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In Search of Meaningful GAIN in Renewal of Prescription Drug Act

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treat pneumonia and skin infections, generated $1.3B in revenues last year, but this was achieved relatively slowly and has flattened with only 3.5 years of patent life left. Compare this with the situation at Cubist, which reported about $800 million in revenues last year, largely from the sales of daptomycin (Cubicin). Growing Cubist’s revenue by five percent would necessitate generating only about $40 million in new revenues. That can be achieved by the second year on the market for a reasonably differentiated hospital antibiotic. Daptomycin generated $59 million in revenue in its second year on the market in 2004). With approximately another six years of patent life left, Cubicin could generate revenue growth for Cubist that scales appropriately with the company’s size. Scaling revenue potential to the market is critical to companies and their investors.

Secondly, under the current FDA regulatory paradigm, achieving that $1 billion in peak sales would require any company to make an enormous investment in multiple sets of expensive, global Phase 3 trials. Antibiotics are the only therapeutic area in which multiple sets of registration-quality Phase 3 trials are necessary to gain full market potential. As an example, under the current regulatory paradigm in the U.S., a new agent for treating methicillin-resistantStaphylococcus aureus (MRSA) would have to undergo 6 Phase 3 trials—2 each in skin, lung and bacteremia—to be labeled for those indications even though MRSA is the common pathogen in each. Is there any wonder why large pharmaceutical companies have backed out of this area when they can deploy their development dollars in more lucrative therapeutic areas? The GAIN Act does not address this critical issue.

Nevertheless, there is a glimmer of hope in terms of addressing this issue in provision 5, “Pathogen-focused drug development.” Should the FDA truly revamp the antibiotic approval process in a manner that is more consistent with how clinicians treat patients—i.e. by the type of pathogen causing the infection rather than by what body part the pathogen happens to reside in—we would likely see an enthusiastic response from clinicians, patients, companies and investors. There is precedence for this in Japan where, in the case of MRSA, a single “all comers” Phase 3 trial is conducted that enrolls patients with MRSA skin, lung and bacteremia infections. This single trial enrolls much faster, is significantly less expensive to conduct and gets new antibiotics in the hands of clinicians and their patients much faster.

Are Japanese regulatory authorities more cavalier about the treatment or safety of patients? Of course not. As part of the approval process, all prior clinical and non-clinical supportive data are reviewed and must be consistent with efficacy and safety in the targeted indications. One important advantage that antibiotics have is that such early nonclinical data are highly predictive of Phase 3 results. If this is recognized and adopted in the FDA’s guidance in time to address the growing epidemic of multidrug-resistant infections, the U.S. populace will experience a truly meaningful “gain.”

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  • mgw6

    If the need is for antibiotics to treat these resistant strains then one
    of the biggest challenges for antibiotic development is not just
    finding new antibiotics but finding new antibiotics that can prove they
    are better against these pathogens, with clinically meaningful better
    outcomes, than currently available antibiotics. Providing incentives to
    develop another mediocre (“me too”) antibiotic merely because it has
    MRSA or some other resistant pathogen in its in vitro (lab) spectrum is a
    waste of money. For new antibiotics to qualify for the benefits of
    GAIN, for example, shouldn’t they be required to demonstrate (in the
    clinic, not just in the lab) that they actually can treat multi-drug
    resistant pathogens that are resistant to currently available

    • Jeff Stein

      You are certainly correct about the importance of clinical demonstration of efficacy and safety and this is why the FDA is updating guidance for antibiotic clinical trials. Keeping guidance up to date with the current science is a key objective. The challenge in an antibiotic clinical trial setting, however, is how to design a trial that is ethical, feasible and generates statistically meaningful results. For example, as much as we would like to design a trial that targets patients with linezolid resistant strains, to demonstrate that tedizolid is effective and linezolid is not, we cannot ethically conduct such a study knowing that 50% of the patients in the double blind linezolid controlled study will likely fail treatment. However, we can conduct animal studies to demonstrate this and there is ample evidence that the results of such studies for antibiotics translate to human clinical efficacy. With respect to your question about the GAIN Act, the QIDP designation is only given to drugs that have an approved new NDA based on clinical efficacy, not in-vitro activity against MRSA (in this example). In the article, I advocated for a clinical trial design that is more consistent with how clinicians treat infections and this is entirely consistent with your comments. Points well taken.