Friday, February 12, 2010

Pharmaceutical Companies are Chicken

Actually, this is not a blog about the use of antibiotics and hormones in poultry. It is about the pharmaceutical industry’s risk averse approach to developing antibiotics. In the interests of balance, I think we have to look critically at the industry as well as regulatory agencies.

Vancomycin has been a real workhorse antibiotic for the treatment of MRSA infections in our hospitals. But we now have three new antibiotics for the treatment of these infections, linezolid, daptomycin and, in 2009, telavancin. At the same time, there have been a number of scientific and clinical studies to suggest that vancomycin isn’t such a great antibiotic for the treatment of MRSA infections. Both linezolid and daptomycin were compared, in their late stage clinical trials, to vancomycin and both were shown to be “non-inferior.” Thus, they both were no worse than vancomycin within a reasonable statistical margin of error. Because antibiotics work so well in a normal clinical trial, it is usually impossible to actually show superiority of one antibiotic over another. In a few, more specialized trials, there is some evidence that linezolid might be superior to vancomycin, but these data were never approved by the FDA. Had the FDA actually accepted these data and approved a label suggesting that linezolid was superior to vancomycin, Pfizer would have been allowed to make that claim in their marketing efforts. At the time that daptomycin and linezolid were studied, there was no antibiotic other than vancomycin for them to use as a comparator. But for telavancin, which was just approved in 2009, both linezolid and daptomycin had been approved and on the market for several years before the pivotal telavancin trials were started. Cerexa/Forest is developing a cephalosporin antibiotic active against MRSA. For their recently completed Ph. III trials, they also chose to use vancomycin as their comparator.

So why did Theravance - Astellas and Cerexa/Forest choose vancomycin as the comparator? I can think of a number of reasons why they should not have done so. First, vancomycin sells at a lower price. In Europe, the price of your comparator comes into consideration when you get into the ultimate price negotiations that you have to go through with each individual country to market a new drug. So using a higher priced comparator would have made the argument that you too can charge a higher price more palatable to the national authorities in Europe. In addition, some influential clinicians believe strongly that vancomycin is an inferior drug compared to both linezolid and daptomycin. There is some evidence to support this view even though the data could not be used by regulatory authorities to approve such a claim. In that case, why would you not want to show non-inferiority compared to what might be an inferior antibiotic? It is of interest that Cerexa/Forest are running a Phase II trial comparing ceftaroline to linezolid in the treatment of skin infections. This suggests that they are aware that some clinicians consider linezolid a superior drug but made an active decision not to pursue linezolid as a comparator in their first pivotal trials.

I think the answer to this question goes back to risk. Companies are risk averse and they worry that they might be wrong and that they might not succeed against the newer antibiotics even though the risk, in my view, is a small one given everything we know about all these drugs. I’m sure other considerations come into the discussion as well. Both daptomycin and linezolid are expensive. The companies, in this example Theravance-Astellas and Cerexa/Forest, would have to pay the going rate for the comparator drug for hundreds of patients. This would significantly increase the cost of the trials. Also, they might have considered that because vancomycin had been used in so many trials as a comparator, it was much better characterized and provided a more reliable comparator. Finally, they might not have wanted to provide additional data for their future competitors, Cubist (daptomycin) and Pfizer (linezolid). Perhaps they were all dissuaded by Arpida who carried out two Ph. III trials of their antibiotic, iclaprim, compared to linezolid and failed to show non-inferiority.

Theravance-Astellas or Cerexa/Forest might argue that, based on volume of use, vancomycin is still the most widely used antibiotic for the treatment of serious Gram positive infections in hospitals where MRSA is common. That vancomycin is the most widely used of the anti-MRSA drugs remains true partly for cost reasons, where vancomycin is considerably less expensive than linezolid and daptomycin. The fact that there are no data approved by a regulatory authority recognizing the superiority of either daptomycin or linezolid over vancomycin in the treatment of MRSA infections probably also contributes to this situation.

I believe that companies should be providing the best data for physicians and patients. This should be a prime consideration in the choice of a comparator for pivotal clinical trials. The comparator should be the gold standard. The gold standard is not always the same as the so-called standard of care.

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