Clinical management guidelines for Friedreich ataxia: best practice in rare diseases

Figure 1 summarizes the overall process for guidelines development, with each phase described below.

Fig. 1figure 1

Flow chart of the stages of the guidelines development and stakeholder involvement. Red arrows indicate process for obtaining indirect evidence. CMG = Clinical Management Guidelines; PICO = Patient, Intervention, Comparator, Outcome; FACOMS = Friedreich’s Ataxia Clinical Outcomes Measures; EFACTS = European Friedreich’s Ataxia Consortium for Translational Studies; FRDA = Friedreich ataxia

Stakeholders

The key stakeholders in the development of the guidelines were:

Guideline panel. An executive guideline panel comprising seven international clinicians provided oversight of the guideline development process and endorsed the final recommendations.

Project coordinator. The panel was supported by a project coordinator and administrative support.

Expert authors. International expert clinicians and researchers were invited by the guideline panel to author chapters and develop recommendations for their designated topic.

Methods experts. Expert authors were assisted by two methodological experts who completed the literature searches and summarized and synthesized the evidence using the GRADE structure.

Individuals with FRDA and/or their families. In contrast to the preceding iteration of the guidelines, individuals with FRDA and/or their families were included throughout the development of the guidelines to provide a lived perspective of FRDA on the development of topics and the final recommendations, in particular the lay summaries of recommendations.

Figure 1 shows how and when these stakeholders contributed to the development of the guidelines.

Topic list

The guideline panel reviewed the topic list from the previous CMG iteration, identified gaps in the available topics and suggested new topics for inclusion.

Developing the Patient, Intervention, Comparator, Outcome (PICO) questions

Expert authors were allocated topics relevant to their expertise and were asked to define the scope of their designated topic. Authors were instructed that each recommendation should answer a focused and sensible healthcare question designed according to the Patient, Intervention, Comparator, Outcome (PICO) framework. Individuals with FRDA and/or their families provided feedback on the PICO questions. The PICO questions guided the literature review and generation of other evidence if required.

Grading of Recommendations Assessment and Evaluation (GRADE)

The GRADE approach is a system for rating the quality of a body of evidence for clinical practice guidelines and grading recommendations in health care. GRADE offers a transparent and structured process for developing and presenting evidence summaries and for carrying out the steps involved in developing recommendations [12]. The GRADEpro Guideline Development Tool (GRADEpro GDT: GRADEpro Guideline Development Tool [Software]; McMaster University and Evidence Prime, 2021; available from https://www.gradepro.org), including the evidence table, summary of findings table and evidence to recommendation table, was used to generate the guidelines. The bespoke structured observation forms used to develop these guidelines were based on those presented in the GRADE tool (see Additional file 1 for an example of a structured observation form).

Literature search

A literature search for each PICO was completed using a comprehensive search of three electronic databases (Cochrane Library, CINAHL and MEDLINE) for publications from January 2014 to June 2020, including only English-language publications. Reference lists and the authors’ personal libraries were searched for further publications. Randomized, non-randomized controlled and observational studies were included. Papers identified in the 2014 guidelines (published prior to 2014) were included in the review if not superseded by more recent, higher quality literature.

The populations included adults and/or children with FRDA. However, when there was minimal published evidence, populations with like conditions (such as spinocerebellar ataxia and multiple sclerosis) were included in the search.

For each PICO, the review of the literature was summarized and presented to expert authors via the GRADE evidence table and summary of findings table.

Registry data

In instances where there was limited published evidence on the PICO question, authors had the opportunity to interrogate registry data from two international natural history registries of clinical information from individuals with FRDA: the Friedreich’s Ataxia Clinical Outcomes Measures (FACOMS) and the European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS). The information provided was descriptive only; for example, frequency of use of a medication in individuals with a specific impairment related to FRDA.

Structured observation forms

If the expert authors anticipated there was limited or no published evidence on the PICO question, structured observation forms were used to systematically document clinical observations by experienced clinicians that could contribute to the strength of the recommendation. In the first instance, the expert authors (clinicians) working on that topic completed the form/s independently. If responses showed large discrepancies, all expert authors were invited to complete the structured observation forms. The questions were targeted at clinicians known to provide healthcare to individuals with FRDA.

Generation of recommendations

GRADE Evidence to Recommendation tables were used to provide the structure for expert authors to decide the strength of the recommendation and the level of evidence. The evidence base related to each question was evaluated according to the criteria of: problem (is the issue a significant problem?); desirable effects (of the intervention); undesirable effects (of the intervention); certainty of evidence; values; balance of effects; and acceptability (of the intervention). Based on the responses to these criteria, the type (for or against the intervention, or neither) and strength of the recommendation (strong or conditional) were generated. For the rating of the strength of the recommendation, in addition to evidence from studies in FRDA, evidence from like conditions, clinical experience and expert consensus were taken into account when published evidence was not available. In this situation, the level of evidence was rated as “low” or “very low”. Table 1 provides an explanation of the symbols used to grade recommendations.

Table 1 Symbols used to denote strength of recommendation and level of evidence

For strong recommendations, consistent with the GRADE working group we suggested authors should use terminology such as "we recommend…" or "clinicians should…", “clinicians should not…” or “do…”, “don’t…” For conditional recommendations, we suggested less definitive wording, such as "we suggest…" or "clinicians might…" or “we conditionally recommend…” or “we make a qualified recommendation that…”.

Along with each recommendation, authors provided clinical and research justification for the recommendation and a description of subgroups that might need particular consideration in implementing the recommendation, if any.

Best practice statements

Best practice statements were included when application of the GRADE framework was not appropriate. This was in circumstances where the reverse would not be credible; for example, ambulant individuals with FRDA who are falling frequently should be offered a detailed assessment of balance and gait. In addition if recommendations from the 2014 guidelines were deemed still relevant, yet not incorporated into a new PICO thus enabling scrutiny from a GRADE framework, they were included as best practice statements.

Chapter content

For each topic, expert authors were asked to write a chapter elaborating on the evidence and providing background and context to the best practice statements and recommendations. For chapters that did not include recommendations or best practice statements, expert authors provided an evidence-based overview of the topic.

Lay summaries

Expert authors wrote a lay summary of the recommendations related to the topic. Given the target audience for this section is individuals living with FRDA, review of the lay summaries by individuals with FRDA and their families was a crucial component of the guideline development.

Achieving consensus

Each of the expert authors needed to agree on the grading of recommendations. In the case of not achieving consensus we proposed the authors use a Delphi survey to achieve consensus.

Process of endorsement

The executive panel reviewed the chapter content and recommendations and responded to a set of questions via an online survey (see Additional file 2). If the panel had any reservations about the wording of a recommendation, this was discussed with the relevant authors and agreement was reached. Endorsement was then established after resolution of these issues with the authors.

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