My source of information for this blog comes from John Rex
who has been instrumental in the thinking leading to these considerations. I did not participate in any of the relevant
meetings. We don’t agree on everything...
An email to the FDA (Ed Cox) inquiring about this has gone
unanswered.
By way of context, there have been a number of conversations
over recent years about the potential value of a clinical network for
antibacterial development. This idea was discussed at some length, for example,
during a July 2014 NIH-NIAID-FDA workshop
where examples of this work in other areas (e.g., oncology) were discussed.
But, the challenge of designing trials focused on MDR and
XDR pathogens are formidable and recent efforts (e.g Achaogen)
have shown us how hard this can be. Indeed, enrolling patients with MDR and XDR
infections is hard for lots of good reasons – indeed, we want these infections to be rare.
But, we also know that infection prevention will never be
perfect and we definitely need new drugs.
As a strategy for circumventing this problem, a recent Request
for Information from BARDA suggests a very different approach. In brief,
the RFI proposes creation of a network that is focused on pathogens that are
susceptible to least one reasonably available drug.
Here’s where John Rex comes in. Along with his several of
his colleagues, he’s proposed a new acronym for us to consider along with the
well-known acronyms MDR and XDR:
·
UDR: Usual Resistance
·
MDR: Multi-drug resistance
·
XDR: Extensive multi-drug resistance
Importantly, UDR is not the same as wild-type. Rather, UDR
speaks to the ease of selection of therapy and by extension, ease of selection
of a comparator for a global trial:
·
UDR: Many easy choices. Easy to choose a single
global comparator.
·
MDR: Harder – may need 2nd-line drug. Single
comparator is harder
·
XDR: Needs a difficult or unusual drug.
Comparator must be ad hoc.
The core notion that a network could be built out of studies
of UDR isolates. Indeed, John points out, the BARDA RFI proposes creation of 3
networks designed to run for up to 10 years. There would be one network for
each of the three major Gram-negative infections (cUTI, cIAI, and HABP/VABP).
The network would be constantly running clinical trial that would permit
investigational drugs to rotate in and out efficiently. A picture is really
helpful … here’s the graphic from the BARDA RFI.
Imagine Control #1 as a carbapenem and you begin to see how
the UDR idea works — basically the network could be established at a collection of
hospitals and most patients with cIAI would (probably) be eligible. Indeed,
patients known to be infected with something NOT susceptible to a carbapenem
would be ineligible.
The sponsor is still free to pursue MDR or XDR pathogens in
parallel studies, but putting a drug through this network is a low-risk way to
get a good clean trial run against a high-end comparator and hence build a
solid foundation for registration.
The success of this strategy depends also, in part, on being able
to make a strong PK/PD (pharmacokinetic/pharmacodynamic) argument that if the
drug works against UDR organisms, it will also work against highly resistant
ones IF the resistant ones are “susceptible” to the new drug.
That means that the dose used must achieve adequate systemic
levels of the drug over an adequate time period such that the infection can be
cleared even if caused by organisms resistant to many other antibiotics. For this to occur, the growth of the organism
in question must be inhibited by a concentration of the new antibiotic
previously shown in test tubes (MICs) to indicate that the antibiotic will work
in systemic therapy.
Both regulatory authorities, I am told by John, support the
UDR approach to approving drugs. The
label might read – “shown to be efficacious in the treatment of cUTI (for e.g.)
due to susceptible strains of X,Y and Z bacteria.” And this makes wonderful
sense and shows that the FDA in particular agrees that PK/PD arguments are
valid.
Companies, though, are concerned that even if the FDA and
EMA will approve new antibiotics under these circumstances, physicians still
want to see controlled trial data showing convincing activity against these
resistant pathogens. The “community”
apparently is not ready for the PK/PD argument yet. Or at least, that is the
concern of some companies. My view is
that this is a matter of education.
PK/PD rules! So I completely support the UDR stance.
Notice that all of the above considerations work for non-inferiority trials of relatively broad spectrum agents. For rare diseases, rare pathogens or pathogen specific antibiotics, these designs will probably not be feasible. But – I believe that there are other ways to skin this
cat. For further discussion with John see the next blog.
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