Friday, April 4, 2014

The Wall Street Journal, the FDA and Antibiotics

I don’t know what happened.  Suddenly, the Wall Street Journal has been struck by the superiority trial disease in antibiotic development. Luckily, in most (but clearly not all) cases, this is a curable condition.  In two (1, 2) recent editorials, the WSJ has reiterated the complaints of Senator Grassley and Congressman (at that time) Markey that non-inferiority trials for new antibiotics are insufficient to show that they actually provide any advantage over older drugs, many of which are cheap and generic. But this is an utter falsehood and is misleading to consumers and practitioners.

Don’t get me wrong – I think, unlike some of my colleagues, that it will be possible to succeed in superiority trials for antibiotics.  But these will be very small, externally controlled trials for patients with unmet needs or they will be in embedded in a very targeted way in non-inferiority trials where resistance to the comparator drug is common. Superiority trials will never replace the non-inferiority approach to antibiotic development as some would prefer.

In one of the WSJ editorials, they highlighted two drugs recently reviewed by the FDA Advisory Committee on Anti-infective Drugs (AIDAC), tedizolid and dalbavancin.  Both drugs were studied in non-inferiority trials against comparator antibiotics in the treatment of serious infections of skin and soft tissues. Both these new drugs and their comparators were about 80-90% efficacious in treating these infections according to the FDA’s interpretation of the data. The AIDAC voted unanimously in favor of approval.

Tedizold was studied in comparison to linezolid or Zyvox.  Linezolid is given twice per day while tedizolid is taken once per day. Tedizolid was given for a six day course of therapy while linezolid was used for its FDA approved 10 day course of therapy. Although the phase III trial could not show a difference, it is very likely that with prolonged therapy, tedizolid will cause less bone marrow toxicity than linezolid and that it will be associated with fewer problems with drug-drug interactions – especially those with anti-depressant drugs. So both the phase III trial data and other data provided by the sponsor on tedizolid suggest that is will be superior to linezolid in a number of important parameters – less toxicity, shorter length of therapy, less worry about drug interactions.

Dalbavancin is in the same class of antibiotics as vancomycin and the latter was the comparator for its non-inferiority phase III trials. Both vancomycin and dalbavancin are administered intravenously.  But dalbavancin can be administered as a single dose of a one-week treatment period.  This opens up the possibility for single dose therapy in the emergency department and prevention of hospitalization for some patients. For patients with kidney failure, a single dose of dalbavancin could last for up to a month. Even though, from a treatment efficacy point of view, vancomycin and dalbavancin were comparable, dalbavvancin may still offer advantages over vancomyin. There were some safety concerns for dalbavancin and I have my own concerns about using a drug that you cannot get out of a patient if there is a problem.  But none of these were important enough for the AIDAC to ignore the potential advantage of single dose therapy of serious skin and soft tissue infections.

It is theoretically possible to show superiority even in the context of a non-inferiority trial.  But when your treatment success rates are 85% as was the case in these trials, it is hard to show that your drug would be superior at the 10% level (95% success). Nevertheless, other advantages may be more important than efficacy.  Simpler dosing regimes, potential for prevention of hospitalization, for earlier discharge from hospital, lower toxicity, fewer drug interactions to name a few.

The other issue that the entire process raises for me is, once again, that of the competence of the FDA’s advisory committees.  I looked at the roster for the meetings that occurred on March 31. I’m not sure that there is anyone there with clinical trial design experience in the area of antibiotics.  Certainly there is no one from industry with such expertise. This again shows that the FDA is hog-tied by its inability to get good advice from true experts because of overbearing and, in my view, unnecessary conflict of interest regulations.

So – I am thankful that the AIDAC did the right thing.  I am surprised and disappointed that the Wall Street Journal is trying to take us back to the bad old days of 2006 and the Ketek scandal. And I remain frustrated by the FDA’s inability to get good advice from experienced antibiotic developers.

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