When considering the likely implications of good news arriving during Q2 from the dog toxicity and Cystic Fibrosis studies, the key unknown for me is in whether or not the FDA will view the Arikace clinical trial data primarily as proof of efficacy of a delivery vehicle.
Would effective delivery of amikacin to a given pulmonary infection be viewed under the new legislation as a "surrogate endpoint" for effective delivery of amikacin to similar pulmonary infections? -
"The Secretary may approve an application for approval of a product for a serious or life-threatening disease or condition, including a fast track product, under section 505(c) or section 351(a) of the Public Health Service Act upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit ..."
If the CF study proves that Arikace delivers an effective concentration of amikacin to a pulmonary pseudomonas infection, would not that convey a "reasonable likelihood" that Arikace will deliver an effective concentration of amikacin to any amikacin-susceptible gram-negative pulmonary infection?
And if the NTM study proves that Arikace delivers an effective concentration of amikacin to a pulmonary NTM infection, would not that convey a "reasonable likelihood" that Arikace will deliver an effective concentration of amikacin to any amikacin-susceptible mycobacterial pulmonary infection?
Provided these two studies evidence a compelling level of efficacy, I believe it is now within the FDA's mandate to approve Arikace for the treatment of pulmonary infection by amikacin-susceptible strains of five of the nine potential threats to public health specifically targeted by the new legislation.
It seems to me there would have to be a very good reason for the FDA not to allow physicians to take full advantage of a far safer delivery of an antibiotic with such a wide spectrum of activity. I'm hoping nobody here can suggest a very good reason :-)
"I'm hoping nobody here can suggest a very good reason"
Unrealistic expectation is almost as bad as unrealistic bashing. If anybody here sees an obvious barrier to the FDA approving Arikace as a therapy for ALL amikacin-susceptible pulmonary infections you'd be doing us all a favour by speaking up.
"During the 2 decades following the establishment of the accelerated approval mechanism, advances in medical sciences, including genomics, molecular biology, and bioinformatics, have provided an unprecedented understanding of the underlying biological mechanism and pathogenesis of disease. A new generation of modern, targeted medicines is under development to treat serious and life-threatening diseases ..."
"As a result of these remarkable scientific and medical advances, the FDA should be encouraged to implement more broadly effective processes for the expedited development and review of innovative new medicines intended to address unmet medical needs for serious or life-threatening diseases or conditions, including those for rare diseases or conditions, using a broad range of surrogate or clinical endpoints and modern scientific tools earlier in the drug development cycle when appropriate."
"The Secretary may approve an application for approval of a product for a serious or life-threatening disease or condition, including a fast track product, under section 505(c) or section 351(a) of the Public Health Service Act upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments. The approval described in the preceding sentence is referred to in this section as `accelerated approval'."
While your post will undoubtedly get a dozen or so thumbs down from various ID's(one person), I listened to the Cowen conference, and Lewis said that arikace will be used on a compassionate use basis for NTM sometime around mid year. The guidelines for a drug beng used for compassionate use are very similar to those you just posted for accelerated approval.
Expanded access, sometimes called "compassionate use," is the use of an investigational drug outside of a clinical trial to treat a patient with a serious or immediately life-threatening disease or condition who has no comparable or satisfactory alternative treatment options.
For anybody who isn't familiar with the distinction between a surrogate endpoint and a medical endpoint -
A study of the effect upon a medical endpoint in the CF patient population might have entailed treating 150 patients with Tobi and 150 patients with Arikace for the rest of their lives - and then determining if the patients on Arikace lived longer.
Clearly a short-cut was preferable.
If a drug has a modest effect upon the rate of deterioration in FEV-1, that in itself doesn't translate to an improvement in the patient's health. Lung capacity could still be gradually deteriorating, but more slowly. However, if a drug does meet that surrogate endpoint it is considered by the FDA as reasonably likely to prolong the lives of CF patients (a medical endpoint).
The new legislation specifically identifies four gram-negative pathogens which have developed multi-drug resistant strains with the potential to pose a serious threat to public health. Pseudomonas is one, but all four are pathogens for which the FDA has already approved amikacin as a therapy.
The FDA could simply use the current Arikace clinical trial to approve Arikace only for CF. Insmed could then initiate four additional programs, to determine the potential of Arikace to control infection by each of those pathogens in the wider patient population.
Alternatively - if Arikace meets surrogate endpoints in the CF clinical trial such as "Change in density in Pseudomonas aeruginosa in sputum", the FDA could consider it reasonably likely that Arikace would prolong the life of any patient seriously ill with an amikacin-susceptible gram-negative pulmonary infection.
A high priority in countering the threat to public health posed by the proliferation of drug-resistant strains is to eradicate an infection as quickly as possible once antibiotic treatment is initiated. Arikace seems likely to eradicate pulmonary infection by amikacin-susceptible pathogens far more quickly than is currently possible.