CROSSOVER AND PARALLEL GROUP STUDY

Crossover and Parallel Group Study

Crossover and Parallel Group Study

Crossover studies

These have been a source of controversy for many years as different aspects of their design, conduct, and analysis have been subjected to close scrutiny. Vere (1979) dismissed them altogether 'when a disorder presents in attacks it is probably better to rely on long periods of observation and large numbers to reduce variation, rather than a crossover design' and the FDA discouraged their use. Despite this crossover trials have retained some popularity in the assessment of new antiepileptic drugs (AEDs) as add-on therapy compared with add-on placebo.

One reason for this may be that with seizure counts in patients with drug-resistant, chronic epilepsy, between-patient variation is two, perhaps three, orders of magnitude greater than within-patient variation, exactly the situation in which crossover trials are much more economical than parallel- group studies. They are much less useful in newly diagnosed patients the majority of whom suffer far fewer, if any, seizures once AED treatment is commenced.

The crossover design in epilepsy is universally thought of from the very restricted viewpoint of the two-treatment, two-period design; here there some strengths and weakness are:

1. lack of difference of a new AED from placebo in patients who may respond to neither — one solution is use of a two-period, three-treatment trial, which incorporates an established AED as a calibrator (Johnson, 1991);

2. interactions of new AED with (some of) those already taken-solution is to restrict entry or perhaps stratify on maintenance AEDs;

3. statistical tests for carryover effect of treatment from one period to the next are useless and anyway the statistical model of the carryover effect is pharmacologically naïve (Senn, 1993) — solution is to include a washout period of sufficient duration to guarantee no carryover;

4. there may be a treatment by period interaction arising from sources other than the 'carryover effect' (Millar, 1983);

5. loss of patients during the first treatment or washout period, which could bias conclusions.

The principal endpoints in crossover trials are seizure counts, seizure severity, and side effects; they are too short to assess changes in quality of life or cognition, and too small for reliable estimation of costs.

Parallel- group studies

To assess the efficacy of new AEDs in treating newly diagnosed, drug naïve patients in the community, crossover trials are not useful mainly because treatment periods would be too long; in addition use of placebo is not ...