Auspar attachment 3: Extract from the Supplementary Clinical Evaluation Report for Daclizumab

10.First round benefit-risk assessment

10.1.First round assessment of benefits

The benefits of DAC HYP in the proposed usage are:

DAC HYP appears to reduce annualized relapse rate by about 50 to 54%, relative to placebo (p ≤ 0.0002)

DAC HYP reduces relapse rate by about 45%, relative to once-weekly IFN β-1a (p < 0.0001)

DAC HYP reduces the proportion of subjects relapsing by 44 to 47%, relative to placebo, and by 34 to 35%, relative to IFN β-1a, depending on the duration of follow-up. (Note that this is less benefit than claimed by the sponsor)

DAC HYP reduces radiological evidence of disease activity, including the reduction of new Gd-enhancing lesions by 69 to 78%, and new or newly enlarging T2 lesions by 70 to 79%, relative to placebo (p < 0.0001)

DAC HYP is associated with a strong trend to reduced disability progression

DAC HYP produced a broadly similar benefit across all major subgroups in the study population.

DAC HYP has not been studied in subjects with overt SPMS, and its efficacy in this population is unknown.

10.2.First round assessment of risks

The risks of DAC HYP in the proposed usage are:

a high incidence of skin reactions (about 37%, with about 2% rated as serious)

hepatic reactions, including potentially severe or fatal autoimmune hepatitis

hypersensitivity reactions, including anaphylaxis

lymphopaenia, especially affecting CD4+ and CD8+ lymphocytes

a theoretical risk of progressive multifocal leukoencephalopathy.

10.3.First round assessment of benefit-risk balance

DAC HYP reduces relapse rate in subjects with RRMS, but its use is associated with significant safety concerns. The efficacy of DAC HYP appears to be broadly comparable to other new disease-modifying agents, in terms of reducing relapse rate in subjects with RRMS, so it needs to be considered alongside those other agents. Like most other disease-modifying agents at the time of their registration, DAC HYP has not produced clear benefits in terms of reducing disease progression, but it is expected to reduce the accumulation of disability by preventing overt clinical relapses as well as new plaques evident on MRI. The submitted evidence suggests that a benefit on progression is very likely, but robust statistical proof is still lacking. Despite this, a benefit in terms of reducing relapse rate is a worthwhile clinical achievement in its own right, even without a proven benefit on progression, and one that would be attractive to patients and clinicians, if that reduction in relapse rate could be delivered with acceptable risk, relative to other available agents. Whether the observed reduction in relapse rate outweighs the safety concerns will depend on the extent to which the individual patient considering treatment is at risk of further relapses (and at risk of disability related to those relapses).

Compared to the first generation disease-modifying agents, such as beta interferon and glatiramer acetate, DAC HYP does not offer the same relatively benign safety profile. Although beta interferons have been associated with a number of tolerability concerns and can cause abnormalities of liver function tests, the risk of severe reactions (including severe derangements of liver function) appears higher with DAC HYP. The risk of skin reactions also appears high, with 2% of subjects experiencing serious skin reactions that led to use of systemic steroids. Like other monoclonal antibody preparations, DAC HYP may also cause acute hypersensitivity reactions and poses a risk of anaphylaxis. It is likely to increase the risk of PML, but this remains unclear.

The efficacy of DAC HYP is clearly superior to once-weekly IFN β-1a, which might justify increased safety risks, but DAC HYP has not been directly compared to more frequently administered beta interferon which is widely believed to be more effective than once-weekly IFN β-1a and has proven to be superior to IFN β-1a in head-to-head comparisons. The benefit of DAC HYP against more effective interferon regimens is likely to be minor, meaning that a substantial safety risk may not be justified.

For subjects with highly active disease, and particularly for subjects with a proven failure of beta interferon therapy, a low risk of serious complications is likely to be considered acceptable when choosing a new disease-modifying agent. Balanced against the high likelihood of frequent relapses, progressive motor disability, sensory disturbances and cognitive decline in the absence of an effective MS treatment, the rare occurrence of hepatic reactions and other serious complications carries less weight. If DAC HYP were known to reduce disability progression, patients would be expected to accept significant safety risks, but unfortunately there is no robust confirmation of this at present. The fact that DAC HYP reduces relapse rate by at least 50%, coupled with the fact that a large proportion of disability progression is known to come from incomplete recovery from relapses, suggests that DAC HYP could have a useful role in subjects with a high risk of relapses. Provided that the risks and benefits are made clear to patients and clinicians, they are in the best position to decide what risk they are prepared to accept to achieve a 50% reduction in relapse rate, and whether DAC HYP is an appropriate choice compared to other available agents. None of the new agents is without some significant safety concerns and some patients show poor tolerability of other new agents, such as dimethylfumarate, so it is expected that DAC HYP will find a use in some patients.

Like most other disease-modifying agents, DAC HYP has not been tested in subjects with overt SPMS, so the benefit-risk profile in this group is unknown. Immune-modifying agents have generally been less effective in subjects with progressive disease, and the same is expected to be true of DAC HYP. The supplementary evaluator was not convinced by the sponsor’s argument that, despite clear entry criteria that excluded SPMS, the pivotal studies inadvertently included some SPMS subjects, and this inadvertent inclusion therefore justifies use of DAC HYP in the broader population of subjects with SPMS. Only a study that explicitly focussed on SPMS subjects could demonstrate efficacy in this group with sufficient clarity that a rational decision could be made about the benefit-risk profile in SPMS.

In conclusion, the benefit-risk balance of DAC HYP for the proposed indication, which includes all forms of relapsing MS, is not known to be favourable. There is not sufficient evidence to recommend the use of DAC HYP in subjects with SPMS and the proposed indication does not match the entry criteria of the pivotal studies.

The benefit-risk balance for DAC HYP for a modified indication is expected to be favourable, if DAC HYP is used exclusively in subjects with RRMS, who are still experiencing relapses (or who are avoiding relapses by use of an alternative disease-modifying agent), who accept the risks, and who can receive DAC HYP in a closely monitored prescribing environment.