Biomedical Engineering Reference
In-Depth Information
Why do we need LPAD
? It is not feasible for antibacterial drugs that treat serious infections
due to highly resistant bacterial pathogens to be developed using traditional, large scale
clinical trials due to the limited numbers of patients in which such serious infections occur.
Examples of these organisms include
Acinetobacter baumannii
(which is threatening
soldiers returning from Afghanistan as well as patients throughout the U.S. and the
world), carbapenemase-producing
Klebsiella pneumoniae
, and
Pseudomonas aeruginosa
.
Such infections kill an astonishingly high percentage of infected patients (e.g., greater than
50%-60% of patients with infection in the blood, greater than 40%-50% of patients with
lung infection, etc.) despite any available treatment. Furthermore, extended-spectrum beta
lactamase (ESBL)-producing Enterobacteriaceae (e.g.,
Escherichia coli
[
E. coli
] and
Enterobacter
spp.), which often are resistant to all orally administered antibiotics, have
spread through health care systems and more recently into communities.
“For serious diseases for which few if any acceptable treatments are available, the tolerable
level of uncertainty regarding a potentially life-saving drug's effectiveness and safety
profile is much greater. As an example, before the first HIV drug was approved, even
highly toxic drugs were appropriately deemed approvable, because the infection itself
caused nearly a 100% mortality rate. As more and more new anti-HIV drugs were
approved, the death rate from HIV infection plummeted, and there was an increasingly
safe group of antiretroviral drugs already on the market. As such, the tolerability for risk for
each successively approved new agent became lower and lower, appropriately so. Similar
to the early years of HIV drug development, the benefit-risk ratio of approved LPAD drugs
will be quite different than for antibiotics approved under traditional development pro-
grams where the drug is indicated for use more broadly.” (FDA Docket No. 2012-N-1248
2013
).
The precedent for regulatory flexibility extended to AIDs drugs is highly relevant to
the current need for regulatory facilitation of new treatments for infections caused
by antibiotic-resistant bacteria, including antibiofilm agents. As reported by CDC
researchers (Klevens et al.
2007
), in 2005 there were an estimated 94,000 life-
threatening MRSA infections in the USA, resulting in 18,650 deaths, more than the
estimated 17,011 Americans who died of AIDs that same year (CDC
2007
revised).
“Under the LPAD approval mechanism, an antibacterial drug's safety and effectiveness
would be studied in substantially smaller, more rapid, and less expensive clinical trials—
much like the Orphan Drug Program permits for other rare diseases. LPAD products then
would be narrowly indicated to be marketed to and used in small, well-defined populations
of patients for whom the drugs' benefits have been shown to outweigh their risks. Many
bacterial diseases have a broad spectrum of severity. The LPAD mechanism is intended to
address the needs of a special population of patients with serious manifestations of such
diseases who lack satisfactory treatments. In caring for such severely ill patients with
limited treatment options, the patients, health care providers, regulators, and society can
tolerate a greater degree of uncertainty about overall risk associated with a drug than can be
tolerated in patients with milder manifestations of the disease, or those who have more
satisfactory therapeutic options. The LPAD mechanism will not be used to approve
antibacterial products that treat more common, less serious infections or infections where
sufficient alternative therapeutic options exist” (FDA Docket No. FDA-2012-N-1248
2013
).
In the Personal Views section of the March 2013 issue of Lancet Infectious
Diseases, a group of pharmaceutical company physicians and researchers proposed
a four-tiered regulatory framework for registration of new treatments that address
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