Goal attainment scaling as an outcome measure in rare disease trials: a conceptual proposal for validation.

BACKGROUND: Goal Attainment Scaling (GAS) is an instrument that is intended to evaluate the effect of an intervention by assessing change in daily life activities on an individual basis. However, GAS has not been validated adequately in an RCT setting. In this paper we propose a conceptual validation plan of GAS in the setting of rare disease drug trials, and describe a hypothetical trial where GAS could be validated. METHODS: We have used the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) taxonomy to deduce which measurement properties of GAS can be evaluated, and how. As individual GAS scores cannot be interpreted outside the context of a RCT, the validation of GAS needs to be done on trial as well as on individual level. RESULTS: The procedure of GAS consists of three steps. For the step of goal selection (step 1) and definition of levels of attainment (step 2), face validity may be assessed by clinical experts. For the evaluation of the goal attainment (step 3), the inter and intra rater reliability can be evaluated on an individual level. Construct validity may be evaluated by comparison with change scores on other instruments measuring in the same domain as particular goals, if available, and by testing hypotheses about differences between groups. A difference in mean GAS scores between a group who received an efficacious intervention and a control group is an indication of well-chosen goals, and corroborates construct validity of GAS on trial level. Responsiveness of GAS cannot be evaluated due to the nature of the construct being assessed. CONCLUSION: GAS may be useful as an instrument to assess functional change as an outcome measure in heterogeneous chronic rare diseases, but it can only be interpreted and validated when used in RCTs with blinded outcome assessment. This proposed theoretical validation plan can be used as a starting point to validate GAS in specific conditions.

The patient's view on rare disease trial design - a qualitative study.

BACKGROUND: Clinical trials in rare diseases are more challenging than trials in frequent diseases. Small numbers of eligible trial participants, often complicated by heterogeneity among rare disease patients, hamper the design and conduct of a 'classical' Randomized Controlled Trial. Therefore, novel designs are developed by statisticians. However, it is important to be aware of possible design aspects that may jeopardize the feasibility of trial conduct. If the burden of participation is considered out of proportion by patients or parents, recruitment may fail or participants may drop out before trial completion. In order to maximize the chance of success of trials in small populations, it is important to know which aspects of trial design are considered important by patients. RESULTS: We have interviewed all ten members of the Patient Think Tank (PTT) of the ASTERIX project, a European research consortium on methodology for clinical trials in small populations. The PTT members are rare disease patient representatives who have completed extensive training in clinical trial methodology. We have analyzed the interviews qualitatively according to Grounded Theory using a thematic analysis, and we structured the topics in four chronologically ordered themes: 1. Involvement in trial design; 2. Opinions on trial design; 3. Trial participation; 4. Phase after the trial. Our main findings are that the PTT-members recommend that patients are involved in trial design from an early stage on, and have influence on the outcomes and measurement instruments that are chosen in the trial, the length of the study, the choice of participants, and the information that is sent to potential participants. Also, according to the PTT-members, patient groups should consider setting up disease registries, placebo groups should be minimized, and more education on clinical trials is advised. CONCLUSIONS: Rare disease patient representatives who have been educated about clinical trial methodology think it is important to involve patient representatives in research at an early stage. They can be of advice in trial design in such a way that the ratio of potential benefit and burden of trial participation as well as the chosen outcome measures and in- and exclusion criteria are optimized.

The negative predictive value of breast Magnetic Resonance Imaging in noncalcified BIRADS 3 lesions.

PURPOSE: The purpose of this study is to determine whether breast MRI can provide a sufficient NPV to safely rule out malignancy in mammographic BIRADS 3 lesions. MATERIALS AND METHODS: In a 3-year consecutive mammographic examination study 176 out of 4391 patients had a lesion classified as BIRADS 3. 76 out of 176 patients underwent breast MRI as diagnostic work-up. Lesions which MRI classified as BIRADS 1 or 2 were considered negative for malignancy. Sensitivity, specificity, PPV and NPV were calculated. RESULTS: In 27 out of 76 (35.5%) patients MRI showed no enhancement and was classified as BIRADS 1. In 25 (32.9%) patients MRI showed focal or mass enhancement classified as BIRADS 2. In these 52 (68.4%) patients no malignancy was found during at least 2 years study follow-up. The other 24 (31.6%) patients had a lesion classified as BIRADS ≥ 3. Thirteen of these 24 lesions were malignant by pathology. MRI had a sensitivity of 100% (95% CI: 75-100%), specificity of 82.5% (95% CI: 71-91%), PPV of 54.2% (95% CI: 33-74%) and NPV of 100% (95% CI: 93-100%). CONCLUSION: Breast MRI should be used in a diagnostic strategy for the work-up of noncalcified BIRADS 3 lesions. Malignancy is ruled out with a very high level of confidence in the majority of patients (68%), herewith avoiding invasive diagnostic procedures.