Lemtrada: a tale of three regulators
Local health authorities, such as Health Canada, the European Medicines Agency (EMA) or the U.S. Food and Drug Administration, must review and approve all prescription medications before they can be sold. Experts base their decisions on the safety and effectiveness of a treatment according to data from clinical trials. But this seemingly black-or-white process – does a drug work and is it safe? – can be decidedly grey.
Case in point: Lemtrada (alemtuzumab). The same data from two large studies, CARE-MS-I and CARE-MS II, were submitted to regulators in different countries. In Canada, Lemtrada was approved in December for people who haven’t responded adequately to a prior MS treatment. In Europe, the EMA was even less restrictive, ruling that the drug could be used in anyone with active MS, not just those who have been on a prior medication.
The FDA took a different view. In December, it decided that there wasn’t enough evidence to show that the benefits of Lemtrada outweigh the risks. That means more trials are be needed – a costly and time-consuming prospect. It’s now unlikely that Lemtrada will be approved in the U.S. for several years (if at all), unless the FDA reverses its decision.
So how is it that three health authorities can view the same information and come up with three different conclusions?
Part of the problem was the two key trials. Both of the CARE-MS studies compared Lemtrada to Rebif, so there was no placebo group to show how people would have done with no treatment. In CARE-MS I, which looked at people who hadn’t been on treatment before, the annualized relapse rate (ARR) was 54% lower with Lemtrada than with Rebif (Cohen and colleagues. Lancet 2012;380:1819-1828). This is comparable to what is seen with Gilenya, which showed a 52% lower ARR than Avonex among previously untreated people in the TRANSFORMS trial (Cohen and colleagues. N Engl J Med 2010;362:402-415).
CARE-MS II looked at people who had been on another MS drug. Although this is a better real-world scenario, it’s a bit unfair to compare Lemtrada with Rebif since most people in the trial had already shown that they weren’t responding to Rebif or another interferon. This may explain why Lemtrada was better than Rebif on measures of disability. In CARE-MS I, both treatments had a similarly small effect on disability.
Perhaps the key problem with both studies was that they were unblinded. A “double-blind” trial means that both the doctor and the patient don’t know which treatment is being given. This is used to prevent bias: if you knew you were taking a placebo (or Rebif), there may be a tendency to expect that it will be less effective (on the part of the doctor as well). People are also more likely to quit a trial if they don’t like the group to which they’ve been assigned. In addition, trial participants were told that their treatment would be stopped if they reported a relapse, which may have motivated some people not to report relapses if they wanted to keep receiving their drug.
As a result of these effects, unblinded studies tend to report that a drug is more effective (by about 15%) than it really is (Savovic and colleagues. Ann Intern Med 2012;157:429-438; Schulz and colleagues. JAMA 1995;273:408-412). According to the FDA’s calculations, this bias would mean that there was no difference between Lemtrada and Rebif in most instances (Marler JR. FDA clinical review, October 1, 2013, p. 82). In consequence, the lack of blinding was flagged as a significant problem of the trials during discussions between the FDA and the drug’s manufacturer as far back as March 2010 (Marler, p. 18). The FDA raised this same concern in January 2011, but the design of the trial was never changed by the manufacturer.
Of course even if the treatment is blinded, side effects are often a give-away. Lemtrada is administered by intravenous infusion (a slow drip) and 90% of people taking the drug in the CARE-MS trials had an infusion reaction (headache, rash and/or fever), even though they all received a course of steroids beforehand. So a person would be very likely to know that they were taking Lemtrada even if attempts were made to hide which group they were in.
These issues about how the trials were conducted may seem a bit obscure. But they are critical in determining just how effective is a drug. In looking at the studies, the FDA reviewers remained unconvinced. “Evidence to support a claim that alemtuzumab [Lemtrada] slows the accumulation of physical disability is particularly weak,” one reviewer wrote (Marler, p. 8).
The other side of the benefit-risk equation when approving a new drug is the risks of taking a therapy. A concern is the possible serious side effects with Lemtrada, such as thyroid disease, new autoimmune disorders, infections and cancers. Indeed, the phase II study (called CAMMS223) of Lemtrada was suspended when three people developed serious side effects; one person died (CAMMS223 Trial Investigators. N Engl J Med 2008;359:1786-1801). While the risk of individual serious side effects is very low (about 1%), a concern is people would need to be monitored for a range of problems. Monitoring would have to be continued for years after stopping the drug because of Lemtrada’s extremely long treatment effect.
So the FDA’s view was that the benefits of Lemtrada were unclear whereas the risks were known.
In making this same calculation, the European Medicines Agency (EMA) had fewer concerns about how the studies were done so the Agency’s view was that the drug provided substantial benefits. (Health Canada hasn’t published its decision.) So the EMA ruled that the benefits of Lemtrada were greater than its risks (www.ema.europa.eu). However, educational materials must be provided to prescribers and to people taking the drug. A risk-management plan will also be in place to ensure that people on Lemtrada are monitored closely so serious side effects can be treated quickly.
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