Evidence for rare diseases is available, but poses challenges to synthesis: a case study




Poster session 1


Sunday 16 September 2018 - 12:30 to 14:00

All authors in correct order:

Roqué i Figuls M1, Solà I1, Salas Gama K2, Requeijo C2, Estrada D3, Espallargues M3
1 Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB-Sant Pau), Spain
2 Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB-Sant Pau), Spain
3 Agency for Health Quality and Assessment of Catalonia (AQuAS), Spain
Presenting author and contact person

Presenting author:

Marta Roqué i Figuls

Contact person:

Abstract text
Sanfilippo disease is a rare, devastating, hereditary disease that causes neurologic decline and death, for which there is no effective treatment. The over-the-counter drug genistein is reported to improve neurologic and behavioural status in people suffering from Sanfilippo disease.

To assess the efficacy and safety of genistein for Sanfilippo disease.

We conducted a rapid systematic review with comprehensive searches on MEDLINE, Embase, CENTRAL, trial registries and rare diseases resources, up to January 2018. We used the Cochrane 'Risk of bias' tool for randomized clinical trials (RCT), and the Institute of Health Economics’ checklist for uncontrolled clinical or observational studies. We assessed the quality of evidence (QoE) with the GRADE system.

We included experimental or observational studies where genistein was administered in any dose to Sanfilippo patients. Primary outcomes were cognitive and behavioural scales and adverse effects. Secondary outcomes included quality of life and urine level of glycosaminoglycans (GAG).

We identified nine studies that included 162 participants: one cross-over RCT, seven uncontrolled experimental studies (UES), and one case-report. Studies were heterogeneous in size (6 to 35 participants), age of participants (1 to 19 years), and genistein dose (5 mg/kg/day to 150 mg/kg/day). The RCT had a low risk of bias whereas the UES were of low quality. Genistein at high doses (150 mg/kg/day) had no clinically relevant effect on behaviour or GAG urinary levels, based on low QoE from one UES. Genistein at low doses (5 mg/kg/day to 15 mg/kg/day) had no clinically relevant effect on neurocognition (2 UES; low QoE), behaviour and symptoms (1RCT, 3 UES; low QoE), or GAG urinary levels (1 RCT, 3 UES; moderate QoE). It is apparently safe (1 RCT, 5 UES; low QoE).

The difficulties in conducting large RCTs in rare diseases limits the QoE that can be obtained. The pressing need for evidence requires the incorporation of evidence from non-randomized and uncontrolled studies. Specific tools to assess the validity of UES are needed. Recommendations for rare diseases need to balance evidence of low quality against a dearth of therapeutic options and needs from patients and families.

Healthcare consumer involvement:
This review was peer-reviewed by patient associations representatives. Outcomes were chosen and prioritized based on published consensus with families and caregivers. Our recommendations include patients values and preferences.

Relevance to patients and consumers: 

This rapid review identifies and synthetizes evidence on a rare disease. It applied rigorous methods and took into account views and needs of Sanfilippo families, from the protocol (with the choice and prioritization of outcomes) to the recommendations stage (considering values and preferences of Sanfilippo patients and their families). But it also highlighted the challenges in conducting high quality methodological research in rare diseases, where answers are needed and there may not be the best evidence available.