Monday, 19 May 2014

Clinic Speak: off-label and private prescribing in PPMS

Rituximab is an off-label treatment for a subgroup of PPMSers. #ClinicSpeak #MSResearch #MSBlog

"As you are aware there are no licensed DMTs for primary progressive MS. Why? There are several reasons for this. Firstly, PPMS is uncommon only 10-15% of MSers have PPMS. To date trials may have not been done properly; for example, we need to extend the length of follow-up in PPMS trials to beyond the standard 2 years currently used in relapsing-remitting trials. This longer duration of trials may relate to the so called therapeutic lag in relation to inflammation in PPMS and SPMS. Despite not having a DMT that works there is a subgroup of PPMSers that have been shown to respond to a potent DMT called Rituximab. Rituximab is a monclonal antibody that targets B cells depleting them from the body for several months. In the trial below PPMSers who were younger than 50 and had evidence of inflammation on MRI responded to the treatment. Based on this trial I have used rituxumab off-label in PPMSers who fulfill these criteria. To get the NHS to fund this treatment we have had to apply for funding via the so called IFR or indiviudal funding request. Based on the data several local commissioners said yes to funding in the past and we have treated a handful of PPMSers with Rituximab. With the reconfiguration of the NHS the IFR process is now centralised under specialist commissioning which run by NHS England. NHS England have a rule that if more than 5 people exist in a specific treatment group then an IFR route is not appropriate for funding and we would therefore have to put in a business case to be able to use rituximab in a subgroup of PPMSers. The problem is that the data supporting rituximab in PPMS is based on the subgroup analysis of a single trial and hence is unlikely to be enough evidence to allow us to use rituximab across the NHS. We therefore find ourselves in a Catch-22."

"This situation has caused private prescribing to rear its ugly head. What happens if someone with PPMS who is young and has active inflammation on MRI and wants to pay for his or her own treatment? Do I say no? I predicted this scenario more than 12 months ago and my prediction has come true. One of my patients with PPMS, who is young and has active disease, wants to be treated with rituximab under the NHS and pay for the drug privately. What do I do? You have helped me make a decision. When I ran a survey on this topic last year you suggested that neurologists should prescribe off-license and privately under the NHS. I have now rationalised this and realised that my primary responsibility is to individual patients and not the NHS collective. The politicians have deliberately created this situation of private prescribing under the NHS for a purpose. Legislation was passed under New Labour and it now transpires that the policy has cross party support. We are therefore going ahead and arranging for this patient to be treated with Rituximab."

"As rituximab is about to come off patent and is associated with infusion reactions the company that markets Rituximab has decided not to take it forward as a treatment for MS, but has taken forward a more humanised version called ocrelizumab that is associated with a lower incidence of infusion reactions. Ocrelizumab is now in late stage phase 3 development. At present there are two relapsing-remitting and one primary-progressive trial running."

A Study of Ocrelizumab in Patients With Primary Progressive Multiple Sclerosis. ClinicalTrials.gov Identifier: NCT01194570

A Study of Ocrelizumab in Comparison With Interferon Beta-1a (Rebif) in Patients With Relapsing Multiple Sclerosis. ClinicalTrials.gov Identifier: NCT01247324

A Study of Ocrelizumab in Comparison With Interferon Beta-1a (Rebif) in Patients With Relapsing Multiple Sclerosis. ClinicalTrials.gov Identifier: NCT01412333


"What the study below also exposes is that our current classification of MS is probably wrong. Instead of basing it on clinical observations we should include MRI characteristics as part of the classification. Clearly PPMSer with focal Gd-enhancing lesions are behaving, when it comes to a response to DMTs, as if they have RRMS. This is another reason why we should redefine relapses to include sub-clinical relapses as detected using MRI. I say this knowing that some of my colleagues will disagree with me." 


Hawker et al. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol. 2009 Oct;66(4):460-71.

OBJECTIVE: Rituximab, a monoclonal antibody selectively depleting CD20+ B cells, has demonstrated efficacy in reducing disease activity in relapsing-remitting multiple sclerosis (MS). We evaluated rituximab in adults with primary progressive MS (PPMS) through 96 weeks and safety through 122 weeks.

METHODS: Using 2:1 randomization, 439 PPMS patients received two 1,000 mg intravenous rituximab or placebo infusions every 24 weeks, through 96 weeks (4 courses). The primary endpoint was time to confirmed disease progression (CDP), a prespecified increase in Expanded Disability Status Scale sustained for 12 weeks. Secondary endpoints were change from baseline to week 96 in T2 lesion volume and total brain volume on magnetic resonance imaging scans.

RESULTS: Differences in time to CDP between rituximab and placebo did not reach significance (96-week rates: 38.5% placebo, 30.2%rituximab; p = 0.14). From baseline to week 96, rituximab patients had less (p < 0.001) increase in T2 lesion volume; brain volume change was similar (p = 0.62) to placebo. Subgroup analysis showed time to CDP was delayed in rituximab-treated patients aged <51 years (hazard ratio [HR] = 0.52; p = 0.010), those with gadolinium-enhancing lesions (HR = 0.41; p = 0.007), and those aged <51 years with gadolinium-enhancing lesions (HR = 0.33; p = 0.009) compared with placebo. Adverse events were comparable between groups; 16.1% of rituximab and 13.6% of placebo patients reported serious events. Serious infections occurred in 4.5% of rituximab and <1.0% of placebo patients. Infusion-related events, predominantly mild to moderate, were more common with rituximab during the first course, and decreased to rates comparable to placebo on successive courses.

INTERPRETATION: Although time to CDP between groups was not significant, overall subgroup analyses suggest selective B-cell depletion may affect disease progression in younger patients, particularly those with inflammatory lesions.

CoI: multiple

9 comments:

  1. If PPMS was an orphan disease would we need more trials of rituximab?

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    1. Re: "If PPMS was an orphan disease would we need more trials of rituximab?"

      Yes, the overall trial was negative it was only a small subset of PPMSers who had a positive response. Analysis of this subgroup was preplanned, which is why I think the results are real. The other argument is that in any new classification of MS that characterises Gd-enhancing lesions as subclinical relapses this subgroup of PPMSers will be reclassified as having relapsing disease.

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  2. If Ocrelizumab is successful and gets through its trials and NICE approval, then it will presumably cost the NHS a lot of money, whereas rituximab, a very similar drug, would be much cheaper. At that stage you wouldn't prescribe rituximab privately any longer as there will be an NHS drug available. Seems likely that the company who are not taking rituximab forward as an MS drug are more concerned with it coming off patent than its side effects.

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  3. "I have now rationalised this and realised that my primary responsibility is to individual patients and not the NHS collective."

    I hope more Doctors come to this conclusion.

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  4. Erm, what happens to the PPMSer that is the equivalent of your case patient but cannot afford a private prescription for rituximab? How does your conscience feel in that situation, Don Giovannoni?

    Begging of the end, if you ask me. It's shameful, actually. The heart has gone out of Britain. You're a decent bloke, Don Giovannoni. You know how abhorrent this Blair-sanctioned legislation is. It's breaking your heart, kid.

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    1. You are right it is breaking my heart; a great tragedy, in fact a national tragedy. The NHS is a changing and it happened under New Labour. Blair's legacy is not going to be a good one.

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  5. Where was the grand debate when you need one?

    Remember it is now a cross party stitch up.

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  6. How is a patient meant to decide which drug is good for them? I can read the info but not necessarily ingest all the relevant info-how much do you guide your patients ? Bear in mind that my neuro and his team say no to everything without thinking.

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    Replies
    1. http://multiple-sclerosis-research.blogspot.com/2015/10/ms-decisions-new-guide-from-ms-trust.html

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