APPENDIX FOUR
Quality of Life

Definition:

Quality of life is "The extent to which hopes and ambitions are matched by experience". It is an individual concept. An ideal QoL instrument must be applicable across a range of disability, relevant to ALS, easy to administer, cost effective and efficient, as well as sensitive to clinically significant change. Ideally, QoL is measured by direct assessment, from patient-derived data, rather than through any other person's intervention. It involves domains of health perception, personal and social achievement and physical and mental well-being. Inter-personal relations are important determinants of these concepts. It is an independent measure of the effectiveness of a therapy.

Recommendations:

1. QoL can not be used as a primary or sole outcome measure at this time.
2. More specific and quality related scales are needed that should be valid, reliable, sensitive to change and relevant to the disease. Any ALS - specific measure should be used in conjunction with a recognized generic QoL measure to allow comparisons across disease states.
3. The following generic scales have been used in previous ALS clinical trials:
   SIP - Sickness Impact Profile
   SF-36 - Short form 36
   The SIP has proved difficult to use, and has been reported to cause patient distress. In addition the SIP is weighted towards functional measures and may partially replicate functional scales, such as the ALSFRS. There are a variety of other generic QoL measures that could be used such as the Quality of Life Questionnaire (QLQ-C30), the Nottingham health index and the Quality of Well Being (QWB) scale. These have not been validated in ALS. Generic scales are important because they have been used in many different clinical disorders, both in trials, and in the evaluation of the results of clinical practice. Their sensitivity, however, varies in these different clinical contexts.
4. The SF-36 is recommended for both screening and for pivotal ALS Clinical Trials. This generic instrument should be applied in conjunction with an ALS-specific measure, once this has been developed.
5. There is a risk that if questions are isolated from validated and balanced QoL measures they may replicate data obtained from functional rating scales. This should be avoided.
6. As part of trial design, consideration should be given to the collection of direct and indirect cost data for pharmaco-economic analysis. This is important in relation to marketing, and to decisions made by third party payers in relation to the availability of the drug once it has been licensed.
7. Consideration should be given to assessment of QoL of caregivers during the trial.
8. The frequency of administration of QoL instruments should be driven by the nature of the specific instrument. In general, current generic measures should not be administered more than four times annually, because of the lack of validated alternative forms of these tests. More frequent administration results in unreliable data due to learning and familiarity effects.
9. Consideration should be given to the use of a depression scale, e.g. Beck scale, to recognize treatable factors in altered QoL. Psychological factors have been shown to influence survival (MacDonald et al 1996).
10. Problems of nonlinearity: QoL measures are ordinal and should be treated accordingly in statistical analyses.

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