Clinical Guidelines Protocol

Introduction

With this protocol, we hope to assist in the process of developing and endorsing clinical guidelines within ERN RITA and its 4 streams.
The development of evidence based, consensus driven clinical guidelines on diagnosis and treatment of rare disorders within the ERN RITA framework is an elaborative piece of work. We advise you to form a core group as kind of steering committee during the process, this could/should include: the expert-coordinator, one or two junior research associates (PhD, resident, research fellow or equivalent), 2-3 clinical experts with dedicated time during the whole process and 1 methodologist/epidemiologist ensuring the validity, quality and transparency of the process.
It is important that the guidelines in the end are widely supported and used in clinical practice. Moreover, they should be supported and preferably widely communicated by patient organisations. We therefore advise to involve colleagues from different ERN RITA centers in the different stages and tasks within the process as well as to timely organize for proper patient involvement.
In addition, it is advised to timely plan the ‘on site’ consensus meeting (-s), which ideally have a group size of 20-25 (max). Within the number of 20-25 participants, ideally 2 patient representatives, 1 methodologist and 1 independent, experienced chair are included.

Endorsement of existing guidelines

For guidelines that have already been developed in the past 1-2 years, or are currently in development (and / or are financed by other means than ERN funding) we already facilitate ‘official’ endorsement by ERN-RITA in a formal process. . Click HERE [https://ern-rita.org/endorsement] for the ERN-RITA endorsement form.

Process of developing new guidelines

The involvement of an experienced methodologist in the process of developing the guideline is really helpful. You may contact the ERN RITA desk to bring you in contact with a methodologist that has worked in our field before if desired.

The process of developing the guidelines includes the following key elements:

1. Systematic Literature Review (SLR)
2. From evidence to statements: developing provisional statements
3. Pre-testing of statements: sensing feasibility, strengthening support and refining of provisional statements
4. Consensus meeting (-s): voting on and finalization of the statements
5. Patient representatives involvement
6. Publishing and outreach strategy

Below, the key elements of the process are being elaborated.

1. Systematic Literature Review (SLR)

The SLR may easily take up to 3 months of work from one or two (junior) research associates.

Key points (click on each to view details)

Involve an experienced librarian in the work of developing a search string, save the string and date of search.

• Aim to search in PubMed/MEDLINE, EMBASE and Cochrane databases
• Define a proper time frame / period for the topic (for example 30-35 years)
• Only look for English literature
• Define the minimum required number of described patients when including case reports or series (for example at least 3 patients in a series)
• Use MeSH/Emtree terms where possible, search for title and abstract
• (Manually) screen the hits by title and abstract, independently by two reviewers, and check full text when necessary to determine eligibility. Disagreement can be resolved by a third reviewer.

Validity assessment:

Assess validity by members of the expert panel (two reviewers per paper) using standardized data extraction and predefined scoring forms for demographics, diagnostic and therapeutic studies. Discrepancies need to be resolved by a third expert.

Level of evidence

	For diagnostic observational studies	For treatment studies
1A	Meta-analysis of cohort studies	Meta-analysis of randomized controlled trials
1B	Meta-analysis of case-control studies	Randomized controlled trial
2A	Cohort studies	Controlled study without randomisation
2B	Case-control studies	Quasi-experimental study
3	Non-comparative descriptive studies	Descriptive study
4	Expert opinion	Expert opinion

2. From evidence to statements: developing provisional statements.

When you have identified all relevant papers and assessed their quality and validity, you can start the process of developing provisional recommendations or statements. This is in principle done by the core group and can start by grouping all papers regarding relevant topics or aspects of the disease.
This also allows for a first provisional indication of the level of evidence of the recommendation:

Factors that affect the strength of a recommendation

Factor	Examples of strong recommendations	Examples of weak recommendations
Quality of evidence	Many high quality randomised trials have shown the benefit of inhaled steroids in asthma	Only case series have examined the utility of pleurodesis in pneumothorax
Uncertainty about the balance between desirable and undesirable effects	Aspirin in myocardial infarction reduces mortality with minimal toxicity, inconvenience, and cost	Warfarin in low risk patients with atrial fibrillation results in small stroke reduction but increased bleeding risk and substantial inconvenience
Uncertainty or variability in values and preferences	Young patients with lymphoma will invariably place a higher value on the life prolonging effects of chemotherapy than on treatment toxicity	Older patients with lymphoma may not place a higher value on the life prolonging effects of chemotherapy than on treatment toxicity
Uncertainty about whether the intervention represents a wise use of resources	The low cost of aspirin as prophylaxis against stroke in patients with transient ischemic attacks	The high cost of clopidogrel and of combination dipyridamole and aspirin as prophylaxis against stroke in patients with transient ischaemic attacks

Notes: when developing recommendations out of the SLR, try to keep the recommendations simple and short where possible, avoiding very complex sentences and language. Involve a native English speaker (this can also be done later, in the consensus meeting itself for example).

3. Pre-testing of statements: sensing feasibility, strengthening support and refining of provisional statements.

When the provisional statements or recommendations are developed, the process of pre-testing can start. This can be done by an online survey, for example by SurveyMonkey or a similar tool. Here, you will get an idea whether it might be feasible to reach consensus (≥ 80% agreement in the expert consensus meeting) on a specific recommendation or topic. Moreover, you can include a wider panel of experts (for example 40-50, including the intended experts of the on-site consensus meeting) to allow for broadening the support and involvement of ERN-RITA members.

4. Consensus meeting (-s): voting on and finalization of the statements

The consensus meeting can be organised onsite (preferred) or online (possible with very good preparation and chairs). ERN RITA provides funding for traveling to a consensus meeting (budget 104k for 8 meetings, so 13k/meeting on average). Reimbursement of funding is dependent on the travel distance and location of event, ERN RITA coordination will provide the exact amounts and process the reimbursements once your proposal is selected for funding.
Ideally the number of voting attendants at the consensus meeting is around 20 (25 max) plus an independent non-voting chair as well as a methodologist (may assist online). Ensure proper patient representative involvement (ideally 2 representatives, costs reimbursed from a separate budget). Experts from outside of ERN-RITA / European Union can participate in the consensus meetings, however as their traveling costs are tentatively higher, this is something you have to take into account in the planning and budgeting (there may be a need to ensure extra budget outside of ERN RITA).

5. Patient representatives involvement

Ideally, patient representative involvement should start early in the process (not only in the voting part), already in discussing the specific topics that the CPG will cover. ERN RITA can provide a list of potential patient organisations, as well as share contact details of patient representatives with experience in developing guidelines already, to discuss with. It is advised to involve (at least) 2 representatives of a patient organisation to ensure a more objective / broader involvement. These (2) patient representatives may collaborate / have their participation backed up by a dedicated patient involvement committee from the patient organisation involved, that allows for a broader perspective.

6. Publishing and outreach strategy

The CPG guidelines need to be submitted for publication, and ERN RITA needs to be acknowledged. It is recommended to also ask the patient representatives to develop a ‘patient translation’ of the guideline for their outreach as well (examples can be given upon request).

Financial support

ERN RITA can provide limited budget for the development of up to 8 guidelines until the 30th of September 2027, with a maximum of 2 guidelines per stream. The ERN 2023-2027 grant allows for the following reimbursements:

• Reimbursement of travel, accommodation and subsistence costs to attend consensus meetings. One consensus meeting per CPG.
• Reimbursement of systematic literature reviewing per guideline, up to a maximum of €9500 per guideline.
• Reimbursement of costs for two patient organisation representatives per CPG, up to a maximum of €2174 per representative per guideline

Total budget for travel & accommodation 8 consensus meetings: €104.000.
Total budget reimbursement of SLR and patient representative contribution: €111.000.

Eligibility Criteria

To apply for (financial) support for the development of clinical practice guidelines through ERN RITA, applicants must be a full or affiliated member of ERN RITA.
The subject of the CPG should be agreed upon with the relevant scientific society of the respective stream.
Financial support for the CPG development outside of ERN RITA must be disclosed when applying.

Application Process

Complete the online application form HERE.

Review Process

Applications will be reviewed every 3 months by the ERN RITA Clinical Practice Guideline Committee, consisting of the CPG Chair, Stream Leads and scientific society CPG representatives (ERN-RITA ex-officio’s).
Evaluation will consider the following objective measures of the proposed clinical guidelines.

• Evaluation of the topic with the stream leads
• Number of ERN centers involved
• Relevant patient organisation involved
• Global budget assessment

Timeline

Applications can be submitted on a rolling basis and will be reviewed every three months.
Deadlines first of the month and continue until the budget is exhausted. Updates will be given on the website RITA member section/via email.

• December 2024
• March 2025
• June 2025
• September 2025
• December 2025

Approval Notification

Notification from ERN RITA regarding the approval or rejection of your application will be done via email.
All successfully reviewed applications will be listed on Basecamp (or on the ERN RITA website with RITA member access only).
If approved, begin the development of the clinical guidelines in accordance with the proposed plan.

Cost Reimbursement

Requirement:
Any publication or presentation related to the CPG must acknowledge ERN RITA according to the publication rules.
ERN RITA can only reimburse the costs for:

• Travel, accommodation and subsistence.
  After receiving the required travel & accommodation documents and signature of attendance.
• Systematic literature reviewing costs.
  After completion and receiving report of the SLR, as well as the invoice from the respective ERN RITA HCP.
• Patient representatives’ CPG contribution.
• The CPG chair makes the final assessment based on the following:
  o Patient representatives have given their input in discussing the domain of the SLR.
  o Have participated in the consensus meeting.
  o Have contributed to a plan for translation to patients (a patient summary).
• After receiving the invoice from the patient organisation.
  If your HCP or patient organisation requires a collaboration agreement in order to issue an invoice, please contact the ERN RITA coordination team for the agreement.

All invoices and additional required documents should be sent to the ERN RITA coordination team.

Summary rules for reimbursement

1. Individual travel and accommodation expenses are reimbursed via the UMC Utrecht reimbursement form.
2. SLR costs via invoice issued by the HCP organisation
3. Patient contribution costs via invoice issued by the patient organisation.