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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