at some point in their lives. In the UK this equates to approximately 3.5 million people. There are over 6,000 rare diseases; approximately 80% are of genetic origin. 75% of rare diseases affect children.

The project (GeL) recognised the significant unmet need by patients and their families affected by conditions with an undefined genetic basis. Providing a clear diagnosis to these patients is important to provide certainty regarding the likely prognosis for those affected and allow parents to make informed choices about their family. The identification of the genetic basis for conditions is also the first step in the development of potential therapies. In addition, understanding the genetic basis for rare disease can provide important biological insights into human biology with a much wider relevance. Similarly the genetic analysis of cancers will reveal the key genetic changes associated with different forms of the disease. The 100,000 Genomes Project is advancing the understanding of clinically relevant genetic signatures that will improve predictions of prognosis and potentially identify new therapeutic possibilities in both rare diseases and cancer.

The 100,000 Genomes Project has directly tackled many issues of wider relevance to genomics technologies in general. This has included establishing robust methodologies suitable for a routine clinical setting, creating a network of centres of excellence in the form of NHS Genomic Medicine Centres and building a bioinformatics architecture to handle the vast amounts of data in a secure and accessible manner. Engaging patients and the wider public is another key aim of the project, from the initial seeking of consent through to awareness of the use of data by researchers.

As of January 2016 approaching 18,000 whole genomes have been sequenced as part of the main Project, including patients with cancer and rare disease. The full Project data set also includes 8,000 sequenced genomes from the NIHR BioResource BRIDGE study, which started as a pilot before the 100,000 Genomes Project but whose genomes were planned to be a part of the Genomics England dataset, subject to the appropriate consent.

The 100,000 Genomes Project is currently the largest national sequencing project of its kind in the world.  It is both a scientific discovery and NHS transformation project and as such there are significant delivery challenges including:

• Putting in place the pipeline – this has included establishment of a network of 13 NHS Genomic Medicine Centres, building an informatics architecture from scratch and putting in place standardised approaches to data definition and collection.  Genomics England now has one of the first semi-automated bioinformatics and clinical interpretation pipelines in the world.

• Scientific challenges relating to cancer genomics – here the NHS is operating at the edge of scientific knowledge to identify a way to extract enough high quality DNA from tumours to enable successful Whole Genome Sequencing. By embedding new cancer sample handling in routine care, for example the use of ‘fresh frozen’ samples the project is equipping the NHS for future genome-based diagnostics.

A more detailed description of the project is provided in Annex A.

Training and education

The potential for genomics to transform so many aspects of healthcare means that staff training is critical to the successful adoption of the new technologies within the healthcare system. Health Education England (HEE) is delivering a £20m Genomics Education Programme (GEP) for both specialist scientific staff and front line clinicians, the aim of which is to increase the capacity in the NHS workforce to deliver the 100,000 Genomes Project and mainstream genomic medicine. This programme has been developed in partnership with NHS providers, professional bodies and regulators, and Higher Education Institutes. Further information on the role and training support provided by HEE and the training is provided in Annex B.

Translational research in genomics

The National Institute of Health Research (NIHR) funds a variety of other initiatives also to use genomic technologies for health research and to support the development of new therapies based on genomics and gene editing technologies. This support includes programme support for defined projects, provision of research infrastructure and investment in training which includes fellowship and research degrees. A detailed description of the NIHR support available is provided in Annex C.

The complete value of genetic information can only be realised in a broad clinical context and this is a central objective of the NIHR Rare Disease Translational Research Cooperative (RD-TRC). The RD-TRC use deep phenotyping approaches to provide a holistic view of the clinical and biochemical features of patients with genetically based rare diseases. This approach makes it possible to understand how genetic changes lead to a clinically relevant phenotype and may suggest how these conditions can be treated. This approach is particularly valuable for poorly characterised genes where the biological function is unclear.

The NIHR directly supports the translation of advances in genomics into new clinical approaches and therapies through support for NIHR Biomedical Research Centres. These centres provide the world-class biomedical research infrastructure in the NHS to support and enable research funded by NIHR and public, charity and industry research funding partners. They support the development of new, ground-breaking treatments, diagnostics, prevention and care for patients in a wide range of diseases. In September 2016 a record £816 million investment in NIHR BRCs was awarded to 20 NHS and university partnerships across England that will provide support for 5 years from 1 April 2017. Genomics will be relevant to all these centres but particularly to the ten NIHR BRCs with dedicated Genomics-related research themes (totalling over £44.5 million).

The delivery of genomics research studies and trials is also supported by the NIHR Clinical Research Network (NIHR CRN). This provides a managed research delivery network across all of the NHS in England supporting commercial and non-commercial studies. The network makes it possible for patients and health professionals to participate in genomic research across the country. The support available includes advice and support for study feasibility, streamlined NHS permissions and the management of effective patient recruitment.

Genomics is relevant to understanding human health in the broadest sense as it partly defines why individuals differ in their chances of developing different conditions. Likewise genetic differences will underlie a spectrum of patient responses to medicines. The ability to predict the chances of an individual developing a condition and how they will respond to treatment is central to the strategy of employing personalised or precision medicine approaches.

Genetic analysis complemented by other clinical measurements will increasingly be used to ensure that patients receive the most appropriate treatment. The NIHR supports these approaches in a number of ways including the work of the NIHR BRCs but also through investigation of large-scale patient based studies. The NIHR BioResource provides a national cohort of healthy volunteers, patients and their relatives who wish to participate in experimental medicine research on the basis of phenotypic and genotypic data. The NIHR National Biosample Centre also working in partnership with Genomics England to store samples from rare disease and cancer patients. The Centre provides high throughput and high quality biosample storage and retrieval services to support NIHR supported research and research funded by partner organisations as well as industry. The Department of Health has also contributed £10 million towards a project using participants in the UK Biobank to investigate the complex interaction of lifestyle and genes in cause of heart disease, dementia, cancer and other life-threatening conditions.

An important element of a personalised approach to medicine is the development of new diagnostic approaches and the NIHR supports four Diagnostic Evidence Co-operatives (DECs). The DECs are centres of expertise that act to catalyse the generation of evidence on commercially available in vitro diagnostic devices (IVDs) which is required by the NHS and by in diagnostic device manufacturers to enable patients to access the most appropriate treatments more quickly and help the NHS make the best use of its resources. In September 2016 it was announced that up to £14.25 million will be made available for new NIHR Medtech and In vitro diagnostic Co-operatives (NIHR MIC). These NIHR MICs will retain of the current remit of DECs and incorporate this alongside the existing remit of the current NIHR Healthcare Technology Co-operatives.

A personalised approach is increasingly being developed and refined in the treatment of cancers which can be tailored against the specific genetic changes in each cancer. This is a rapidly expanding area where the number of clinically actionable genetic changes is increasingly rapidly. The NIHR supports the development of targeted approaches for cancer treatment in collaboration with Cancer Research UK through the network of Experimental Cancer Medicine Centres. These centres are actively engaged in developing ways to use genomic information to improve the clinical outcomes of cancer treatments.

Genomics have also had a transformative impact on the control of infectious diseases. Molecular signatures in bacterial and viruses make it possible to track the epidemiology of infection with a new level of accuracy. Genomic analysis bacteria is also critical to monitoring the addressing the issue of antibiotic resistance by following the genes involved. Public Health England has been working with Genomics England to implement a National Mycobacterial Reference Service (NMRS) which will use Whole Genome Sequencing in the diagnosis of Tuberculosis.

Wider policy implications of genomic technologies

The ethical, legal and social implications of genomic technologies have been highlighted since the original Human Genome Project.  The Department has been active in considering the issues first identified by the Human Genetics Commissions and other Parliamentary enquiries. The Department has highlighted the importance of public confidence in genomics technologies. This is a major focus of the 100,000 Genomes project and is also aligned to the key priorities of the National Data Guardian review on data security, consent and opt-out. The 100,000 Genomes project has focussed on patient engagement, on explicit consent and on safeguarding patient data. All genomic data is held securely and can only be accessed by researchers – academic or commercial – via the Genomics England secure environment. There are also safeguards around the use of genetic information for insurance purposes. These are based on a long-standing agreement between the Government and the Association of British Insurers which is kept under review.

The potential use of genomic technologies for reproductive purposes is largely regulated by the Human Fertilisation and Embryology Authority who have responsibility for considering the use of such technologies for embryo research and for pre-implantation genetic diagnosis. The recent decision to introduce Non-Invasive Prenatal Testing into the newborn screening programme will also include a specific focus on addressing concerns about the provision of accurate information to parents.

The Government is aware of the considerable public interest in genomic technologies and gene editing and has in the past made use of the Sciencewise programme to support public dialogues on related matters such as mitochondrial diseases, stratified medicine and genetically modified animals. The potential for future funding for public engagement activities will be kept under review.

Therapeutic approaches including gene editing

Genetic analysis means that the basis for many inherited conditions is now much more clearly understood. In some cases the identification of the underlying cause of the condition is sufficient to select an appropriate treatment using an existing medicine. Similarly, genetic similarities between cancers arising in different tissues and may offer the potential to use treatments targeted at a specific molecule or pathway.

In most cases the identification of the genetic basis for rare inherited conditions will not be sufficient to suggest using a pre-existing therapy. In these situations correcting the genetic defect may be the only realistic prospect. Whilst there would be advantages in being able to correct inherited genetic defects early in human development there are technical barriers that mean that this unlikely be a practical option for many years. The genetic modification of human embryos or gametes is prohibited by law in the UK and raises significant ethical questions. Furthermore, a significant proportion of inherited genetic conditions result from de novo mutations or from parents with no specific history of genetic conditions and are unlikely to be detected, let alone treated before birth.

Correction of genetic defects in somatic cells - through gene therapy and/or gene editing poses many fewer issues and is now becoming a practical possibility. Many groups are developing methods to replace a missing or defective gene product and the one such treatment has recently received marketing authorisation. It is likely that increasingly sophisticated approaches will become a practical possibility for example using gene editing to repair endogenous genes so they regain their normal function. This is particularly the case for very large gene products which are incompatible with current delivery methods based on viral vectors.

Regulatory Challenges

The development of new treatments based on genomic technology creates a range of regulatory challenges. The Medicines and Healthcare products Regulatory Agency (MHRA) has been at the forefront of developing regulatory frameworks that enable the development of new diagnostic devices and therapies and ensure that any treatments are safe. These span entire potential impact of genomics and gene editing including reclassification of diseases, predicting clinical outcomes of disease and risk, new diagnostic and therapeutic approaches and the potential to cure hitherto incurable diseases. Detailed information on the role played by the MHRA is provided in Annex C.

The MHRA has developed strong mechanisms to identify scientific, technical and commercial developments so it can respond to high impact developments in a timely manner. The MRHA has taken a proactive approach in supporting the academics and companies developing new therapies involving gene editing approaches and supports the Regulatory Advice Service for Regenerative Medicines (RASRM) that provides a co-ordinated single response service for the entire regulatory landscape.

Conclusions

The Department of Health continues to support the use of genomics and genomic technology through a variety of mechanisms. The Department has consistently maintained policies and strategies for healthcare and research that build upon the UK’s global leadership in the fields of genetics, genomics and rare diseases.  The quality of our clinical, academic, research and industry sectors is second to none and the Government has set out a clear direction of travel that will harness these skills and expertise to benefit healthcare and the economy.  The ground-breaking nature of the 100,000 Genomes Project is an example of the confidence we have in skills and talent that can be found across all areas of UK innovation in emerging technologies. GeL has played a leading role in establishing a framework that will enable the healthcare system to realise the benefits of genomics technology. There is no comparable project to be found elsewhere in the world that is embedded in the patient pathway of a national healthcare provider.

The Department’s investment in physical infrastructure, research projects and staff development by the NIHR and others mean that the full potential of this technology is actively being translated into new approaches and therapies.

The overarching nature of the change that genomics will bring to healthcare is recognised by the fact that the Chief Medical Officer has chosen Genomics as the topic for her next themed annual report. This report is expected to be published spring 2017 and will be an important contribution to the inquiry by the Science and Technology Committee.

February 2017

Annex A

Genomics England’s 100,000 sequenced genomes initiative, including its progress and safeguards (including data consent and security)

Through the ground-breaking 100,000 Genomes Project we are leading the world in taking genomics from research setting into a clinical environment.

The project is being delivered by Genomics England (GeL), a company wholly owned by the Secretary of State for Health.  It is working in partnership with NHS England, Health Education England, Public Health England, the sequencing company Illumina and a range of external partners including the Wellcome Trust, Cancer Research UK and the Medical Research Council.

Since the project was announced by the former Prime Minister David Cameron in December 2012 over 17,000 Whole Genome Sequences (WGS) have been completed and good progress has been made against all four of the wider project aims.

Bring benefit to patients and NHS transformation

The potential for genomics is considerable – genomic technologies integrated into healthcare will change how we think about and treat many diseases and supports the move to an era of personalised medicine – moving from a ‘one size fits all’ approach to treatments and interventions,  to more individually tailored approaches.

The 100,000 Genomes Project is acting as a proof of concept for the use of genomics in routine care and it is already providing answers and changing the lives of NHS patients. Such examples include two little girls who joined the project earlier this year through Great Ormond Street Hospital, the lead organisation for North Thames Genomic Medicine Centre: 

• Four year old Jessica Wright has a rare condition which causes epilepsy and affects her movement and general development. Whole genome sequencing as part of the 100,000 Genomes Project revealed that she has a rare genetic variant - which neither of her parents have - causing Glut 1 deficiency syndrome. After years of inconclusive tests and invasive procedures, this result means that Jessica can now be put on a particular high-fat diet (ketogenic) to reduce the number of seizures.

• Georgia Walburn-Green who is also four years old, has physical and mental developmental delay, a rare eye condition and verbal dyspraxia meaning it is uncertain whether she will ever talk. Standard genetic testing brought up nothing but just before Christmas last year, the 100,000 Genomes Project was able to find a mutation in a gene called KDM5b which is likely to be the cause of her problems. This, for the first time, gives Georgia a molecular diagnosis for her condition. While the knowledge will not change the way Georgia is treated today, it offers hope that there will be a therapy in the future.

Over 1,000 reports have now been returned to clinicians and Genomics England is working hard to reduce the length of time it takes to return these. 

These results are only happening thanks to the significant NHS transformation which is taking place as a result of the project.

NHS England has established a nationwide network of 13 Genomic Medicine Centres (GMCs) supported by local hospital delivery partners to consent patients and take samples at the start of the process and then validate and use findings to inform patient treatment once the sequencing and interpretation is complete. The establishment of this network of genomic centres of excellence links to NHS England’s forthcoming re-procurement and designation to create a national genomics laboratory structure for England.

Data and informatics are key components of the project. As well as introducing standardised approaches to data capture and quality in the NHS, Genomics England is also drawing life course data from NHS Digital and Public Health England to make the data as rich as possible and lead to the best possible medical and research outcomes. Genomics England has built an informatics architecture from scratch which enables GMCs to provide the necessary data to enable both successful Whole Genome Sequencing and interpretation of the results. 

With a project as ground-breaking and ambitious as this one, there are some big delivery challenges to overcome in particular around establishing new pathways in the NHS to handle, process and extract DNA from fresh or fresh frozen cancer samples. No-one else in the world has a solution for extracting enough, high quality DNA from cancer samples to enable successful Whole Genome Sequencing and so this is another example of how we are operating at the limits of science and current practice. As a trailblazer, other countries are coming to us for advice and Genomics England is sharing its expertise internationally for example by working with Genome British Columbia in Canada and the Garvan Institute in Australia.

Closer to home, Scotland and Northern Ireland have already joined the 100,000 Genomes Project and Wales are in the process of doing likewise following confirmation of securing funding from the Medical Research Council. This means that patients across the UK can benefit from advances in genomics medicine.

Create an ethical and transparent programme based on consent

Retaining patient, public and professional support is critical to the success of the 100,000 project and its legacy and there is a key set of principles underpinning it:

• Patients always participate in the project on a fully consented basis so they are aware of who can access their data, and have agreed that their de-identified data can be used for research by clinicians, academics and industry. The project has ethical approval from the Health Research Authority (East of England – Cambridge South) Research Ethics Committee and the model was recently highlighted in Dame Fiona Caldicott’s 2016 review of data security, consent and opt-outs.

• The Secretary of State for Health has stated that data will always be held in a secure data centre in the UK and never sold.

• Researchers cannot remove data – the secure, monitored environment represents a reference library, not a lending library.

• Any profits generated by Genomics England will be reinvested back into the research infrastructure to maintain the UK position in genomics.

Genomics England is also delivering a communications strategy for engaging key stakeholders including the media, front-line staff, parliamentarians and the general public. Highlights this year have included: the Prime Minister opening the sequencing centre on the Wellcome Genome Campus in Cambridge; collaborating with the All-Party Parliamentary Group on Personalised Medicine to host a breakfast meeting at the House of Lords for over fifty parliamentarians and stakeholders; delivering the Socialising the Genome campaign to help the public understand the science and implications of genomics, as well as listen to their hopes and worries.

The Chief Medical Officer, Dame Sally Davies has confirmed that her annual report for 2016 will focus on genomics, addressing some of the emerging issues in the field.

Enable new scientific discovery and medical insights

Through the project we are delivering one of the largest datasets in the world and an unrivalled national resource – a secure dataset linking genomic and medical data. The interest amongst the research community has been considerable – over 2,500 clinicians and scientists from 300 institutions in 24 countries have joined Genomics England’s Clinical Interpretation Partnership (GeCIP). This is the method by which researchers and clinicians will analyse the dataset and interpret the findings with a view to identifying new scientific and medical breakthroughs. Over 40 domains of research are included.  Most cover a single disease or group of diseases but some are wider; these include epigenomics, health economics and technology.

The project is truly an example of the use of Big Data. To give a sense of scale, 100,000 genomes will equate to 21 Petabytes of data. 1 Petabyte of music would take 2,000 years to play on an MP3 player.

Kickstart the development of a UK genomics industry

Exploring how industry will work with the unique dataset along with driving up the quality of the interpretation of genomic data are crucial to us in finding out how to understand and treat disease better in the future.  On this basis, Genomics England formed the Genomics Expert Network for Enterprises (GENE) Consortium which brings together 12 companies including Roche, AstraZeneca and GlaxoSmithKline to oversee a trial to test how industry will engage with the data. They are providing useful input into the development of the commercial model.

A number of companies are also playing direct roles in the project pipeline including Illumina who are providing sequencing capacity, Congenica a UK company and spin-out from the Wellcome Trust Sanger Institute who are a clinical interpretation partner and Skyscape who are providing compute-as-a-service solutions.

Examples of how the project is contributing to growth include:

• Following the announcement of the £78 million partnership with Genomics England, Illumina committed to investing around £162million into the work in England over four years, creating new knowledge and jobs in the field of genome sequencing.

• As a result of £8m Small Business Research Initiative (SBRI) funding, Genomics PLC and Seven Bridges have set up businesses in the UK.

• Genomics England have generated over £2m in commercial revenue in membership fees from the GENE Consortium and are pursuing the possibility of direct engagements.

Next Steps

Going forward, there are two priorities.  The first is to work at pace to deliver the 100,000 Whole Genome Sequences as early as possible whilst ensuring we maximise the scientific learnings from the project which will help healthcare of the future. The second is to develop the 2020 vision for genomics which we anticipate will be characterised by the routine use of WGS in clinical pathways, a single national genomics knowledge base to support care and research and the acceleration of industrial and research usage to make the UK the ‘go to’ place for any serious genomic company or researcher.

The adequacy of investment in infrastructure and skills/training in the NHS to take forward genome medicine

Over half a billion pounds has been invested in the 100,000 Genomes Project.  This includes:

• £350 million from the National Institute for Health Research (NIHR) budget to fund Genomics England including £250 million as part of the 2015 Spending Review.

• £10 million capital funding from the Department of Health to support set up of informatics architecture in GMCs.

• £20 million funding from NHS England for the set-up of the 13 GMCs plus payment for supply of 90,000 main phase samples.

• £24 million grant from the Medical Research Council to establish a shared, secure, high-performance data and computer infrastructure as a platform for innovative clinical genomics research by researchers and clinicians.

• £27 million investment by the Wellcome Trust for a world class sequencing hub at Genome Campus near Cambridge housing GeL’s operations alongside those of the internationally respected Sanger Institute.

In addition, Health Education England are delivering a £20 million Genomics Education Programme (GEP) to ensure that all healthcare professionals and staff working in the NHS have the knowledge skills and experience to be effective in their roles in the development and delivery of genomic services within mainstream medicine. This includes funding for: 550 Master’s in Genomics Medicine places at 10 universities; forty extra healthcare science training places in genomics and bioinformatics in 2014/15 – 27 of these at HSST (consultant) level; a Massive Open Source Online Course on Whole Genome Sequencing which over 1,200 people have signed up to undertake. Following completion of the GEP in March 2018, genomics education will become part of Health Education England business as usual.

Annex B

England’s National Genomics Education Programme

About the programme

The Health Education England Genomics Education Programme (GEP) was established in 2014 to ensure that all healthcare professionals and staff working in the NHS have the knowledge skills and experience to be effective in their roles in the development and delivery of genomic services within mainstream medicine.

The Genomics Education programme is achieving this by:

1.              Directly supporting professionals within the designated NHS Genomic Medicine Centres in the delivery of the 100,000 Genomes Project

2.              Upskilling the workforce through increasing capacity and capability

3.              Supporting wider transformation of services including the development of communities of practise

The GEP sits within Health Education England, the organisation with responsibility for the education and training of all healthcare staff within the NHS, and has a budget of £20M up until March 2018.

The GEP includes a new full or part time dedicated Masters in Genomic Medicine, as well as modular training opportunities which will enable the wider workforce to develop new knowledge and skills as part of their continuing professional development. Ten universities have been appointed as preferred providers to deliver this training and the first programmes were available for NHS staff to take up from the spring of 2016.

The training audience

Our programme aims to reach all staff within the NHS including those in general practise and the community.  To achieve this we have stratified our approach, enabling us to range from awareness materials for all staff and the public to very specific resources for specialised and highly specialised staff currently involved in the delivery of the 100,000 genomes project.

The resources

We have adopted a range of approaches to delivery of our resources including face to face, blended learning, and online courses. Most of our resources can be undertaken in the learner’s own time and at their own pace but others such as the MOOC are synchronous and moderated.  Formal Master’s programmes can be undertaken part time or full time and are largely distance based.  Some of our resources will be accredited through the Royal Colleges.

Resources to support the 100,000 Genomes project

We have developed and continue to develop a range of free online resources to support the 100,000 Genomes Project pipeline. These include:  The consent conversation, DNA extraction and sample preparation for whole genome sequencing, a tumour assessment tool, validation and feedback, and data security.

Increasing capacity and capability

We have developed a multidisciplinary Genomic Medicine curriculum and procured 10 universities to deliver the course in a collaborative manner at Masters, Diploma and Certificate level.  We are funding over 550 places for NHS staff on this blended learning programme. In addition, the modules are  also funded to be available individually as CPD.

We have developed new Clinical Scientist curricula for Genomic Counselling and Clinical Bioinformatics  at Masters level,  which leads to professional registration with the healthcare Professions Council.  We have also developed doctoral level curricula for Clinical Bioinformatics and Molecular Pathology of Acquired Disease.  This is increasing the capacity in the NHS workforce to mainstream genomic medicine. These will prepare the scientific workforce for new technological developments and develop the scientific and research capability of the NHS.

Within the NHS the Genomic Medicine Centres play an important role in workforce development offering introductory training to nurses on genomics that create a pool of trained staff to help deliver the 100, 000 Genomes project.

A Massive Open Source Online Course on Whole Genome Sequencing was launched in September 2016.  Over 1200 people signed up to undertake this. It will be re-run several times over the next 18 months.

Evaluation plans

On completion of each resource the learner has the opportunity to undertake an exit knowledge based test and/ or reflective piece of work.  We also plan to undertake longitudinal studies to assess the impact of our training interventions on workforce transformation. These will be analysed to ensure that our resources are fit for purpose and inform future direction and strategy.  Our goal is to contribute to the pedagogical literature in this area.

Genomics Education website: https://www.genomicseducation.hee.nhs.uk

Annex C

NIHR infrastructure

• NIHR’s world-class research infrastructure in the NHS has directly facilitated delivery of the 100,000 Genomes Project pilots, including through:

• NIHR Biomedical Research Centres and Units
• Experimental Cancer Medicine Centres
• NIHR BioResource
• NIHR National Biosample Centre
• Clinical Research Facilities

Genomics and NIHR Biomedical Research Centres and Units

• The NHS Genomics Medicines Centres are underpinned by the NIHR Biomedical Research Centres (BRCs) and Units (BRUs). The NIHR supports 11 BRCs and 20 BRUs across NHS England covering the whole range of disease areas. The BRCs and BRUs provide the world-class biomedical research infrastructure to support and enable research funded by NIHR’s public, charity and industry research funding partners. In the five years since April 2012 the Government has invested £800m within these leading NHS and University partnerships to drive progress on innovation and translational research in biomedicine into NHS practice.

• The Health Secretary announced on 14 September a record £816 million investment in the NIHR BRC designation and funding, over 5 years from 1 April 2017, which has been awarded to 20 NHS and university partnerships across England. Each of the 20 BRCs will host the development of new, ground-breaking treatments, diagnostics, prevention and care for patients in a wide range of diseases. Genomics is expected to remain an important element of the research portfolio for these newly designated BRCs, including ten BRCs with dedicated Genomics-related research themes (totalling over £44.5 million).

Genomics and Experimental Cancer Medicine Centres

• Most of the 14 Experimental Cancer Medicine Centres funded by NIHR in England (in partnership with Cancer Research UK) are researching genomics-based diagnostic and treatment interventions, including close integration with the cancer aspects of the 100,000 Genomes Project.

Genomics and the NIHR BioResource

• In March 2014, the Government launched the NIHR BioResource to provide a national cohort of healthy volunteers, patients and their relatives who wish to participate in experimental medicine research, and are willing to provide clinical information and samples that will enable them to be recalled for specific studies. 

• The BioResource is working with, and supporting, the 100,000 Genomes Project.  As part of this, the NIHR BioResource and GeL are working together around the opportunity for rare disease cohorts to become part of the GeL Rare Diseases Pilot of Whole Genome Sequencing in 2,000 people. This commenced in December 2013 and has since achieved its target of recruiting 2,000 participants.

Genomics and the NIHR National Biosample Centre

• The NIHR National Biosample Centre was established, funded with a £24million capital grant from DH, to provide high throughput and high quality biosample processing, storage and retrieval services to support NIHR supported research, and research funded by DH partners, such as publicly funded research funders (eg MRC), charities (eg Wellcome, CR-UK), as well as industry. 

• The NIHR National Biosample Centre is working in partnership with GeL to store the samples of rare disease and cancer patients taking part in the 100,000 Genomes Project.

Genomics and Clinical Research Facilities

• The NIHR is supporting 116 projects in genomics within its Clinical Research Facilities (CRFs).

• Six NIHR CRFs have reported involvement with the 100,000 Genomes projects and between them have reported in excess of 550 subjects recruited in 2015/16 (Sheffield; Cambridge; Imperial; Kings/Maudsley; Southampton; Christie).

Other ways NIHR infrastructure is contributing to the area of ‘omics’ sciences

NIHR BioResource

• NIHR is funding the BioResource to undertake exome or whole genomic sequencing of 8,000 rare diseases samples (£15 million) and what is referred to as high density array sequencing of 60-80,000 general BioResource samples (£5m).

• The NIHR is also providing funding to expand the national resource of volunteers who are willing to be recalled by genotype (or phenotype), and enhance our ability to deliver research in the field of rare diseases. This is through the INTERVAL study, a randomised controlled trial that has been supported by funding from the MRC/Wellcome Trust, NHSBT and the NIHR Cambridge BRC. INTERVAL is recruiting 50,000 whole-blood donors recruited at 25 locations across England.  The total cost (the genetic assay in 50,000 volunteers and the cost of the biomarker panel in 50,000 volunteers) was £3.3m in 20/13.  

Rare Diseases Translational Research Collaboration

• The NIHR is funding (£10m) the RD-TRC sequencing of 5,000 rare diseases samples - whole genome sequencing and associated clinical and bio-informatics leading to model / ontology based integration and analysis of phenotypic and genomic data of patients recruited to the RD-TRC.

• The RD-TRC has identified OpenClinica as the hub system for a federated national database of in-depth phenotyping data sets, embedding the clinical data definitions developed by the work of GeL through a process of data standardisation, import and consolidation.

BioBank

• UK Biobank announced plans (22 March 2013) to undertake detailed DNA analysis of its 500,000 participants to better understand the complex interaction of lifestyle and genes in causing heart disease, dementia, cancer and a wide range of other life-threatening and disabling disorders. This genetic analysis (‘genotyping’) project, which will cost over £20million, will examine several hundred thousand genetic ‘markers’ on each UK Biobank participant. MRC and DH have each contributed £10 million towards the project, with the British Heart Foundation (BHF) providing a further £1 million.

Metabolomics

• The NIHR is funding (£800k) the RD-TRC to undertake metabolic profiling of 5,000 samples from NIHR cohorts (NIHR BioResource, NIHR BioResource Rare Diseases, and Rare Diseases Translational Research Collaboration), through Metabolon.

• The NIHR is funding the NIHR BioResource (£3m) to undertake metabolomic profiling of an 18,000 sample subset of the NIHR BioResource; enhancing the ability to recall volunteers according to phenotype and providing important insights into disease mechanisms.

Annex D

MHRA contribution to Department of Health evidence to House of Commons  Science & Technology Committee inquiry on genomics and genome editing

MHRA’s contribution to this inquiry will cover the following areas:

A.    About the MHRA and MHRA’s work regarding regulating genomics and genome editing (pp.2-9)

B.    Legislation governing genomics and genome editing (pp.9-15)

C.    MHRA’s current engagement with genomics and gene editing (pp.15-21)

D.    The role of the MHRA in ensuring the safe regulation of genomics and gene editing (pp.21-28)

E.     Continuing MHRA support for genomics and genome editing (pp.28-30)

F.     Conclusions (pp.30-1)

MHRA’s contribution to selected terms of reference for the inquiry:

1. The MHRA recognises the huge potential of genomics and genome editing on human health in many areas including reclassification of diseases, predicting clinical outcomes and disease risk, new diagnostic and therapeutic approaches and the potential to cure or substantially modify hitherto incurable diseases.  This contribution from MHRA will cover aspects of the terms of reference listed below relevant to our work in medicinal products, medical devices and standards:

1(c). The impact of genomics and genome-editing on human health, with regard to treating disease, avoiding genetic disease and human enhancement.

2.  Whether current regulations in particular areas of genomics and genome-editing are consistent, and whether they are adequate to meet the requirements of different 'product’ and 'process' based approval processes;

3. The ethical, social and safety concerns from genomics/genome-editing in the treatment of disease and its impact on the environment.

2. MHRA’s contribution will set out current and developing legislation for medical devices and medicinal products which ensures that the area is regulated consistently and adequately meets applicable standards of safety, quality and efficacy to protect the public and patients from potential safety issues in a rapidly developing area. MHRA as a regulatory body facilitates innovative science, research and development which have a positive impact on human health, with regard to treating disease and avoiding genetic disease.

3. Regarding human enhancement, where this term is taken to include disease treatment or prevention, the MHRA’s remit includes support for and regulation of medical devices and medicinal products.[1]However, MHRA’s remit does not include human enhancement considered to be ‘beyond the norm’ for humans.

4. MHRA does not have a remit for ethical and social concerns or environmental impact; however we do have a responsibility for patient safety in relation to medicines and medical devices.

5. Other terms of reference for the inquiry are not within the remit of MHRA or any of its 3 centres.

A.    About the MHRA and MHRA’s work regarding regulating genomics and genome editing

The MHRA

6. The Medicines and Healthcare products Regulatory Agency (MHRA) regulates medicines, medical devices and blood components for transfusion in the UK. The Agency plays a leading global role in protecting and improving public health and supports innovation through scientific research and development. The MHRA is an executive Agency sponsored by the Department of Health. It has three centres:

-              The MHRA regulatory centre which is the UK’s regulator of medicines, medical devices and blood components for transfusion, responsible for ensuring their safety, quality and efficacy/effectiveness.

-              The Clinical Practice Research Datalink (CPRD), a data research service that aims to improve public health by using anonymised NHS clinical data.

-              The National Institute for Biological Standards and Control (NIBSC), a global leader in the standardisation and control of biological medicines.

MHRA and Genomics

7. Genomics England states that  genomics is “the study of the whole genome (the complete set of genes plus DNA between the genes) and how it works, but has also come to have a broader meaning to include the way that the genome is interpreted and the technologies that have been developed to help do this”.

8. Genomics therefore helps to understand how diseases develop, how to make earlier and more accurate diagnosis, which existing treatments will be most effective for groups of people with specific disease ‘subtypes’ and identifies new targets for future medicinal products.

9. MHRA regulation of genomics covers aspects of our work on standards as well as our regulatory work on devices and medicines which have positive impacts for human health, with regard to treating disease, avoiding genetic disease and human enhancement

10. The MHRA engages with genomics in three different ways, through:

• Medical devices
• Medicinal products
• Standards

Medical Devices

11. The number and range of medical devices is vast and includes healthcare products (other than medicines) used for the diagnosis, prevention, monitoring and treatment of disease, injury, or disability. This means everything from artificial hips to wound dressings, incubators to insulin injectors, software algorithms to diagnostic tests and scanners to scalpels.

12.  In general, a medical device cannot be marketed in Europe without carrying a CE marking. A CE marking is applied by the manufacturer and means that the device meets the relevant regulatory requirements and, when used as intended, works properly and is acceptably safe.

13. For lower risk devices, manufacturers may self-certify but higher risk devices must be verified by an independent certification body, called a Notified Body, before the CE marking can be affixed. The MHRA is responsible for appointing UK Notified Bodies and regularly audits them to ensure that they perform to the required standards.

14. The MHRA regulates in vitro diagnostic medical devices (IVDs) including those that use genomic techniques. This might include equipment, assays, diagnostic kits and software for the detection of single nucleotide polymorphisms - SNPs - or for gene sequencing with associated bioinformatics.

15.  Clinical uses of genomics IVDs might include:

•Predicting the likelihood of disease

•Prognosis of some diseases including cancers to help determine progression

•To suggest options for treatment based on genomic profile for example by using in vitro diagnostic tests for:

•ERBB2 (HER2) gene amplification/over-expression in patients with breast cancer,

•the ‘Philadelphia chromosome’ in patients with chronic myeloid leukaemia,

•‘wild-type’ KRAS gene in patients with colorectal cancer and

•mutations in the transmembrane conductance regulator (CFTR) gene in patients with cystic fibrosis).

•Near patient tests for infective agents and antimicrobial susceptibility.

•Predicting responses to specific drugs and in the development of targeted drugs using tests for known mutations.

•Personal genomics services which can give information on genetic traits, carrier status, drug response and disease risks.

•Invasive & non-invasive prenatal testing (NIPT) for a variety of clinical purposes including Down syndrome antenatal screening.

•Pre-implantation genetic testing.

16. MHRA regulates medical devices that are combined with medicinal products (including advanced therapy medicinal products ATMPs). For example a 3D matrix embedded with cells used for cartilage repair would be a combined ATMP which includes a device component (see paragraph 45-8 for further details).

Medicinal Products

17. A medicinal product is defined in legislation in Article 1,(2) a and b of EC Directive 2001/83/EC as (a) Any substance or combination of substances presented as having properties for treating or preventing disease in human beings; or (b) Any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis.

18. The range of diseases covered and the type of substances is vast. The active substances contained within medicinal products can have human, animal, vegetable and chemical origins including human blood and blood products such as coagulation factors for blood clotting disorders which represent some of the more ‘traditional’ medicines alongside vaccines. A large number of medicines are now produced using biotechnology techniques, examples being human insulin, one of the earliest medicines to be manufactured using these recombinant DNA approaches, and the increasing number of monoclonal antibodies such as Herceptin and other ‘targeted medicines’ which are discussed below.

19. The newest class of medicinal product are the ‘advanced therapy medicinal products’ (ATMP’s) which contain living cells and/or vectors for transfer of genes. These are discussed further below as they directly relate to the treatment of genetic disease by gene-editing.

20. A medicine cannot be marketed in Europe without being licensed, known as a Marketing Authorisation, an MA. This authorisation is obtained following assessment of each products’ quality, safety and efficacy which are obtained from clinical trials. Medicines, whether for clinical trials or those with a Marketing Authorisation have to be made to Good Manufacturing Practice (GMP) standard which is assessed on a regular basis by inspection typically at two year intervals. The evaluation of products and manufacturing sites is conducted directly by assessors and inspectors from EU national authorities such as the MHRA, which is the national competent authority for the regulation of medicines in the UK. The Marketing Authorisation means that the product meets the relevant regulatory requirements and, when used as intended, works properly and is acceptably safe. There are currently about 15,000 MA’s on the UK market.

21. Examples of targeted medicines include the following:

Trastuzumab (Herceptin) is a monoclonal antibody which specifically treats breast cancers that show ERBB2 (HER2) gene amplification/over-expression;  Imatinib (Gleevec) was developed to specifically target the BCR-ABL fusion protein expressed from the ‘Philadelphia chromosome’ found in commonly chronic myeloid leukemia.  Cetuximab (Erbitux) and Panitumumab (Vectibix), are monoclonal antibodies used for the treatment of metastatic colorectal cancer. These drugs specifically inhibit the epidermal growth factor receptor (EGFR). EGFR inhibition however is countered by activating mutations in the downstream KRAS protein, hence the drugs are prescribed only to patients whose tumours are wild-type for KRAS.

22. Medicinal products may directly influence functional aspects affected by particular mutations (loss of function mutations) as seen with Kalydeco in cystic fibrosis. Cystic fibrosis is a genetic disease caused by several mutations in the transmembrane conductance regulator (CFTR) gene resulting in poor regulation of fluid flow within cells and affects the components of sweat, digestive fluids, and mucus, typically affecting the lungs.  Ivacaftor (Kalydeco) is a "potentiator" of CFTR, and facilitates the defective channel to transport chloride ions in those patients with particular ‘gating’ mutations

23. Developments are underway for similar treatments for other genetic diseases such as Duchenne muscular dystrophy including exon skipping treatments or altering nonsense mutations. Translarna is one such product that makes ribosomes less sensitive to premature stop codons (referred to as "read-through") by promoting insertion of certain near-cognate tRNA at the site of nonsense codons thereby making a functional protein similar to the non-mutated endogenous product. 

24. Of the approximately 25,000 annotated genes in the human genome, mutations in over 3,000 genes have already been linked to disease phenotypes. One of the most advanced genetic therapeutic techniques developed thus far is gene-therapy, which generally involves addition of a therapeutic gene in a viral vector. Gene-editing offers the potential to directly correct genetic mutations in affected tissues and cells with high precision without the direct addition of a gene, potentially also improving the safety profile of existing gene-therapy products. This has significant potential to treat genetic diseases which have otherwise proved refractory to standard small molecule/biological treatments. From a regulatory perspective medicines based on gene-editing techniques fit into the existing regulatory framework for gene-therapy/biological products.

25. Gene-therapy medicines belong to the advanced therapy medicinal products (ATMP) category of medicines. Several gene-therapy medicines are currently licensed, and several are in development as discussed below. ATMP’s are broadly divided into somatic cell therapy, gene therapy, tissue engineered and combination products (medicinal product in combination with a CE-marked device).

26. Of the eight licensed ATMPs here are currently five on the market.[2]   One of these is Glybera, a gene therapy product for the treatment of lipoprotein lipase (LPL) deficiency, a rare autosomal recessive inherited condition leading to mutations in the LPL enzyme. Treatment consists of the administration of the gene for the functioning LPL enzyme which has been inserted into a replication-deficient viral vector. Glybera was the first ever gene therapy medicinal product in the Western hemisphere to be authorised.

27. Other gene therapy products that MHRA is involved in regulating include, Imlygic, for the treatment of melanoma, Zalmoxis, a gene therapy product consisting of genetically modified T cells with a retroviral vector encoding for herpes simplex I virus thymidine kinase (HSV-TK Mut2) as a “suicide gene” in order to “switch off” immune cells causing graft-versus-host disease in haematological stem cell transplantation in patients who have no matching donor for a stem cell transplant;  Strimvelis, a gene therapy intended for the treatment of patients with adenosine-deaminase-deficient severe combined immunodeficiency (ADA-SCID),containing CD34+ cells transduced with a retroviral vector containing the gene for adenosine deaminase.  The fifth ATMP currently on the EU market is Holoclar, a tissue engineered product consisting of stem- cells used to replace damaged cells on the surface of the cornea in the treatment of limbal stem-cell deficiency.

28.Genome editing is a rapidly developing area although there are no products yet on the market that have used gene editing methodology. Genome editing allows for the manipulation of DNA such that genes can be deleted, corrected or added. There are currently several variations on this relatively new molecular biology  technology, for example Transcription Activator-Like Effector Nucleases (TALENS) ‘TALENS’ and Clustered Regularly Interspersed Short Palindromic Repeats ‘CRISPR/Cas9’, in which a nuclease cuts the DNA at a specific sequence and repairs it via a guide RNA  (Ribonucleic acid)  template which can be used to introduce specific base alterations.

29. At a high level, these products are regulated in the same way as all other medicinal products with evaluation of quality, safety and efficacy of the product. ATMPs are also regulated under medicines legislation with specific provisions being brought in through the ATMP Regulation (see paragraphs 52 and 62).

30. There are a number of scenarios where genome editing could be used in the production/manufacture of medicinal products. Biological medicines, for example proteins including antibodies and vaccines, can be manufactured using genetically modified bacterial and mammalian cells lines where the gene for the protein of interest has been inserted into the host cell using standard recombinant DNA/genetic engineering  techniques – this is classical and successful methodology which has been used for many years already. These can be naturally occurring proteins such as human growth hormone or erythropoietin, or man-made proteins that do not occur in nature, e.g. insulin analogues or fusion proteins such Alprolix, a stable, synthetic construct comprising a human coagulation factor IX fused to a fragment of a human antibody, for patient with haemophilia B. Banks of these genetically engineered cells which carry the genetic material for the medicinal protein,  such as E.coli, containing human insulin and Chinese Hamster Ovary cell banks which carry the genetic code for the  monoclonal antibody Herceptin are used to start production in the Good Manufacturing Practice (GMP) manufacturing plant, where the cells are grown up in industrial-scale bioreactors and the expressed protein is subsequently purified leading to the final medicinal product. Genome editing techniques could therefore be used to modify the genes of bacterial and mammalian cells for the production of therapeutic proteins to further modify their structure, for example, making sugar structures added to them more “human-like”.

31.  Genome editing techniques could also be used in the production of genetically modified organisms which themselves could be used in the treatment of disease, for example genetically engineered bacteria used in dental treatments to reduce the incidence of cavities, or engineered gut bacteria to treat digestive or metabolic disorders. These would then be regulated as advanced therapy medicinal products under the current regulatory framework.

Standards

32. One of MHRA’s centres, NIBSC has a well-established programme of production of genomic reference standards for infectious disease. Through NIBSC, the MHRA will develop internationally recognised reference materials to aid the accuracy of DNA-based tests for the use of precision medicines, particularly in cancer treatment. Standards will also be made to aid the monitoring of efficacy of gene therapies.

33.  NIBSC’s involvement in the standardisation of genomic assays is not new, having produced genomic standards for infectious disease assays (Polio and HIV) for over 20 years. More recently WHO International Standards and CE marked nucleic acid external control materials have been produced for a variety of viruses including Ebola, JC virus, BK virus, Influenza, Norovirus and Zika, with an on-going program to address the standardisation of emerging diseases and syndromic pathogen detection. The institute has also played a key role in the development and application of DNA-sequencing-based assays to identify bacterial meningitis strains in disease outbreaks.

34. The programme of reference material production for human genomic assays began over 10 years ago and was borne out of a need to standardise the more complex assays for genetic diagnostics which had been demonstrated to have high error rates. This association with the genetic diagnostic laboratories led to NIBSC acting as active participant in the drafting of the OECD Guidelines for Quality Assurance in Molecular Genetic Testing. Recently standards have been made for complex leukaemia diagnostic and measurement assays for personalised medicine treatments, and this work continues in the development of standards for nucleic acid-based solid tumour diagnostic assays. NIBSC is now an established leader in the genomic standards having produced the first international genomic standards for both genetic disorders and cancer diagnostics.

B.  Legislation governing genomics and genome editing

35. Legislation including regulations and directives in this area are made at an EU level, with the active participation of Member States’ national authorities.

36. MHRA’s participation is based on understanding developed from early and on-going engagement with those working in these areas in order to bring innovation and new products speedily and safely to patients. The EU legislation is transposed into UK law as described below.

37. Legislation is supported by guidelines which are regularly updated based on scientific, technical and commercial developments. MHRA is responsible for regulating emerging technologies which sit within its jurisdiction. MHRA is involved in a dynamic process where regulation evolves alongside the science, to ensure that regulations which are responding to rapidly developing science are comprehensive and practical whilst ensuring products are safe.

38. It is important to note that there is separate legislation covering medicines and medical devices. Applicable EU Legislation associated with genomics/genome editing for medical devices and medicines are as follows:

a). Medical Devices Legislation

39.  UK regulation of medical devices associated with genomics is governed by the MHRA operating in accordance with European legislation for medical devices and in vitro diagnostic medical devices. The legislation that underpins MHRA’s work in the regulation of medical devices is:

•              the Medical Devices Regulations 2002 (SI 2002 No 618, as amended)

•              the General Product Safety Regulations 2005 (SI 2005 No 1803)

These safety regulations fall under the Consumer Protection Act 1987.

40. The Medical Devices Regulations 2002 are the UK umbrella under which the following three European directives are transposed into UK law:

•              Directive 90/385/EEC active implantable medical devices

•              Directive 93/42/EEC medical devices

•              Directive 98/79/EC in vitro diagnostic medical devices

In Vitro Diagnostic Medical Devices

41. The regulation of in vitro diagnostic medical devices (IVDs) is governed by the In Vitro Diagnostic Medical Devices Directive 98/79/EC. Article 1(2)(b) of the directive defines an IVD as;

‘any medical device which is a reagent, reagent product, calibrator, control material, kit, instrument, apparatus, equipment, or system, whether used alone or in combination, intended by the manufacturer to be used in vitro for the examination of specimens, including blood and tissue donations, derived from the human body, solely or principally for the purpose of providing information:

-              concerning a physiological or pathological state, or

-              concerning a congenital abnormality, or

-              to determine the safety and compatibility with potential recipients, or

-              to monitor therapeutic measures.’

42. The essential characteristics of an IVD are that it has an intended medical purpose in accordance with the above definition. Note that ‘intended purpose’ means the use for which the product is intended according to information provided by the manufacturer on the labelling, instructions for use and/or promotional materials of the product.

43.  IVDs should also be intended for use in vitro for the examination of a specimen derived from the human body where the specimen is never reintroduced into the body. IVDs are therefore regulated differently to those devices which, for example process blood and tissue donations where the blood or tissue will be reintroduced into the body.

44. Products for general laboratory use are not IVDs unless they are intended specifically by the manufacturer to be used for in vitro diagnostic examination of samples derived from the human body for the purposes outlined in the above definition and have specific characteristics which bring them within this definition.  .

45. Products which are intended to be used for research purposes only, without any medical purpose, are not regarded as IVDs and fall outside of the remit of the above directive. Additionally, tests intended solely for detecting drugs of abuse or alcohol for the purpose of law enforcement or for the detection of e.g. pathological agents in the environment are not IVDs.

CE marking

46.  IVDs falling under the above directive should be CE marked prior to being placed on the market or put into service.

‘Placing on the market’ is defined as making available the IVD in return for payment or free of charge (other than devices for performance evaluation) to the Community market.

‘Putting into service’ means the stage at which the IVD has been made available to the final user as being ready for use on the Community market for its intended use for the first time.

47.  Genomics tests including equipment, assays and software with an intended purpose that brings them within the definition of an IVD should be CE marked by the manufacturer when they are placed on the market in the UK.  Manufacturers wishing to market their products under this directive should ensure that the IVD meets the essential requirements of the directive and follow the appropriate conformity assessment procedure.  Once the manufacturer has fulfilled the applicable obligations of the directive, he should prepare and issue a declaration of conformity and apply the CE mark to the IVD. The CE mark represents the manufacturer's declaration that the product meets all of the relevant requirements of the IVD Directive.

48. The essential requirements aim to ensure that the products do not compromise the health and safety of patients and users, and are designed and manufactured to achieve the performance specified by the manufacturer for the stated medical purpose. In the context of genomic IVDs, the manufacturer’s stated medical purpose should be in accordance with the definition of an IVD and might include the detection of genetic biomarkers or it may extend to the diagnosis or prognosis of a clinical condition. There is no specific requirement in the IVD Directive for clinical utility or other health economic evidence as part of the CE mark. UK manufacturers should register the product with MHRA prior to placing their IVDs on the market.

Revision to the IVD Directive

49. These Directives are currently undergoing revision and will be incorporated into two new regulations on:

i)              medical devices

ii)              in vitro diagnostic medical devices.

34. MHRA anticipate that the revised regulations will be published in April/May 2017. These regulations will eventually replace the existing three medical devices directives.

50.  Manufacturers of in vitro diagnostic devices will have a five year transition period during which they can apply either the current Directive or the revised regulations, and a further period of up to two years where products certified under the current Directive can continue to be placed on the market, although there may be competitive advantages to marketing their products under the new regulation.

51. Although after the referendum on membership of the EU, we cannot predict which regulatory system the UK will adopt following Brexit, it is likely that the requirements set out here will be common across a range of regulatory systems.

b) Medicinal Products Legislation

52. Regulation of all medicinal products, including those which would use gene editing to treat diseases come under the following EU medicines legislation:

•              Directive 2001/83/EC – medicinal products for human use

•              Regulation 726/2004 – authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency

•              Regulation 1394/2007 - advanced therapy medicinal products (ATMPs) and amending Directive 2001/83/EC and Regulation 726/2004

•              Directive 2009/120/EC - amending Directive 2001/83/EC relating to medicinal products for human use as regards ATMPs

•              Directive 2001/20/EC – implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use.

•              Directive 2003/94/EC - laying down the principles and guidelines of GMP in respect of medicinal products for human use and investigational medicinal products for human use

•              Directive 2005/28/EC – principles and detailed guidelines for good clinical practice regarding investigational medicinal products for human use, as well as the requirements for authorisation of the manufacturing or importation of such products

53. The above Regulations and Directives have been transposed into UK medicines legislation through The Human Medicines Regulations 2012 and clinical trials through the Medicines for Human Use (Clinical Trials) Regulations 2004 [SI 2004/1031] on the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use.

54.  In addition to the above Directives and Regulations which provides the main framework and high level expectation, the medicines regulatory framework includes guidance documents which interpret the legislative requirements. The guidance documents are developed at an EU level to provide more detailed information and expectations and are developed and revised in shorter timelines than legislation. This is key for keeping pace with rapid scientific, technological and commercial developments. MHRA plays a key role in taking issues to the EU level (European Medicines Agency, EMA) for the creation or revision of guidance documents, which arise from problems encountered during assessment and inspection and from engagement with academia and industry.

55.  MHRA is the UK competent authority for medicinal products and regulates applications for clinical trial authorisations, national marketing authorisations and sites that conduct clinical trials, manufacturing and distribution activities.  MHRA also regulates non-clinical regulatory studies that must comply with good laboratory practice and pharmacovigilance activities for medicinal products. 

56. Forthcoming changes to the clinical trials legislation (replacement by Regulation 536/2014, expected to apply from October 2018) will not affect medicinal products in the context of genomics and genome editing. However, the new legislation allows for extended timeframes (a further 50 days) for assessment of ATMPs or products developed by means of one of the following biotechnological processes (a) recombinant DNA technology, (b) controlled expression of genes coding for biologically active proteins in prokaryotes and eukaryotes including transformed mammalian cells, (c) hybridoma and monoclonal antibody methods.

57. Article 9(6) of the 2001/20/EC Directive provides that no gene therapy trials may be carried out which result in modifications to the subject's germ line genetic identity. This prohibition is transposed through Regulation 19(3) of the Clinical Trial Regulation 2004/1031 which provides that the licensing authority shall not authorise a clinical trial involving products for gene therapy if the use of those products in that trial would result in modifications to any subject's germ line genetic identity.

58. The 2001/20/EC Directive is to be replaced and repealed by REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 16 April 2014 on clinical trials on medicinal products for human use. The preambles of this new Regulation make it clear that it is appropriate to maintain the provision in the 2001/20 Directive. Consequently Article 90 of the new Regulation provides that no gene therapy clinical trials may be carried out which result in modifications to the subject's germ line genetic identity. The implementation timeline for the EU Regulation is that it will become applicable six months after the European Commission publishes a notice of confirmation that the EU clinical trial portal and database is fully functional. This is likely to be during 2018.

59. A further marketing authorisation procedure exits, the centralised procedure, which is mandatory for certain types of medicines which includes ATMPs and therefore products manufactured by genome editing. Almost all new active substances are now authorised through the centralised procedure. The centralised assessment procedure is coordinated by the EMA and the scientific assessment is conducted by national experts drawn from national authorities such as the MHRA. Details of the centralised procedure can be found on the EMA website at: 

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_001595.jsp&mid=WC0b01ac0580b18a3d

60.  Although technologies for gene editing are new for application in human medicines, the standard elements of medicines development and fundamental aspects of scientific evaluation still apply in order to assure the quality, safety and efficacy of the resulting medicinal products, so they fit within the existing legislative framework.

61. Medicinal products manufactured by genome editing to date have been classified as ATMPs, however future developments may include medicinal products manufactured by genome editing that are not ATMPs. However these would still fit into the current medicines regulatory framework (as biological medicines)

62. ATMPs comprise four main legal categories: somatic cell therapy, gene therapy, tissue engineered and combined ATMP’s. Combined ATMP’s “incorporate, as an integral part of the product, one or more medical devices within the meaning of Article 1(2)(a) of Directive 93/42/EEC or one or more active implantable medical devices within the meaning of Article 1(2)(c) of Directive 90/385/EEC” (or the equivalent text in the revised devices legislation. The device component of a combined ATMP must be able to meet the essential requirements of the relevant device directive.

63. Although gene editing could result in products in either somatic cell therapy or gene therapy or their combined equivalents, of the first two ATMP categories, experience to-date is of somatic cell therapy products.

64. Where a medicinal product contains or consists of a genetically modified organism (GMO), Directive 2001/83/EC and regulation 726/2004 require that the applicant evaluates the potential risk of GMO containing medicinal products to the environment. This includes gene-therapy products. Therefore an application for marketing authorisation of a medicinal product for human use must be accompanied by an environmental risk assessment (ERA), performed in accordance with the principles of Annex II of Directive 2001/18/EC (Deliberate Release Directive). The MHRA conducts the initial assessment and presents this to the DEFRA/HSE Advisory Committee on Release into the Environment (ACRE), who are the UK competent authority for deliberate release into the environment.

65. As with other types of medicinal products there are a significant number of guidance documents covering key aspects of the development of ATMP’s, for example ‘Note for guidance on the quality, non-clinical and clinical aspects of gene transfer medicinal products (CHMP/GTWP/671639/2008) and the ‘guideline on human cell-based medicinal products (EMEA/CHMP/410869/2006)

66. Guidance documents for ATMP’s can be found at the following link:

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000298.jsp&mid=WC0b01ac05800862bd

C. MHRA’s current engagement with genomics and gene editing

I. Risk Categorisation for devices

67. Currently the IVD Directive includes different categories of risk which determine the level of regulation. The majority of IVD devices are self-certified by the manufacturer, requiring them to register with their Competent Authority and hold all relevant data to support the CE marking of the device.  IVDs in higher risk categories (i.e. those listed in annex II of the IVD Directive such as tests for blood grouping and blood borne viruses) are required to be audited by a third party independent certification organisation (a notified body) who will issue the CE certificate upon satisfactory review.

68. A notified body is an entity that has been designated by a Member State to assess whether a medical device to be placed on the market meets the necessary requirements. MHRA is the designating authority for UK notified bodies.

69. The current list of higher risk IVDs generally includes tests for a specific clinical condition so does not specifically include or exclude genomic tests. Whether they are biochemistry-based or genomic, tests and software for the risk evaluation of trisomy 21 are included in the annex II list. Some tests for infectious diseases listed in annex II will also use molecular techniques (eg nucleic acid testing for HIV and hepatitis B and C virus) and so would require scrutiny by a notified body. However, for most genomic tests, the manufacturer must fulfil the applicable obligations and must declare and ensure that the device meets the provisions of the Directive which apply without the intervention of a notified body. A manufacturer may choose to use a quality management system which will be audited by an accredited body. 

70. Once an IVD is intended by the manufacturer to be used for medical purposes it must either fall under the category of a product undergoing performance evaluation for the purpose of CE marking or be a product which is CE marked. Performance evaluation means an investigation of the performance of an IVD based upon data already available, scientific literature and clinical or laboratory studies. The manufacturer of an IVD must undertake a performance evaluation to verify that the IVD meets the analytical and clinical performance requirements of the Directive. Once these have been successfully completed the IVD may be CE marked.

71. In 2009 the House of Lords report[3]  recommended that IVDs for genetic conditions should be reclassified into a higher risk category within the IVD regulations.

72. Under the new regulations, genetic tests will be in a higher risk classification and therefore the evidence supporting test performance will be scrutinised by a notified body prior to the test being placed on the market or put into service. As now, human genetic tests providing information on the predisposition to a medical condition or disease will need to meet all of the safety and performance requirements of the regulations.

II. Companion diagnostics

73. Companion diagnostics are IVDs that are essential for the safe and effective use of a corresponding medicinal product. Such tests may be intended to stratify patients in clinical trials or to select patients for treatment. Many of these IVDs use genomic technology or measure markers of gene expression. The IVD Directive does not include a definition of ‘companion diagnostics’ and so there are no additional requirements for performance evaluation or conformity assessments of these tests. Companion diagnostics, however, should meet all the relevant requirements of the IVD Directive.

74. For IVDs (including companion diagnostics) to be used to stratify patients in a clinical trial, the IVD should first be CE marked. An IVD may also be part of a performance evaluation study during a clinical trial, but if the IVD does not have a CE mark it cannot be used to stratify patients for the purposes of selecting treatment, or including/excluding from the trial.

75. The new European legislation will bring in a new definition and a new conformity assessment route for companion diagnostic tests. Prior assessment of clinical performance studies will be needed before the start of the study and prior scrutiny by a notified body and a medicines authority will be needed before the IVD can be CE marked.

III. Use of genomic tests in clinical trials of medicinal products

76.  Clinical trials of medicinal products can include the use of a genomic test to stratify patients.

77. Under the current directives, any test where the results would be used to influence the treatment of any patient, either in prescribing a particular drug or to amend the treatment of a patient participating in a trial would be considered to be an in vitro diagnostic medical device and should be CE marked unless covered by an exemption (e.g. for health institutions).

78. This includes any test intended to be used to determine the inclusion or exclusion of an individual patient from a specific clinical trial. However, tests undertaken in the context of clinical trials, where there is no intention to provide information on individual patients or amend the treatment of the individual patients within the context of the clinical trial would not be considered to be IVDs, but rather products for research use only.

79. Thus a test intended to predict a response to a specific drug would be likely to be considered to be an IVD, since it would be likely to be used to determine whether or not the specific drug will be prescribed to a specific patient. On the other hand, tests undertaken to provide information to the company undertaking the clinical trial, where the data is not used in any way to determine or influence the treatment of a patient and is primarily an information gathering exercise for use in potential next stage trials would be unlikely to be considered an IVD.  This is because products used specifically for research purposes only are not considered to fall within the remit of the IVD directive: tests involved in clinical trials in this context (i.e. where there is no intention for the information gained to be used with relation to individual patients) may therefore be deemed to be for research use.

80. The new IVD regulations include provisions for competent authorities to review applications for interventional clinical performance studies such that an IVD in early stage development could be used within a clinical trial of a new medicinal product before it has a CE mark.

81. The planned new regulations will include a clarification that the performance claims made by manufacturers should be underpinned by evidence from evaluation studies. Where the manufacturer makes a clinical claim then that should be supported by evidence from clinical studies.

•              The performance characteristics described in the new regulations include:

•              analytical performance (the ability of a device to measure the analyte),

•              clinical performance (the ability of a device to yield results that are correlated   with a clinical condition) and

•              scientific validity (the association of an analyte to a clinical condition).

IV. Testing services and the health institution exemption for ‘in house manufacturing’.

82.  In both the existing IVD Directive and the planned IVD regulations, there are provisions for health institutions to be exempt from the requirements of the regulations.

83.  A health institution is a body whose primary purpose is the care and/or promotion of public health - for example NHS trusts, NHS Blood & Transplant and private hospitals (provided that the primary purpose of the hospital is the care and/or promotion of public health). Free-standing laboratories that provide diagnostic services do not qualify as health institutions.

84. The IVD Directive also applies to those devices that are put into service without placing that device on the market: devices that are manufactured and used in a professional testing service are covered by the Directive even if the device itself is not placed on the market. IVDs that are placed on the market or put into service are regulated by the MHRA, but testing services themselves are not.

85.  Health institutions may develop/ manufacture products to be used only within the same health institution. The Directive includes an exemption for health institutions. IVDs which are used within the same health institution in which they are made are exempt from the requirements of the IVD Directive, but should conform with guidance published by the MHRA. This is practice is known as “in-house manufacturing”. and includes genomic IVDs used in clinical trials of medicinal products.

86. This is a blanket exemption which applies where a health institution manufactures an IVD in-house and then uses that IVD on the premises of manufacture (or on premises in the immediate vicinity) provided that the use of the IVD is intrinsic to the operation of the health institution, and not for some extraneous purpose that does not form part of the health functions of the institution.

87. Furthermore, products used in testing services (including direct to consumer genomics and data analysis services) which are offered from outside the EU are not covered by this legislation and therefore do not require CE marking.

88. The revised EU regulations will include a specific exemption for devices that are manufactured and used within a single health institution. Health institutions may manufacture, modify and use a device ‘in-house’, in order to target a patient group’s specific needs which cannot be met at the appropriate level of performance by an equivalent device available on the market. In order to apply the exemption, the health institution must meet all of the safety and performance requirements of the regulations but will not need the product scrutinised by a notified body before being put into service, nor will they be required to CE mark the device. Instead, the health institution will need to have a quality system in place and be able to justify the exemption. Some information about the exempted device will be made publically available.  Each Member State has the option of applying stricter provisions for certain aspects of ‘in house’ manufacturing as it deems appropriate.

89. The proposed new IVD regulations outline specific requirements for products used within testing services that are provided via ‘distance sales’. Any devices used in the context of a commercial activity for the provision of a diagnostic or therapeutic service offered by means of information society services (i.e. a commercial website) whether in the EU or elsewhere are required to comply with the regulations.

V. Software

90.  Standalone software including algorithms can be qualified as a medical device or in vitro diagnostic medical device . If the standalone software only collects results obtained from one or more IVDs and transmits this information without modification, it would not be considered an IVD.. Software generally will be more explicitly included in the revised IVD regulations and for genomics this includes the complex data processing software algorithms and bioinformatics pipelines used in next generation sequencing. However data and databases are not included in the regulations unless they are placed on the market or put into service as an 'accessory’ to an IVD.

91. Some software intended to provide information which is used to take decisions with diagnosis or therapy, or monitor physiological processes will be reclassified into risk categories that require notified body involvement  in the new regulations.

92. As with many types of software, the complex clinical algorithms used in genomics are designed to rapidly evolve during the lifetime of the product with regular updates and changes. Artificial Intelligence and machine learning algorithms will evolve with similar speed. Gene panels and genetic databases intended to identify clinical variants will also change over time as more evidence emerges from clinical research. Product developers should be able to demonstrate that they are able to evolve their products to ensure that each new version is safe and effective and performs as intended. Although most updates would not be considered a significant change, where the new version is considered a significant change and a notified body is involved in the CE marking of the device then this will need to be agreed in advance with the notified body.

93. General principles for the quality assurance of processes for the re-validation and verification of rapidly evolving software algorithms, their interoperability with any systems used in combination and the need to identify, correct and contact anyone affected by safety problems will need to be established from the outset as a baseline. This will act both as an assurance of safety and to facilitate and limit regulatory intervention.

94. MHRA will need to adapt and develop procedures to meet this changing environment

VI. Precision medicines   and the use of genome targets .

95. There are several options for developing targeted medicines based on genomic traits( see also section 20-23). These include, identifying genetic/ genomic markers as targets for medicines (monoclonal antibodies such as Herceptin, cetuximab) or products offering benefit in gnomically specific populations based on specific variations or mutations  (Olaparib for BRCA + ovarian cancer, or vemurafenib for V600E + melanoma, ivacaftor for cystic fibrosis patients with CFTR mutations). More advanced genomic targeted therapies such as exon skipping treatments (e.g., for Duchene dystrophy) are evolving. These are regulated under medicines legislation with some under ATMP legislation as applicable including the genomic components. Devices Regulations apply to the diagnostic/ companion diagnostic part where applicable.  As the molecular basis for diseases becomes better understood, diseases will be reclassified, treatments more targeted with the potential to make significant progress in improving the risk benefit of treatments, and with significantly improved outcomes.

VII. Gene editing and ATMPs.

96. Within the MHRA experience with genome-editing has been in the area of ATMP’s. The main approach to development of gene-editing-based ATMP’s at this point is  in the modification a patient’s own cells (ex vivo) for production of specific proteins.  There is ongoing research into the usage of the guide RNA and nuclease in a medicinal product for direct delivery to target cells within the body. Key broad areas where activity at the research, pre-clinical and clinical trial level is currently being conducted include antiviral strategies, cancer immunotherapy (such as chimeric antigen receptor CAR-T cell therapy) haematological disorders, liver-targeted gene editing, neuromuscular disorders, skin and eye disorders, respiratory disorders and also antimicrobials. Several phase I trials have been completed, mainly for HIV treatment and one for recurrent/refractory malignant glioma using a gene-edited T cell. Several more are currently undergoing trials in this new but rapidly developing field, one of which was recently approved by the MHRA for use in patients with relapsed or refractory B-cell acute lymphoblastic leukaemia, published at:

http://www.gosh.nhs.uk/news/press-releases/2015-press-release-archive/world-first-use-gene-edited-immune-cells-treat-incurable-leukaemia

97.  In addition, MHRA and DH met with group of European MPs on a fact finding mission on the subject of emerging biotechnologies with a focus on the CRISPR-Cas9 system for targeted genome editing.

98. MHRA is therefore very aware of a number of situations where gene editing techniques could be used, or are actively being used towards human medicine applications. At a high level, they will be regulated in the same way as all other medicinal products, taking in to account the specific safety and efficacy issues such products may pose. This includes the assessment and inspection on the controls in place of the genome editing materials and equipment used in the manufacture and testing of the medicinal products (manufactured to GMP) and a positive benefit-risk assessment based on quality, safety and efficacy. The existing rules and regulations for genetically modified organisms would also apply to products manufactured using genome-editing techniques.

VIII. Gene-editing and Genomic Standards programme

100.  NIBSC is in the process of generating standards for common cancer gene mutations which will facilitate the determination of limits of detection and cancer cell quantification in both conventional tumour biopsies and liquid biopsies through the analysis of cell-free tumour DNA in the blood. This will help guide personalised medicine treatments and also help determine the level of treatment success.

101. As well as exploiting cell lines derived from tumours, gene editing techniques will be used to generate mutations in cell lines for the production of cancer genomic standards. 

102. Standards may also need to be produced in the near-future to enable the measurement of efficacy of gene-editing patient treatments such as likely treatments for diseases of the blood such as the haemoglobinopathies and haemophilia.

Gene therapy

103. In 2016 the WHO approved the development of a lentiviral gene therapy standard at NIBSC to facilitate the measurement of numbers of cells modified by gene therapy within patient tissue.

D. The role of the MHRA in ensuring the safe regulation of genomics and gene editing

104. One of MHRA’s priorities is to balance the bringing of innovation speedily whilst ensuring the safety of medicinal products and medical devices to the UK Market. In a new and rapidly evolving area such as genomics, this is of particular importance. Regulations regarding this are distinct to both devices and medicines.

Pre and post-market safety for medicinal products

Premarket safety for medical devices including IVD’s

105. Within the devices regulatory system, premarket safety is primarily the responsibility of the manufacturer with notified bodies providing scrutiny for higher risk devices and competent authorities managing the regulatory system by designating the notified body. As already mentioned there is currently little role for notified bodies or competent authorities in the premarket scrutiny of most genomic tests or accompanying algorithms/apps but this will change in the new regulations where genetic tests and some algorithms/apps will have a higher risk classification, thereby needing to be certified by a NB.

Post market safety for medical devices

106. In line with the importance MHRA places on public health and safety, part of MHRA’s role as Competent Authority for medical devices and IVDs is to receive reports of adverse incidents and corrective actions involving those devices.  MHRA also exchanges information regarding these reports with Competent Authorities across the EU and other regulators internationally.

107. An adverse incident is defined in the IVD Directive as:

“any malfunction, failure or deterioration in the characteristics and/or performance of a device, as well as any inadequacy in the labelling or the instructions for use which, directly or indirectly, might lead to or might have led to the death of a patient, or user or of other persons or to a serious deterioration in their state of health”

108. Examples of adverse incidents include:

-              a patient’s treatment being interrupted because of a faulty device;

-              misdiagnosis because of an incorrect result obtained with a genetic test

-              .Patients receiving an incorrect drug because of an incorrect result

109.  Under a system known as “Vigilance”, all manufacturers are required to report adverse incidents involving their medical devices to the Competent Authority where the incident happened.  There is also a requirement to report corrective actions taken to reduce the risk of, or prevent, adverse incidents.

110. There is also a voluntary reporting scheme in the UK known as Yellow Card, which enables healthcare professionals and other users of medical devices to report problems to MHRA.  The Yellow Card scheme is vital in helping the MHRA monitor the safety of all healthcare products in the UK to ensure they are acceptably safe for patients and those that use them.

111. Users are encouraged to report any medical device related problems under the Yellow Card scheme, not just those which meet the formal definition of an adverse incident.  These user reports are made available to the manufacturers, and where they meet the definition of an adverse incident a Vigilance report is required

112. The MHRA assesses and investigates safety issues and monitors the investigation of incidents carried out by manufacturers and takes further action if necessary to supplement the actions of manufacturers.  If sufficiently early and urgent the MHRA will disseminate further information to UK’s healthcare system in the form of Medical Device Alerts if there is evidence of a systematic problem which might lead to further adverse incidents.  Medical Device Alerts are issued via the Department of Health’s Central Alerting System (CAS), which is a web-based cascading system for issuing safety critical information and guidance to the NHS and others, including independent providers of health and social care. 

113. MHRA also gathers intelligence to identify signals which are defined as “information received from any source which indicates that a device may be associated with a previously unrecognised hazard, or that a known hazard is quantitatively or qualitatively different from existing expectations.”

114.  A signal may be identified from a single report, or a collection of reports, or other information which indicates an apparent potential for adverse incidents to occur.  The latter can be identified from a range of sources including registry data, journal articles, and anecdotal reports such as those received via press or social media. Signals would then be reviewed, further investigated as required, and advice/corrective action communicated as necessary. As with adverse incident reports, possible outcomes of a signal investigation include the manufacturer taking corrective action, and MHRA issuing safety guidance to users.

115. MHRA is not currently aware of any adverse incidents involving genomics IVDs, nor have any signals been identified.

Pre and post-market safety for medicinal products

Pre Market Safety for Medicinal Products

116. Safety of medicinal products should be ensured as far as possible. Safety is the responsibility of the manufacturer of the medicinal product and forms a major part of the regulators benefit-risk assessment upon which a product’s approval for licence is based. Safety is also monitored post-approval according to the pharmacovigilance system/risk management plan. Safety includes issues relate to product manufacture and clinical use, for example absence  of adventitious agent contamination and removal of toxic product and process-related impurities, potential for immune reaction and ‘off-target’ effects leading to serious adverse events.117. Aside from the general safety of any medicinal product, because of their novelty, complexity and technical specificity, ATMPs including therefore gene-editing approaches for the targeted treatment of diseases with a genetic basis may bring new, previously unseen risks to public health and individual patients.

118. The most significant safety issue for gene-editing are so-called ‘off-target’effects which could result from lack of specificity of the nuclease ‘homing’ to the ‘wrong’ gene, which could therefore potentially damage unintended sequences. This is similar to the key safety issue known as ‘insertional mutagenesis’ for current gene-therapy products, where some of these technologies use viral vectors which integrate into the host genome. The chances of insertional mutagenesis leading to phenotypic effects is considered to be very rare, however it has happened,  with serious consequences  where insertion effects a proto-oncogene; a gene linked to cancer (‘insertional oncogenesis’)

119. One such widely reported incident involved a patient in a clinical trial for the treatment of SCID who developed leukaemia through insertional oncogenesis involving the retrovirus used for the gene transfer.  Other such instances have been reported in trials for Wiskott-Aldrich Syndrome  and Chronic Granulomatous Disease (CGD) where malignancies have developed several years later which were linked to the gene therapy (‘Reflection paper on management of clinical risks deriving from insertional mutagenesis’ EMA/CAT/190186/2012).  Many patients have been treated in gene-therapy clinical trials involving integrating vectors without vector-triggered cancer and improvements continue to be made to vector design  to reduce still further the likely hood of this occurring. Several products are marketed so the benefits were determined to outweigh the risks for those products.

120. It is however considered that for gene correction/gene replacement strategies using gene-editing the risk of insertional oncogenesis is conceivably the lowest with respect to conventional approaches with integrating vectors, especially as most therapeutic approaches using gene-editing are administering cells with pre-edited DNA and thus also not administering a viral vector.

121. The specific safety issue depends on the precise nature of the product being administered and must therefore be taken into consideration during development of the product. For example cells where genome-editing has been employed will need to show genetic stability, lack of tumourigenicity and also incorporation into the intended location in vivo. ‘Shedding’ is also an issue for gene therapy products, i.e. the dissemination of vector/virus to the environment through secretions and/or excreta.

122. Safety assessment forms an essential part of clinical trials and medicinal product authorisation. There are numerous guidelines for the safety assessment of ATMP’s which developers should  comply with for example ‘guideline on non-clinical studies required before first clinical use of gene therapy medicinal products’ (EMEA/CHMP/GTWP/125459/2006) and ‘reflection paper on management of clinical risks deriving from insertional mutagenesis (CAT/190186/2012). For further guidance documents see

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000298.jsp&mid=WC0b01ac05800862bd

123.  In addition to careful product design, animal studies and in vitro testing form essential parts of a product’s safety profile , prior to first-in-man studies. Although the risks are likely reduced using gene-editing approaches this is still not to underestimate the scientific challenges involved in demonstrating safety regarding potential ‘off-target’ effects.

124. ‘Off-target’ effects for current gene therapy products usually takes years to appear (cancer for example) . So long term patient follow-up and post marketing surveillance are particularly important compared to more ‘traditional’ pharmaceuticals such as small molecules and biotech products where adverse events are more immediate. This will also be the case for treating disease using gene-editing (see below for more on post-market surveillance) .

125. Medicinal products are only allowed where changes are made to non-reproductive cells so that the change is not inherited by future generations. There is a prohibition on the editing of germline cells (sperms, eggs, early stage embryos) which would result in inheritance of gene modifications and preclinical studies are required to be conducted to demonstrate that inadvertent germline integration does not occur. Requirements on this are contained in the Clinical Trial Directive 2001/20/EC and its successor Regulation 536/2014, it is also in the main medicines Directive 2001/83/EC. These have been transposed into UK law through The Human Medicines Regulations 2012 (2012/1916) and the Medicines for Human Use (Clinical Trials) Regulations 2004 (2004/1031).

Post Market safety for Medicinal Products

126. Manufacturers are required to submit a Risk Management Plan with every new marketing authorisation application and this must be approved by regulators prior to granting a licence. The RMP summarises all available safety information generated in support of the licence and uses this to identify what the important known or potential safety concerns are, what gaps in knowledge of the safety profile are, what known risks or benefits may need further characterisation through a post-authorisation safety or efficacy study, and whether any measures are needed to minimise risk to the patient.  Examples of risk minimisation measures include controlled distribution systems or training and education for healthcare professionals and/or patients/caregivers.

127. The safety concerns associated with an ATMP product will depend on the precise nature of the product and are not normally a consideration with other medicinal products e.g. risks to living donors, risks of germ line transformation and transmission of vectors.  Careful consideration is therefore given to any possible safety implications for patients, which could include: risks to living donors, or to patients in relation to the quality characteristics of the product, the storage and distribution of the product, the administration (and re-administration) procedure, for ATMPs at the time of authorisation and so there may be a need for long-term follow-up of efficacy and safety post-authorisation.  This may be particularly relevant for ATMPs that incorporate living organisms, tissue-based ATMPs and cell therapy products that have a limited life-time (and so may need re-application). The nature and duration of safety follow-up is considered on a case by case basis but it is recognised that for some ATMPs, particularly products developed through genomic technologies and genome editing, very long-term or even life-long follow-up of patients is required.  This will be factored into the product’s Risk Management Plan and the emerging data evaluated on an ongoing basis.

128. Manufacturers are required to record any adverse reactions to an advanced therapy as for all medicinal products and notify the MHRA of any suspected serious adverse reactions within 15 days of becoming aware of the suspected ADR. Patients and healthcare professionals can also report suspected ADRs through the Yellow Card Scheme, as described in paragraphs 110-11. All reports should provide the product name and batch number, if this is not provided from the outset these details should be requested via follow up with the reporter.

129. Traceability of ATMPs using unique identification numbers is particularly important to link use of a specific ATMP product to ADR reporting, and to ensure the correct patient is treated with the correct product.

130. All ATMPs would be on the European Additional Monitoring list which means they are subject to close monitoring.  Within the MHRA each ATMP would be assigned to a specific pharmacovigilance assessor who would be responsible for evaluating the RMP and monitoring its safety in the post-marketing environment. Each ADR reported to the MHRA would be reviewed by that assessor who may request further details from the reporter to enable a causality assessment to be performed. 

131.  In the event that a new safety ‘signal’ is identified and confirmed upon further evaluation, all EU member states and the EMA are notified. All confirmed signals are considered by the European Pharmacovigilance Risk Assessment Committee (PRAC) which makes a recommendation for action, to be implemented by the manufacturer.  Depending on the seriousness of the risk a wide range of actions may be recommended including: no action; an update to product information; initiation of a study; distribution of educational materials; or suspension/revocation of the marketing authorisation.

132. Depending on the urgency, importance and nature of the issue, and the target audience a number of options for communicating safety concerns with healthcare professionals and patients exist.  Urgent messages can be communicated to the healthcare network through the CAS (see paragraph 112).  This can be supplemented by a press release, a press briefing, information on the MHRA’s website, use of digital and social media, and collaboration with relevant Professional Societies as appropriate, to help disseminate the message to a targeted audience.  For more routine drug safety messages the MHRA publishes an online monthly drug safety bulletin, Drug Safety Update (DSU) for healthcare professionals.  

133. The European Medicines Agency has published a Guideline on Safety and Efficacy, Follow-up and Risk Management of ATMPs, see: http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500006326.pdf

134. Due to the innovative nature and rapid development of technologies, long term follow up of products developed through genomic technologies and genome editing are essential.   The MHRA will monitor use of such products with investigation of any signal as required, take appropriate regulatory actions including restriction where necessary communicating the risk to public and healthcare practitioners. The processes will be essentially similar to the current techniques updated as appropriate.   It is recognised that close monitoring of gene therapy and genome editing is required in the future.

5. Continuing MHRA support for genomics and genome editing

135.  The MHRA is committed to supporting those developing new medicines and companion diagnostics, through mechanisms such as our innovation office, scientific advice and guidance. The MHRA seeks to build the capacity and skills to deliver a simple route map and support package for appropriate support to the academic and industry sectors to enable proportionate regulation of medicinal products and medical devices in innovative areas such as genomics and gene editing which will have a positive impact on human health and enhancement.

136. Regulators and other agencies will need to collaborate in adapting systems to ensure appropriate levels of scrutiny based on level of risk. The basis for such cross-regulatory collaboration is in place and is described below.

Identifying opportunities for further development and support

137.  MHRA has a cross-Agency Horizon Scanning Working Group which monitors and evaluates scientific, technological and commercial developments. This group informs the MHRA Board of high impact developments in order that the Agency can build its capacity and skills to deliver its strategic objectives – specifically in relation to public health protection and enabling the bringing of innovative new products to patients in a timely and safe manner. Gene editing and companion diagnostics are technology areas identified by this group where developments relevant to medical devices and medicinal products are tracked.

Supporting Innovation in the area of genomics

138. MHRA takes a proactive approach to engaging with academics, small and medium enterprises and organisations of all backgrounds and sizes to help develop innovative medicines, medical devices or novel manufacturing processes through a variety of means. These mechanisms include the Innovation Office (launched in 2013):

https://www.gov.uk/government/groups/mhra-innovation-office

139. The MHRA also provides regulatory and scientific advice through the ‘Regulatory Advice Service for Regenerative Medicines’ (RASRM) , also known colloquially as the ‘one stop shop’, which deals with queries about regenerative medicine and was launched in 2014. The latter provides single point of access from the public bodies in the field, the Human Tissue Authority (HTA), the Human Fertilisation and Embryology Authority (HFEA), Health Research Authority (HRA), National Institute for Health and Care Excellence (NICE) and the MHRA, who will  provide a co-ordinated single response service for free regulatory advice. In addition, the ‘one stop shop’ has arrangements in place with the Health and safety Executive (HSE) and Department for Environment Food & Rural Affairs (Defra) to provide joint advice on medicines which are also genetically modified organisms (GMOs). The MHRA national scientific advice service will provide a face to face scientific advice meeting for developers who want more detailed technical advice for the development of the products. The MHRA also partners with NICE to offer a joint scientific advice service to researchers or manufacturers.

140. General ‘regulatory advice’ meetings have been held for those at an early stage in their medicinal product development and the more detailed ‘scientific advice’ meetings with those at a later stage for the discussion of specific issues. The MHRA has offered this advice service for several years. In 2016, for example, the MHRA held 386 regulatory and scientific advice meetings. 

MHRA Engagement

141. MHRA has established a cross agency 'Genomics for Diagnosis' forum which brings together expertise from across the different  MHRA centres to establish common views with key external stakeholders

142. The MHRA also has a cross-agency ‘Advanced Therapies Forum’ with representatives from MHRA, NIBSC and The Department of Health to share information on the science and regulation of advanced therapies.

The future for regulation of genomics and genome editing

Whole Genome Sequencing-based diagnostics

143. The validation of whole genome sequencing as a diagnostic tool will require a level of pragmatism as it is not feasible to validate assay performance for every possible mutation at every position within the genome. The availability of reference materials for an assortment of challenging mutations will help towards this goal. NIBSC already has some reference materials for difficult-to-detect mutations and further reference materials will be produced for both rare disease and cancer diagnostics.

Epigenetics and Synthetic Biology

144. MHRA has seen several examples, some of which are described above, but from its own horizon scanning work (above), engagement with academia, and organisations such as MRC and with industry it anticipates very large and rapid growth in these areas. A related area of development for in vitro diagnostic tests and medicinal products is in the area of epigenetics. This term has various definitions one of which is “the set of modifications to genetic material that change the way genes are switched on or off but which don’t alter the genes themselves”.  Significant research investments are being made to develop medicinal products directed at epigenetic targets.

145. These are largely focused on the human genome. A broader view of genomics includes the study, new technologies and products that come from these activities from a variety of biological systems and processes, in other words synthetic biology, which along with genomics and regenerative medicine was identified as one of the eight great technologies. Synthetic biology can be regarded as an extension of the long established field of pharmaceutical biotechnology from which a large number of medicinal products have been authorised. However synthetic biology has a strong focus on the engineering aspect of genetic circuitry and genomes to improve the design of well-known cell based manufacturing of advanced therapy medicinal products and in vitro diagnostic medical devices

F. Conclusions

146. The MHRA recognises that the anticipated impact of such developments including gene sequencing devices, bioinformatics software, and genome targeted medicines and gene-editing technologies will be very large.

147. A significant number of targeted medicines have been approved over the last 10 years. Trastuzumab ( Her-2 monoclonal antibody) revolutionised breast cancer treatment in the early 2000s and since then the progress has been rapid. The cumulative incremental life-years saved because of first-line trastuzumab use from 1999 to 2013 in the USA alone has been estimated to be over 150,000.

148. In the 15 years since the introduction of Gleevec, the five year survival rate for people with chronic myeloid leukaemia has risen from ~30% to ~90%. Diagnosis and monitoring of patient response is performed by PCR analysis and accuracy is aided by the WHO Genetic Reference Panel for the quantitation of BCR-ABL translocation made at NIBSC.

149. The advent of Kalydeco for the treatment of cystic fibrosis patients with G551D mutation was a game changing step for several reasons; it engendered the concept of influencing gene function using pharmaceutical products, provided an opportunity to identify candidates for personalised treatment specific to their genetic profile( ie., targeting genetic disease based on the results of a diagnostic test), and brought home the idea of specific smaller clinical trials, an extreme form being n=1 clinical studies.

150. Major developments in gene sequencing and associated bioinformatics software bring new options for treatment and offer new options for the diagnosis of rare conditions and inherited disease as well as predicting clinical outcomes. The effectiveness of targeted treatments will however depend upon accurate diagnostics.  Accuracy is particularly problematic when biomarker measurement is involved and the production of measurement standards will be essential.

151. The MHRA also recognises the potential for further rapid development in these areas.  With clearer understanding of the molecular or genetic basis of diseases, the opportunity for reclassifying diseases is large resulting in better diagnosis of disease, more targeted approaches to diagnosis and treatment with the potential to make significant progress in improving outcomes particularly for diseases hitherto considered untreatable or undiagnosed.

152. As legislation evolves alongside rapid changes in technology, the MHRA continues to be active in meeting and shaping these requirements in order to bring these innovative products safely to market.

153. We anticipate significant developments in the area of genomic technologies influencing and benefitting public health and are actively pursuing innovative methods to work with, develop and monitor these new challenges and opportunities.