Should MRI be the primary endpoint of phase 3 trials in multiple sclerosis?

Because of magnetic resonance imaging (MRI)’s sensitivity to disease activity in multiple sclerosis (MS) patients and its ability to predict clinical therapeutic benefit in patient populations, MRI lesion activity is commonly used as the primary end point in phase 2 studies of new anti-inflammatory agents and as a supporting end point in phase 3 trials. However, MRI parameters correlate weakly with clinical outcomes in individual patients. Therefore, regulatory agencies generally require a clinical outcome (relapses or disability) as the primary end point in phase 3 trials of new agents. We argue herein that, although it is likely that clinical outcomes will continue to be required as the primary end point in phase 3 trials of new agents, MRI lesion activity is appropriate as the primary end point of phase 3 trials in certain special circumstances, which might allow reduced sample size and shorter study duration.

Advances in MRI quality, techniques, and availability have changed how MS is diagnosed and managed. Because MRI is more sensitive than clinical evaluation in detecting central nervous system pathology in MS, MRI findings are a key component of current diagnostic criteria for MS [1]. MRI also is sensitive to ongoing inflammatory disease activity and is used clinically to determine the need to begin disease-modifying therapy (DMT) and assess treatment efficacy [2]. As a result, MRI has become invaluable in clinical practice.

To date, 13 DMTs have regulatory approval to treat relapsing MS. Phase 3 trials of several additional DMTs were recently completed and should lead to their approval in the near future. Regulatory agencies generally require a clinical outcome measure as the primary end point in pivotal trials leading to MS DMT approval. Thus, all currently available MS DMTs were approved based on demonstrated benefit on clinical relapses plus, in some cases, disability accrual as measured by the Expanded Disability Status Scale. However, clinical end points are relatively insensitive for detecting therapeutic benefits of new agents compared to placebo in relapsing MS. As a result, to ensure adequate statistical power, trials with clinical end points require sample sizes of at least several hundred patients and study durations of 2–3 years. With effective therapies now widely available for relapsing MS, using placebo controls in MS clinical trials is becoming increasingly difficult due to ethical and practical constraints [3]. In lieu of placebo, recent trials increasingly use existing DMTs as active comparators against which the new therapy’s effects on clinical disease activity are measured [4]. This design requires even larger sample sizes and longer study durations to provide adequate statistical power.

High-potency DMTs markedly reduce MRI lesion activity, typically within 6 months or sooner [5–7]. As a result, a standard design for phase 2 proof-of-concept trials of new anti-inflammatory therapeutic agents utilizes frequent MRI monitoring (typically monthly for 6–12 months) and gadolinium-enhancing lesion number as the primary end point. Analyses of past DMT clinical trials, including both low- and high-potency DMTs, demonstrated that treatment effects on MRI lesion activity and relapses strongly correlated at the clinical trial level [8]. Moreover, the magnitude of benefit on MRI lesion activity in phase 2 trials predicted the magnitude of benefit on relapse rate in subsequent phase 3 trials [9]. These observations provide the rationale for utilizing MRI lesion activity as the primary end point in MS phase 2 studies. The question arises whether MRI lesion activity is an acceptable surrogate for clinical disease activity, and could it potentially supplant clinical outcome measures in phase 3 clinical trials. In short, the answer is yes, but only in specific circumstances.

At the individual patient level, correlation between MRI lesion activity and clinical manifestations varies greatly and depends on lesion location, compensatory neuroplasticity, and how carefully clinical symptoms and signs are interrogated. Regulatory agencies generally require outcome measures assessing clinical manifestations that are meaningful to individual patients as the primary end point. As a result, historically, MS DMTs for relapsing MS have been approved on the basis of beneficial effects on relapse rate and, in some cases, disability accrual. Because MRI lesion activity correlates weakly with these outcomes in individual patients, MRI parameters primarily serve as supportive end points in phase 3 trials. No MRI outcome has been validated as a surrogate measure in the strict sense [10], and, thus, the regulatory requirement for clinical primary outcomes in phase 3 trials of new agents to treat relapsing MS is not likely to change in the foreseeable future.

Nevertheless, one setting in which MRI lesion activity might be an appropriate phase 3 primary end point is evaluating the equivalence of generic versions of established DMTs coming off patent. MS is an extremely expensive disease, and as healthcare spending continues to rise, there will be greater pressure to bring more affordable MS treatments to market [11]. The availability of generic versions of DMTs offers one opportunity for lower-cost alternatives. However, competitive pricing of generics depends on an efficient development process. Because of the molecular complexity of MS DMTs and lack of understanding of their precise mechanisms of action in MS, in vitro characterization and animal studies, though necessary to confirm similar chemical properties, pharmacokinetics, and immunogenicity, may not adequately predict efficacy and safety in humans [12]. Therefore, in many cases a clinical trial may be needed. However, requiring one or two 2–3-year phase 3 trials with a clinical primary end point typical of an innovator drug would create a significant deterrent to pharmaceutical companies developing generics. A shorter (e.g. 6–12 month) trial demonstrating equivalent efficacy on MRI end points, plus equivalent safety and tolerability, is a reasonable compromise. In the case of glatiramer acetate, the US Food and Drug Administration recently approved one generic version based on in vitro and animal data alone [13]. In contrast, the European Medicines Agency (EMA) advised a sponsor developing a different generic glatiramer acetate to conduct a clinical trial. In consultation with the EMA, an equivalence trial was undertaken utilizing the number of gadolinium-enhancing MRI lesions during months 7–9 on treatment as the primary end point [14]. This situation illustrates the different approaches taken by the two regulatory agencies.

A second situation in which MRI lesion activity might be an appropriate primary end point is phase 3 trials of existing MS DMTs in a new patient population, specifically, pediatric-onset MS (POMS). Despite lack of approval for patients younger than 18 years and the absence of systematic data on safety, pharmacokinetics, and dosing, empiric use of DMTs in this population is common [15]. POMS clinical trials are challenging for a variety of reasons but mainly due to patient scarcity, making large-scale phase 3 trials difficult to enroll. Since none of the existing DMTs have regulatory approval in children, one could argue that all should be tested phase 3 trials in POMS, exacerbating recruitment issues if multiple trials are run concurrently. As in adults, the greater sensitivity of MRI compared to clinical outcome measures translates to smaller sample size and shorter study duration. Ethically, studies with shorter duration and fewer patients reduce harm across POMS populations, particularly for placebo-controlled trials, a practice still used in POMS trials due to the lack of approved therapies [16]. One drawback of the abbreviated MRI-based trial design would be less information on safety compared to a typical phase 3 trial. This issue could be addressed through long-term open-label extension studies and post-approval registries.

A third scenario in which an MRI-related primary end point might be considered is the modification an existing DMT, for example, covalent additions of other moieties to improve pharmacokinetic properties. In the case of pegylation of interferon-beta-1a, although the mechanism of action presumably was unchanged, the resulting molecule was sufficiently altered so that a standard phase 3 clinical trial program with a clinical primary end point was appropriate [17].

The currently approved DMTs have different mechanisms of action but all are aimed at reducing inflammatory demyelination of the central nervous system. These mechanistic differences may manifest differently at the blood–brain barrier, potentially impacting the timing and efficacy with which new medications prevent new MRI-detectable lesions. Thus, as a potential substitute for clinical activity, MRI biomarkers may be more sensitive in some drug classes, and less so in others. What about medications with putative neuroprotective and/or repair-promoting properties but with modest or minimal effects on MRI lesion activity and relapses? Therapeutic strategies with these properties, for example, laquinimod [18] and ibudilast [19], are under consideration potentially to treat progressive MS. Similar to the aforementioned correlation between treatment effects on MRI lesion activity and clinical relapses, analyses have demonstrated good correlation between beneficial effects on slowing whole brain volume loss on MRI and clinical disability worsening [20] across clinical trials, and independent of the treatment effect on MRI lesion activity. In fact, when effect on brain volume loss was combined with effect on MRI lesion activity, correlation with effect on disability was strengthened. These findings support the use of MRI to assess whole brain volume loss in phase 2 studies of potential neuroprotective and repair-promoting strategies. However, because this analysis was restricted to trials in relapsing-remitting MS, the utility of slowing whole brain volume loss in predicting benefit on disability in progressive MS is uncertain and further work is needed.

In summary, the answer to the question of whether MRI-related outcomes can be used as the primary end point in MS phase 3 trials is not straightforward. It is unlikely that regulatory agencies will accept substituting MRI lesion activity for relapse rate as the primary end point in pivotal trials of new agents to treat relapsing MS. However, there are some specific situations in which the primary outcome of a phase 3 trial could be MRI lesion activity.

Financial & competing interests disclosure

I Rossman reports personal compensation for consulting for Teva, and speaking fees from Genzyme. He is supported by National Multiple Sclerosis Society Sylvia Lawry Physician Grant FP 17106-A-1. J Cohen reports personal compensation for consulting for Genentech, Genzyme, Novartis, and Receptos and speaking fees from Teva. He is Co-Editor of Multiple Sclerosis Journal – Experimental, Translational and Clinical. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Notes on contributors

Ian T Rossman

Jeffrey A Cohen