Inherited Retinal Disease (Australia) PSP Protocol

Purpose of the PSP and background

The purpose of this protocol is to clearly set out the aims, objectives, and commitments of the Inherited Retinal Disease Priority Setting Partnership (PSP) in line with James Lind Alliance (JLA) principles.

The JLA is a non-profit making initiative that brings patients, carers, and clinicians together to undertake a PSP. Priority Setting Partnerships identify and prioritise the evidence uncertainties, or ‘unanswered questions’, that key stakeholders agree are the most important for research in a specific topic area. The purpose is to identify the top 10 research priorities that can be used to drive the most meaningful research.

In 2012, a PSP was undertaken in the U.K. regarding “the prevention, diagnosis and treatment of sight loss and eye conditions”. This PSP provided research priorities for several conditions, including Inherited Retinal Diseases (IRDs). However, IRDs were not their primary focus and thus attracted a small sample size (27 patients, relatives, carers, representatives of organisations participated in the interim priority setting exercise; 11 patients, relatives, carers, representatives of organisations participated in the final workshop). Their top research priority was “Can a treatment to slow down progression or reverse sight loss in inherited retinal diseases be developed?”, which encompassed questions such as “How can sight loss be treated in people with an inherited retinal disease?” and “Is it possible to determine which inherited retinal diseases are likely to be treatable with gene therapy?”. Given the significant advancements in the last 10 years in the diagnosis, treatment, and care of individuals with an IRD, and the unique experiences of this cohort, our team advocates for the importance to undertake an IRD-specific PSP with an Australian population.

Inherited Retinal Diseases are the leading cause of blindness in children and adults of working age, affecting around 1 in 3,000 people. Individuals with an IRD can experience the onset of symptoms early in life, or as adults. Symptoms can also differ, depending on the type of IRD and patient. For example, Stargardt disease usually presents in childhood or young adulthood and leads to a loss of central vision, whilst peripheral vision typically remains intact. For individuals with rod-cone dystrophy/retinitis pigmentosa, the most common IRD subtype, symptoms typically commence in childhood with peripheral vision loss which progresses to involve central vision.

With the exception of voretigene neparvovec (a gene therapy for RPE65-associated retinal dystrophy), IRDs are currently untreatable, with patients experiencing significantly poorer quality of life than population norms. For young patients, the impact on quality of life can also extend to parents/caregivers. Regenerative medicine in the form of stem cell therapy and cell transplantation holds great promise for conditions like IRDs. This is because this type of therapy can be applied irrespective of the underlying genetic or acquired cause. Similarly, gene therapy is progressing well in this field due to the largely monogenic cause of IRDs (i.e., variation in a single gene causes the condition). However, current gene therapy relies on the patient having a molecular diagnosis and an approved therapy having been developed to address that specific genetic cause. Research into bionic eyes (electronic chip implants) continues, though the three devices which received regulatory approval (the Argus II (USA), the Alpha AMS/IMS (EU) and Pixium IRIS (EU)) are no longer produced. Given the uncurable nature of IRDs, the management and supportive care provided to patients and their families is integral to improve quality of life.

We will undertake our PSP in Inherited Retinal Diseases to ensure that our research efforts are as meaningful as possible to those that are impacted by it. This PSP is funded through the National Health and Medical Research Council (NHMRC) Medical Research Future Fund (MRFF) Stem Cell Therapies, and is led by researchers from the University of New South Wales (UNSW Sydney) and Children’s Medical Research Institute (CMRI), in partnership with a committed Steering Group who represent consumers, clinicians and researchers from across Australia.

The first Steering Group meeting took place on the August 1st 2023, and we propose that the final priority setting workshop will take place in July 2024.

Aims, objectives and scope of the PSP

The aim of this PSP, herein referred to as the Inherited Retinal Disease PSP, is to identify the evidence uncertainties about IRDs. These evidence uncertainties will be from the perspective of:

• patients, defined as individuals who are 16 years or older, diagnosed with any type of IRD (including syndromic IRDs such as Usher syndrome);
• guardians and family members (e.g., a parent, grandparent, sibling, or partner) who support an individual (of any age) with any type of IRD (including syndromic IRDs); and
• health and supportive care professionals, defined as those who have direct contact with the above defined patients in their role, and have a focus on addressing/supporting vision loss. This may include, but is not limited to:
   
  • ophthalmologists;
  • optometrists;
  • orthoptists;
  • general practitioners;
  • genetic counsellors;
  • clinical geneticists;
  • pharmacists;
  • nurses;
  • allied health professionals; and
  • teachers.

We will exclude responses from individuals impacted by age-related macular degeneration.

The scope of the Inherited Retinal Disease PSP includes questions about:

• IRDs, such as retinitis pigmentosa, and inclusive of syndromic IRDs (e.g., Usher syndrome);
• prevention of disease;
• diagnosis;
• disease progression and control;
• treatment and research into potential treatments;
• epidemiology; and
• management, which includes management of the physical, psychological, emotional, financial, and social aspects of living with an IRD, or caring for an individual living with an IRD.

While the scope of questions is quite broad, our cohort is small. Further defining the scope of Inherited Retinal Disease PSP may be required based on the number of submissions.

The Inherited Retinal Disease PSP will exclude questions that are about:

• Other aspects of syndromic IRDs, not focused on vision loss (e.g., hearing loss);
• Age-related macular degeneration; or
• Other eye diseases (even if they are concomitant with the IRD).

Following the collection of evidence uncertainties, we will:

1. Agree by consensus to the top 10 priorities;
2. Publicise the results of the PSP and process; and
3. Take the results to research commissioning bodies to be considered for funding, and relevant research and non-profit organisations.

The Steering Group

The Inherited Retinal Disease PSP will be led and managed by a Steering Group involving the following people who represent individuals with lived experience, patient advocacy groups, health professionals and researchers:

• Associate Professor Lauren Ayton: University of Melbourne; Centre for Eye Research Australia
• Leighton Boyd AM: Retina Australia; lived experience
• Hollie Feller: Usher Kids Australia; lived experience
• Dr Anai Gonzalez-Cordero: Children’s Medical Research Institute; The University of Sydney
• Julia Hall: Retina Australia
• Dr Kate Hetherington: UNSW Sydney; Sydney Children’s Hospitals Network – Randwick
• Professor Robyn Jamieson: Children’s Medical Research Institute; Save Sight Institute, The University of Sydney
• Sally Karandrews: Blind Citizens Australia; lived experience
• Dr Alan Ma: Sydney Children’s Hospitals Network – Westmead; Specialty of Genomic Medicine, University of Sydney
• Dr Meredith Prain: Able Australia; lived experience
• Emily Shepard: Usher Kids Australia; lived experience
• Matthew Simunovic: Save Sight Institute, The University of Sydney; Sydney Eye Hospital; Sydney Children’s Hospitals Network
• Kanae Yamamoto: Lived experience
• Eric Bohme: Lived experience

Individuals with lived experience will be remunerated $60 per one-hour of meeting attendance.

PSP Lead

The Inherited Retinal Disease PSP will be coordinated by Dr Eden Robertson, Behavioural Scientist, UNSW Sydney / Sydney Children’s Hospitals Network – Randwick.

James Lind Alliance (JLA) Adviser

The Inherited Retinal Disease PSP will be supported and guided by Louise Dunford.

Partners

Organisations and individuals will be invited to be involved with the Inherited Retinal Disease PSP as partners. Partners are organisations or groups who will commit to supporting the PSP, promoting the process, and opportunities to participate to their represented groups or members to participate. Organisations which can reach and advocate for these groups will be invited to become involved in the PSP. Some organisations may not solely support these cohorts (e.g., organisations that support a broader range of vision loss conditions). Partners from across Australia represent the following groups:

• People living with an IRD;
• Guardians or family members of individuals living with an IRD; and/or
• Health and supportive care professionals caring for individuals living with an IRD.

Exclusion criteria

Some organisations may be judged by the JLA or the Steering Group to have conflicts of interest. These may be perceived to potentially cause unacceptable bias as a member of the Steering Group. As this is likely to affect the ultimate findings of the PSP, those organisations will not be invited to participate as an official partner. However, they will be able to promote our PSP at their own discretion.

The methods the PSP will use

This section describes a schedule of proposed steps through which the Inherited Retinal Disease PSP will meet its objectives. The process is iterative and dependent on the active participation and contribution of different groups. The methods used in any step will be agreed through consultation between the Steering Group members, guided by the PSP’s aims and objectives. More details of the method are in the Guidebook section of the JLA website where examples of the work of other JLA PSPs can be seen. 

Step 1: Identification and invitation of potential partners

Potential partners will be identified through a process of peer knowledge and consultation through the Steering Group members’ networks. Potential partners will be contacted and informed of the establishment and aims of the Inherited Retinal Disease PSP and asked for their preferences regarding involvement. Partners will have the opportunity to participate as much or as little as they like, and supported in any promotion endeavours such as:

• webinars;
• conferences presentations;
• newsletter content; and
• videos.

Step 2: Awareness raising

PSPs need to raise awareness of their proposed activity among their patient, carer and clinician communities, to secure support and participation. This will predominately be done via social media, led by the PSP Lead, Steering Group members and Partners. Awareness raising has several key objectives:

• To present the proposed plan for the Inherited Retinal Disease PSP to a wide audience
• To generate support for the process
• To encourage participation in the process
• To initiate discussion, answer questions and address concerns.

Key milestones for raising awareness will be documented in a Communications Plan to ensure that the PSP is promoted as widely and effectively as possible. These milestones include:

1. PSP Launch
2. First Steering Group Meeting
3. Survey (gathering evidence uncertainties) goes live
4. Survey 1 closes
5. Survey 2 (interim priority setting) goes live
6. Survey 2 closes
7. Workshop expressions of interest applications open
8. Workshop dates
9. Final report launched

Step 3: Identifying evidence uncertainties

The Inherited Retinal Disease PSP will carry out a consultation to gather uncertainties via a survey from:

• patients;
• guardians and family members; and
• health and supportive care professionals.

Respondents will be able to submit up to 5 questions that they would like to see answered by researchers regarding:

• prevention of disease;
• diagnosis;
• disease progression and control;
• treatment and research into potential treatments;
• epidemiology; and
• management, which includes management of the physical, psychological, emotional, financial, and social aspects of living with an IRD, or caring for an individual living with an IRD.

Given the broad range of submissions, we will provide example questions from other conditions. Respondents will also be able to share their email address to be notified about participating in Step 5. The survey will remain open for 8-weeks.

The Inherited Retinal Disease PSP recognises the challenge in recruiting:

• culturally and linguistically diverse groups (including Auslan users);
• Aboriginal and/or Torres Strait Islander peoples; and
• those from regional/remote areas of Australia.

We will partner with relevant organisations who will raise awareness with these harder-to-reach groups, and support recruitment. We will include optional demographic questions in our survey to track inclusion of these groups (e.g., rurality, language). Our Steering Group will meet at the mid-point of the recruitment period to explore further opportunities to promote the study should we not achieve adequate representation.

We will incorporate several approaches to collect feedback from these groups, including the opportunity to complete the survey:

• online via Qualtrics;
• on paper (including a reply-paid envelope; and/or Braille version);
• over the telephone; or
• with the support of an interpreter (including an Auslan interpreter).

We will also work closely with our partner organisations and Steering Group members to ensure that our survey is as accessible as possible to all individuals living with an IRD.

Step 4: Refining questions and uncertainties

Step 3 will produce ‘raw’ questions and comments regarding areas of uncertainty. These raw questions will be categorised and refined by the PSP Lead into summary questions which are clear, addressable by research, and understandable to all. Similar or duplicate questions will be combined where appropriate. The Steering Group will have oversight of this process to ensure that the raw data is being interpreted appropriately and that the summary questions are being worded in a way that is understandable. The JLA Adviser will observe to ensure accountability and transparency.

The PSP Lead will work with Steering Group to frame these as researchable questions that capture the themes and topics that people have suggested. The summary questions will then be checked against evidence to determine whether they have already been answered by research. This will be done by the PSP Lead, with input from the Steering Group members on their area of expertise. The Steering Group will agree to the process of evidence checking via the Question Verification Form. This Form includes details of the types and sources of evidence used to check uncertainty. Once signed off by the Steering Group, the Form will be published on the JLA website to enable researchers and other stakeholders to understand how the PSP has decided that its questions are unanswered, and any limitations of this.

This process will result in two lists of questions:

• A list of in-scope summary questions; and
• A list of out-of-scope questions that have already been answered by research

Questions that the Steering Group decides are not adequately addressed by previous research, via the Question Verification Form, will be collated and recorded on a standard JLA template by the PSP Lead. The data will be submitted to the JLA for publication on its website on completion of the priority setting exercise, taking into account any changes made at the final workshop, in order to ensure that PSP results are publicly available.

Any submitted questions considered by the Steering Group as out-of-scope or that has been answered by research, alongside with additional comments collected in both surveys, will be published as a separate manuscript in a peer-reviewed journal.

Step 5: Prioritisation – interim and final stages

The aim of Step 5 is to prioritise, through consensus, the identified uncertainties about the prevention, diagnosis, disease progression and control, treatment and management of IRDs. This will involve input from:

• patients;
• guardians and family members; and
• health and supportive care professionals.

Individuals may have participated in earlier steps of this PSP.

Prioritisation will involve two stages:

1. Interim prioritisation survey
The interim prioritisation involves the Steering Group reducing the list of all the unanswered summary questions from Step 4 and creating a shorter list that can be taken to the final priority setting workshop. To do this, a survey that involves ranking a list of research priorities will be disseminated to:

• patients;
• guardians and family members; and
• health and supportive care professionals.

As with Step 3, we will incorporate several approaches to collect feedback from these groups, including the opportunity to complete the survey:

• online via Qualtrics;
• on paper (including a reply-paid envelope; and/or Braille version);
• over the telephone; or
• with the support of an interpreter (including an Auslan interpreter).

The survey will remain live for 8-weeks. The most highly ranked questions (around 25) will be taken to the second (and final) stage of prioritisation. Where the interim prioritisation does not produce a clear ranking of around 25 questions, the Steering Group will decide which questions are taken forwards to the final prioritisation.

Respondents will also be able to share their email address to be notified about participating in the final priority setting workshops. The survey will remain open for 8-weeks.

2. Final priority setting workshops
Due to the Australian geography and limited funds, the final priority setting workshop will be hosted online as two half day workshops. Interested attendees will be required to submit an Expression of Interest (online, paper, over the telephone) to ensure that we include a representative sample. Workshop participants will be selected by the Steering Group from the Expression of Interest applications. All selected participants will declare their interests, which will be shared to all participants for transparency.

The online workshops will be facilitated by 3-4 JLA Advisors, depending on the number of participants. With guidance from the JLA and input from the Steering Group, up to 30 patients (16+ years old), guardians and family members, and health and supportive care professionals will be invited to participate in the two half day workshops and the ranking to determine the top 10 questions for research. If required, participants will also receive a copy of any readings in advance. Patients, guardians, and family members will be remunerated $40 per one-hour of workshop attendance.

Dissemination of results

The Steering Group will identify audiences with which it wants to engage when disseminating the results of the priority setting process, such as researchers, funders, and the patient and clinical communities. They will determine how best to communicate the results and who will take responsibility for this. Outputs from the Inherited Retinal Disease PSP will likely include:

• academic papers;
• lay reports;
• infographics;
• conference presentations; and
• videos for social media.

A formal dissemination plan will be developed by the Steering Group in 2024.

It should be noted that the top 10 priorities will not be worded as research questions. The Steering Group will discuss how they will work with researchers and funders to establish how to address the priorities and to work out what the research questions are that will address the issues that people have prioritised. The dissemination of the results of the PSP will be led by the PSP Lead and two Steering Group members (Anai Gonzalez-Cordero, Kate Hetherington).

The Steering Group will report back to the JLA, partners and stakeholders about any activities that have come about because of the PSP, including funded research.

Agreement of the Steering Group

The Inherited Retinal Disease PSP Steering Group agreed the content and direction of this Protocol on 19th September 2023.