Version 8.0 19/11/2014

Study Title: NIHR BioResource - Rare Diseases

Date and Version No: 19/11/2014 Version 8.0

Chief Investigator: / Professor K. Chatterjee
Investigators: / Professor W.H. Ouwehand & Dr L. Raymond
Sponsors: / Cambridge University Hospital NHS Foundation Trust & University of Cambridge

AMENDMENT HISTORY

Amendment No. / Protocol Version No. / Date issued / Author(s) of changes / Details of Changes made
1.0 / 2.0 / 07/11/2013 / Prof W.H Ouwehand & Ms Sofie Ashford / 1.Addition of addendum 9.0 to include a new NIHRBR-RD project, Multiple primary malignant tumours
2.Addition of addendum 10.0 to include GeL pilot project.
2.0 / 3.0 / 16/01/2014 / Ms Sofie Ashford / 1.Addition of addendum 10.0 to include a new NIHRBR-RD project, Intrahepatic cholestasis of pregnancy
2.The option of a nurse/suitable qualified member of staff to provide home visits to obtain informed consent and collect samples.
3.0 / 4.0 / 12/05/2014 / Ms Sofie Ashford / 1.Three additional NHS sites to recruit to the GeL pilot
2. A letter to accompany GeL PIL/CF forms for NIHRBR-RD participants to enrol in GeL (this change is not detailed in protocol).
4.0 / 5.0 / 09/06/2014 / Ms Sofie Ashford / 1.Addition of addendum 12.0 to include a new NIHRBR-RD project, Cerebral Small Vessel Disease
2. An invite letter, PIL & CF form specific to the Intrahepatic cholestasis of pregnancy project.
3. A PIL/CF form specifically for Scottish NHS sites.
5.0 / 6.0 / 04/08/2014 / Ms Sofie Ashford /
  1. Ability to invite Adults lacking capacity, through gaining consent of Consultee (English sites)
  2. Withdrawal form, if participants no longer wish to be part of the NIHRBR-RD

6.0 / 7.0 / 17/09/2014 / Ms Sofie Ashford /
  1. Inclusion of an Electronic Data Capture Tool for recruitment of participants for the GEL Pilot Project
  2. Additional criteria and NGS-based testing platform for the Bleeding & Platelet Project
  3. Mention of a leaflet for clinicians to increase visibility of projects

7.0 / 8.0 / 19/11/2014 / Ms Sofie Ashford /
  1. Addition of addendum 13.0 to include a new NIHRBR-RD project, Neuropathic Pain Disorders (NPD).
  2. Addition of addendum 14.0 to include a new NIHRBR-RD project, Paediatric bone marrow failure syndrome (SMD).
  3. Update of inclusion criteria in addendum 3.0, Pulmonary Arterial Hypertension (PAH)

Study Protocol

Project Title: NIHR BioResource - Rare Diseases (NIHRBR-RD)

1.0 Rationale

Rare Diseases affect 1 in 17 individuals, which is a substantial proportion of the population. In order to continue discovering the cause of rare diseases that remain unidentified, a pool of consenting participants with specific rare diseases willing to participate in clinical research needs to be formed. Once formed these issues can be addressed:

  1. Identifying causal variants
  2. Reducing the delay in ascertaining a genetic diagnosis for inherited and acquired genetic disorders

This study will address these issues.

2.0 Objectives

The main objective is to establish a comprehensive BioResource of participants with rare diseases of unknown and known aetiology, and their relatives.The NIHRBR-RD has initial funding for a11,000 participant repository, with an application in progress of increasing this number to 15,000.

Recruitment to the NIHRBR-RD BioResource is driven by specific studies focused on priority themes of the NIHR Biomedical Research Centres:Infection & Immunity, Neuroscience, Cardiovascular Disease, and Rare Disease itself, including rare cancers, but it is foreseen that the remit will widen with time as to include a wider spectrum of rare diseases.

The NIHRBR-RD participants are willing to be approached to participate in further research studies, and are recallable.

2.1 Secondary Objectives

  • The purpose of recruiting groups of participants is to identify the cause of disease in those individuals, by using Next Generation Sequencing Techniques (NGST) to identify causal variants.
  • To improve the rate of diagnosis; through the development of NGST so that it can be used as a screening and, in the near future as a diagnostic test, removing the need for numerous, lengthy, traditional tests. More importantly traditional tests lack sensitivity and only detect a minor fraction of the DNA variants underlying the rare diseases
  • To perform subsequent studies to validate possible novel treatments (any subsequent Stage 2 studies would seek separate ethical approval, and approach participants for additional consent to be included in those studies).
  • Identifying biomarkers that are linked with Rare Diseases.
  • To use the outcome of the studies for health services research and to develop costing models under the Health Technology and similar funding schemes for use in NHS service innovation and pathology modernisation.

3.0Introduction:

3.1 Background

Rare diseases are defined as conditions which have an incidence of less than 5 in 10,000 individuals of the UK general population and thus affect ~3% of the population ( There are approximately 7,000 rare diseases of man and the genetics basis for about half of these has been resolved. Knowledge and identification of the cause of rare diseases has been highly successful in the past 6 decades when samples from families have been genetically and/or biochemically analysed. The task is far from complete with nearly halve of diseases not yet resolved. Since 2009 the rate of gene discovery for rare diseases has exponentially increased due to technological advances (mainly the introduction of NGST) and the challenge now is to identify the remaining causes of rare diseases, and to use this knowledge to improve patient care of those who have specific gene disorders and to understand the contribution of multiple DNA variants to more common conditions.

The National Institute of Health, European Commission, the Canadian Institute for Health Research and several other fund providers have established the International Rare Diseases Research Consortium (IRDiRC which aims to resolve the genetic architecture of remaining inherited diseases, increase the speed of diagnostic tests, and to carry out experimental medicine studies to find novel drug treatments. To this end the NIHR BioResource and Genomics England Ltd have been awarded funding from the National Institute for Health Research (NIHR), Department of Health and other fund providers for the clinical application of NGST. The application of NGST on samples deposited in the BioResource will be mainly used for the following categories of activities: (a) to reduce the delay in ascertaining a genetic diagnosis for inherited and acquired genetic disorders, where the genotype causing phenotype is known by developing NGST-based diagnostic tests covering NHS diagnostically-important genes, (b) to determine the genetic basis of inherited rare diseases, including rare cancers for which the causative locus has hitherto not been identified, but which have potential wider relevance for the common diseases that are the focus of NIHR-supported Biomedical Research Centres/Units (BRC/BRU) translational and experimental medicine research, (c) to ascertain carrier status in close relatives of the propositus.

The BioResource will be formed from thousands of consenting participants with a rare disease, and their relatives, who are willing to provide clinical information and samples that enable recall to studies by genotype and phenotype. The BioResource will collect, isolate, analyse and store DNA, RNA and other biological materials where available (e.g. plasma, serum, urine,etc.) to form a cohort of participants based on the phenotype of their rare disease.The BioResource will allow for the application of NGST, including whole exome sequencing (WES) and whole genome sequencing (WGS) in order to address points (a),(b) and (c) above. On occasions NGST will also be applied to sequence RNA which has been obtained from blood or one of its constituents or cells recovered from other samples (e.g. saliva, urine, etc.).

4.0 The NIHR BioResource – Rare Diseases funding and Organisational Structure:

The NIHRBR-RD has been awarded National Institute for Health Research (NIHR) funding.

The NIHRBR-RD has a local Director, Willem H. Ouwehand MD PhD FRCPath, Professor of Experimental Haematology, Department of Haematology, University of Cambridge and Honorary Consultant Haematologist NHSBlood and Transplant and Assistant Director, Dr Lucy Raymond,MA DPhil FRCP, Reader in Neurogenetics, Department of Medical Genetics, University of Cambridge and Honorary Consultant in Medical Genetics who are responsible for the NIHRBR-RD day to day running.

4.1 NIHR BioResource overall management

The NIHR BioResource (of which Rare Diseases is one arm) is managed by a Steering Committee (SC) which is responsible for establishing the fundamental values and ethical principles of the NIHR BioResource, as stated in the NIHR BioResource Operational Strategy. The SC has representatives from 6 Biomedical Research Centres (BRC) at Oxford, Cambridge, London (Imperial College, Guy’s and St Thomas’, South London and Maudesley, University College London Hospitals) and the Leicester Cardiovascular BRU, plus other future key partners. The SC meets quarterly and is chaired by Dr John Bradley (Director NIHR BioResource) and he is supported by the Assistant Director (Dr Nathalie Kingston) and a Director of Informatics (Dr Tito Castillo).

4.2 Applications to the SIC committee

The Sequencing & Informatics Committee (SIC) is one of the committees of the NIHR BioResource and is accountable to the NIHR BioResource SC. The SIC is responsible for the evaluation of sequencing projects for the NIHRBR-RD and approves projects which are meeting rigorous pre-defined scientific assessment criteria.

The SIC is in place to receive applications from clinicians-scientists who wish to apply for NGST capacity to sequence a group of NIHRBR-RD participants with a specific rare disease. A project application (form attached- NIHR Bioresource Whole Genome Sequencing_Request-form_V4) is submitted by researchers to the SIC and is reviewed by all committee members. Projects are selected on scientific merit as to whether there is a likely identifiable genetic basis to the rare disease in the cohort and that the disease causation is tractable with a large sample size (e.g. n=1000). Projects where at least 3 BRC/BRU centres are collaborating will be prioritized as will priority themes of Infection and Immunity, Neuroscience, Cardiovascular Disease and Rare Diseases itself, including rare cancers as stated in the Operational Strategy of the NIHR BioResource. From time to time sequencing projects outside the NIHR BioResource priority themes will be considered by the SIC. The SIC hold regular meetings to ensure that the NIHRBR-RD is achieving its goals and protecting the health and welfare of the NIHR BioResource volunteers.

For each NGST project that is funded a lead PI is identified who is responsible for oversight and the delivery of the project. In addition to the lead PI there will be a Lead Clinical Investigator in each hospital in which participants are enrolled to that project. All projects will be covered by the overarching NIHRBR-RD ethics and projects will be added into the portfolio as funded.

Any researcher wishing to access participants of the NIHRBR-RD will complete a Stage 2 study request form or data access application indicating the nature of the research they propose and the proposed study design. These applications will be reviewed by the SC. One role of the SC will be to facilitate excellence in research and to support researchers in undertaking high quality Stage 2 studies and to provide assistance in optimising study design. It is responsible for ensuring that the research undertaken meets with the strategic direction of the NIHRBR-RD. The membership of the SC brings a breadth of expertise across the NIHR research themes in order to ensure thorough evaluation of all Stage 2 studies submitted for review.

4.4 Data Access

Genotypic data generated on DNA/RNA samples from NIHRBR-RD participants and the related clinical, including but not limited to laboratory, imaging and prescription data (phenotypic data hereafter) retrieved from hospital information systems and patient files will be initially archived by the University of Cambridge and NHS Blood and Transplant in distinct compute domains. Genotypic and phenotypic data will ultimately be transferred to the European Genotype-to-phenotype Archive (EGA) or a similar archive which will be developed by Genomic England Limited (GEL). GEL is the not-for-profit company wholly owned by the Department of Health, which is responsible for the delivery of the WGS of 100,000 NHS patients. Permanent archiving and sharing of all types of genetic and phenotypic data resulting from the NIHRBR-RD biomedical research projects will be according to strict protocols which govern how information is safely managed, stored and distributed. Here NIHRBR-RD builds on the extensive experience and expertise which has been developed by the Cambridge Biomedical Research Centre when developing the informatics infrastructure for the Cambridge BioResource.

Members of the Data Access Committee (DAC) will review requests from genuine researchers that wish to access archived data, which is stored in EGA or in GEL. Applicants have to register online and then apply to DAC for data, and then receive approval before data is made accessible to them. The DAC will be made up of members of the SIC, SC and other stakeholders where relevant.

5.0 Study Design

Flow chart of study

6.0 Study Criteria

6.1 Inclusion Criteria

The principle inclusion criteria are those that are stipulated by the purpose of the study:

- participants with rare disease (incidence of less than 5 in 10,000 individuals)

- relatives of cases with rare disease

- rare disease fitting into the NIHR BioResource priority themes (Themes will be reviewed from time-to time by SC)

- see addendum 1.0 to 12.0 for additional details

6.2 Exclusion Criteria

There will be no exclusion on the basis of age, sex, ethnicity, religion or sexual orientation. Participants with mental and learning disabilities are included provided they are deemed competent to consent. Adults lacking capacity as a consequence of Rare Disease (criteria of the rare disease fitting within a NIHRBR-RD project (see addendum)), may join, if a Consultee gives consent (this applies to NHS sites in England only, as our Scottish site runs a Cardiac project only, and the cardiac disorder does not affect the participants ability to give consent).

6.3 Identifying Possible Participants

Clinicians/clinical care teams including nurses, coordinators, genetics counsellors in BRC/BRU and NHS Foundation Trusts recruiting for the NIHRBR-RD with local R&D ethical approval in place, will search paper-based and electronic health records with the purpose to identify patients with a specific rare disease, and decide which patients are suitable to contact. This decision will be based on the inclusion/exclusion criteria (see addendum 1.0 to 12.0).

For the purposes of increasing awareness of the study and its projects among clinicians, a leaflet may be produced for some study projects (all leaflets will be sent to ethics for approval before circulation). Such leaflets will contain a summary of the study and the relevant project and the inclusion/exclusion criteria (see addendum 1.0 to 12.0) for the project.

7.0Methods of Approaching Participants

7.1 Face-to-Face

Clinicians/clinical care team staff members (nurses, coordinators, genetic counsellors and other appropriately trained staff)may approach participants during routine clinical care appointments(appointments the participant is attending for their rare disease). The potential participant will be given ethically approved Patient Information Leaflets (PIL) and consent forms, (if potential participant is a minor then consent will be sought from parents/guardian, and the minor provided with age banded PIL and an assent form).

Potential participants will have time to read and digest information, and ask any questions they may have regarding the NIHRBR-RD. Potential participants can decide to give consent immediately, or they may wish to have longer to consider taking part.

7.2 Post

Potential participants may have the recruitment pack posted to them by their clinical care team; this pack will contain the ethically approved “Letter of Introduction (with return slip)”, PIL, consent form & freepost envelope. Participants will have time to read through and digest the information, and then can choose to:

  • Return the slip to say they do NOT wish to be part of the BioResource (in which case they will not be contacted again)
  • Return the slip to say they agree to be contacted by a team member to find out more about the project
  • Return the slip to say they would like to be part of the BioResource & give written consent to participate.

The recruitment pack will also contain contact details for the clinical care team and the NIHRBR-RD BioResource team, so they have the option to phone either for further information. If patients or relatives initiate contact with the clinical care team or the NIHRBR-RD team then the recruitment pack, etc. will be dispatched and “question and answers” about the study can be reviewed in a face-to-face consultation or by phone.

8.0 Consent

8.1 Face-to-Face

Consent will be taken by experienced clinicians, study coordinators, nurses and other trained members of staff during face-to-face appointments. Potential participants and their relatives will be able to ask any questions they might have regarding the study after having time to read and digest the PIL. To give consent the participant needs to follow the instructions on the consent form, initial the boxes and sign and date the bottom section.

If a participant is a minor, parental/guardian consent will be requested and assent will be sought from minors.

If the participant is an adult lacking consent, consent would be sought from a Consultee. Typically this group of patients are accompanied by a parent/relative, and are regular patients of the consultant/clinical care team, that is considering inviting them to join (sites in England only). If the participant shows discomfort, or that they do not want to join, then this would not be pursued.