The committee considered the data on the clinical effectiveness of natalizumab in the subgroup of people whose multiple sclerosis has failed to respond to treatment with beta interferon, that is, the suboptimal therapy group. It noted that the ITT population from the AFFIRM study, which showed that natalizumab significantly reduces relapse rate and delays disability progression compared with placebo, was used in the manufacturer's submission as a proxy for this group. The committee was aware that the SENTINEL study was used to inform the licence for the suboptimal therapy group but that the study considered the use of natalizumab in combination with beta interferon; this combination is not licensed because of safety concerns. The committee noted that there is no direct evidence about the clinical effectiveness of natalizumab monotherapy in the suboptimal therapy group. In addition, the clinical experts confirmed that, although natalizumab may be used in this situation, there are no clinical study data to indicate how clinically effective it is in this group. The committee therefore concluded that the clinical effectiveness of natalizumab in the suboptimal therapy group has not been fully established.