Is it ethical to randomise interferon-beta failures in a trial back onto interferon? #MSBlog #MSResearch
Epub: Cohen et al. Fingolimod vs. intramuscular interferon in patient subgroups from TRANSFORMS. J Neurol. 2013.
Background: In the 12-month phase 3 TRANSFORMS study, fingolimod showed greater efficacy than intramuscular interferon beta (IFNβ)-1a in RRMSers.
Objective: This study analyzed fingolimod efficacy compared with IFNβ-1a in MSer subgroups from TRANSFORMS.
Methods: MSers were randomized to receive fingolimod or weekly IM IFNβ-1a for 12 months. Analyses of efficacy included annualized relapse rate (ARR), and magnetic resonance imaging (MRI) measures [gadolinium (Gd)-enhancing T1 lesions, new/newly enlarged (active) T2 lesions, brain volume change]. Subgroups were defined based on demographics, disease characteristics (baseline EDSS score, relapse rate, and MRI parameters), and response to previous therapy.
Results: Fingolimod 0.5 mg reduced ARR over 12 months by 32-59 % relative to IFNβ-1a in all subgroups defined by demographic factors or baseline disease characteristics. Fingolimod also reduced the number of new Gd-enhancing lesions, active T2 lesions, and the rate of brain volume loss, versus IFNβ-1a in most (95 %) subgroups. In MSers with high disease activity despite IFNβ treatment in the year before study, fingolimod 0.5 mg reduced ARR by 61 % relative to IFNβ-1a. Reductions in lesion counts and brain volume loss also favored fingolimod in these MSers.
Conclusions: In conclusion, consistently better efficacy was observed for fingolimod compared with IFNβ-1a across different subgroups of RRMSers.
Vs.
“This subgoup analysis shows that if you have highly-active MS fingolimod has a greater effect on relapses than in active MSers. This seems to be a common theme across all DMTs; i.e. the more active your disease the greater the therapeutic impact. Why? As always the results are relative, and depend on the activity in the comparator group; the greater the activity in the comparator group the greater the relative efficacy. The problem with the TRANSFORMS study is ~50% of subjects had previously been on interferon-beta before going into the trial and had had at least one documented relapse during the previous year or at least two documented relapses during the previous 2 years; in other words half the study subjects were interferon failures or interferon suboptimal responders. Therefore comparing fingolimod to this groups inflates its relative efficacy. So is fingolimod better than interferon-beta? It probably is but at not at level of 61% in the highly active group. To assess this we would need a head-2-head study in MSers who have never been on interferon-beta in the past. This study is unlikely to happen at this stage.”
“Is it ethical to randomise interferon-beta failures in a trial back onto interferon?”
“Is it ethical to randomise interferon-beta failures in a trial back onto interferon?”
CoI: multiple
Treating a patient with IFN will not reduce to null the occurrence of relapses. Only one third do not have a relapse during the pivotal studies. Included patients might thus correspond to approx 50% of treated patients with IFN.If we consider that a patient with one relapse a year under IFN should be put under tysabri or mitoxantrone, then it would be unethical, but it is not the case : patients having a relapse under IFN are often maintained under IFN. However, it might be considered unethical if the opportunity to be treated with these second line treatments was not proposed or discussed with the patient prior to trial inclusion. Was is written in the inform consent form?In fact, what I really consider as unethical is to consider that all IFN induce a 30% percent decrease in relapse rate. It is obvious that when you exclude from the analysis of a trial a group of patients for which the placebo is doing better than the IFN, you will get a better (biased) final result with the IFN. Unfortunately, this is not obvious for EMA, FDA and all those who said that all IFN induce a 30% reduction in relapse rate. Is it ethical to say that product with different efficacy have the same efficacy? I would answer no but a lot of people say yes, including those who decide who should get what for treatment. More information http://www.la-press.com/redirect_file.php?fileId=4504&filename=Approved-Beta-Interferons-in-Relapsing-Remitting-Multiple-Sclerosis_Odd_One_Out2&fileType=pdf
You need to read the posts on this blog on disease-activity free status and NEDA. It is clear that MSers left to relapse on interferons do very badly. If you are on an interferon or glatiramer acetate and you have relapses and/or MRI activity you need to change treatment. The treatment target is to eliminate all detectable disease activity; i.e. there must be no evidence of disease activity (NEDA). We still need to test treatment strategies, but we need to design trials that are ethical and take into account treatment trends. To be fair to the clinicians who designed the TRANSFORMS study, DAF or NEDA was only just emerging as a treatment concept.http://multiple-sclerosis-research.blogspot.co.uk/2013/01/treat-2-target-neda-no-evidence-of.htmlhttp://multiple-sclerosis-research.blogspot.co.uk/2013/02/neda-defining-cure.html
Thank you for your interesting point.Using NEDA paradigm to implement a trial could have huge implications for clinical trials.Patients included should be switched to another treatment at the first occurrence of an activity sign. Only time to activity could be use as outcome. Induced attrition would limit tolerance evaluation. Placebo controlled would be almost unethical as far as you include patients having had a relapse. I wonder if we would not lose any possibility to correctly evaluate a product if such trials were made mandatory prior to approval (which was the case for TRANSFORM).As you have probably noticed, literature on responders and non-responders is scarce. Providing such data reduces the market for the product ! Without this information, you have to chooseyour treatment according to tolerance, acceptance and a probability of success evaluated on all patients, wait until first activity signals, switch and so on… or put everyone on Natalizumab or when possible Alemtuzumab at treatment start. NEDA might be the good process for treatment but for pre-approval trials, it might not be as good. As a well-known investigator, ask for data on responders and non-responders to quicken the attribution of the right treatment for the right person. Unfortunately, I am afraid you won’t be very successful.Last point : If a patient is doing badly under Avonex, would you switch to another IFN or Glatiramer (considering they are more efficient) or directly to second line treatments?
The study URLed above by anon contains some very disturbing facts: If all patient cohorts in the Avonex trial were followed for 2 years then the reduction in relapse rate would only be 10%, ie statistically insignificant.Since Prof GG has experience in drug trials i think he should comment on this. Is the author of the study (Alexis Clapin) right or wrong in making such statements? Was there statistical manipulation in favor of Avonex, yes or no? Was it acceptable not to follow for a second year a subgroup of patients who did better on placebo?
Re: "If a patient is doing badly under Avonex, would you switch to another IFN or Glatiramer (considering they are more efficient) or directly to second line treatments?"In the UK NICE makes this decision for us. You can only escalate to a more active drug if you meet NICE guidance. In an ideal world the MSer will have the choice of switching to GA or escalation. The latter is a risk:benefit analysis that the MSer need to make based on their own profile. I am not the one with the disease. I have major concerns about spending years on the lower tier drugs with ongoing activity that causes damage. It is clear that time lost is time brain lost. Therefore, if someone has active disease they should be offered the best drug at suppressing that activity. This is what underlies NEDA and treat-2-target.
I guess it would be unethical to have a trial with patients randomized to interferon if they have previously failed interferon.However, the definition of failure of a therapy is not clearly understood by the patients, let alone the doctors treating them.http://www.jhasim.com/files/articlefiles/pdf/ASIM_8_8_p274_283.pdf