Europe, Antibacterials, Pull Incentives and Access

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Europe, as opposed to various national authorities, is well poised to provide funds to support the broken antibiotic market. If this ever comes to be, how will products deserving of such support be chosen? Separately, will European regulators continue their slide back to requiring infeasible clinical trials and thereby limiting access to new antibiotics in Europe or will they wake up?

Without a significant pull incentive, our pipeline of new antibacterials is doomed. This must be our top priority. If a significant pull incentive for new antibacterial research and development is to occur, there must be a mechanism for choosing which products and sponsors will be its beneficiaries. Product novelty, “value” and potential clinical utility (and others) have been proposed as criteria for making this decision. But clear definitions for these criteria are either lacking, vague or conflicting among various authors, organizations and proposals. One example of the result of this lack of clear criteria is the disparity in choices of products to be included in the UK and Swedish antibiotic subscription programs. [Sweden - Zerbaxa (ceftolozan-tazobactam), Recarbrio (imipenem-cilastatin-relebactam), Fetcroja (cefiderocol), Vaborem (meropenem-vaborbactam) and Fosfomycin infectopharm (fosfomycin).  UK - cefiderocol (Fetcroja) manufactured by Shionogi, and ceftazidime with avibactam (Zavicefta)]. This is also a good argument for a European approach (Brexit notwithstanding). 

It is possible that very targeted therapies for infections caused by specific pathogens or pathogens expressing specific resistance mechanisms will be considered for pull incentive awards. But we have still not yet resolved how such therapies will be approved by regulatory authorities nor how we will furnish sufficient relevant data in support of such products to convince physicians and their patients of the value of such products. While similar considerations might apply to novel adjunctive therapies, a consideration of those products goes beyond the scope of this article.  

I would like to offer thoughts bearing on the definition of innovation and clinical utility for the purposes of awarding a pull incentive. I will limit myself to small molecules that act directly against bacteria designed to be used in the acute hospital setting. I would emphasize that considerations for antibacterials designed for use in the community setting might be quite different. 

Innovation vs. Clinical Utility

Many have proposed that innovation be a key criterion for awarding a significant pull incentive to a sponsor. How could that be defined?

Does it mean that the drug acts via a novel mechanism? If so, the assumption is that a new mechanism provides an advantage not seen with drugs exploiting known mechanisms of action. The usual justification for this choice is the avoidance of known resistance mechanisms. The flaw in this argument is that many compounds exploiting traditional mechanisms of antibacterial activity achieve that goal and they do so with less inherent risk of failure. 

Does innovation mean that the chemistry is novel? But innovation in this regard must be placed in context since to acquire a basic patent on composition of matter, the chemistry must have at least some novelty. 

These questions can be explored using current examples of pipeline and recently marketed antibacterials. There are a number of examples of B-lactamase inhibitors utilizing either DABCO (diazabicyclooctane) or boron chemistry (see EntasisVenatoRx and Qpex). These approaches would not be considered by many as novel at this point. But what about boron beta-lactamase inhibitors that inhibit both serine- and metallo-enzymes by assuming different binding modes for each class? To me – this is novel. The chemistry might not be novel.  The basic mechanism of inhibition might not be novel.  But the overall result is clearly novel – and not only that – but will be enormously useful for physicians and their patients. 

DABCO chemistry is not only useful for finding inhibitors of beta-lactamase but can also be used to find inhibitors of penicillin binding proteins (PBPs). This approach goes back to the 1990s (Roussel, Novexel, Entasis).  Does that render it non-innovative? I would say that if such a PBP inhibitor offered clear advantages over our armamentarium of beta-lactam PBP inhibitors, it would be clinically useful.  Examples of such advantages might include avoidance of allergic cross-reaction (up to 10% of patients will give a history of beta-lactam allergy), avoidance of efflux-based resistance or avoidance of hydrolysis by key beta-lactamases.

Let’s put ourselves in the place of a physician in an intensive care unit. Our intubated, ventilated patient had just developed fever, confusion and lowered blood pressure. We know that Pseudomonas is a potential pathogen here and we know that in our hospital about 15%, of our isolates are resistant to carbapenems and multiple other drugs. We also know that some of these isolates harbor a metallo-beta-lactamase. Are we going to care whether our antibiotic choice is "novel" or not as long as it is fit for purpose?

I would argue that our major criterion in selecting compounds deserving of a pull incentive reward should be clinical utility. This clearly takes activity against resistant infections into account. It also can include lower toxicity, avoidance of serious allergic reactions, ease of use (e.g. both oral and IV formulations available), and the potential to avoid the rapid selection of resistance. Compounds that are difficult to fit into current clinical paradigms for use should not receive our highest priority without a clear consideration as to their clinical use, utility, and acceptance by physicians and patients. 

Access and EMA

In thinking about Europe, I must turn to the new European Medicines Agency. In brief, the US FDA learned after six (some would say 12) long years of stifled antibacterial development, that requiring clinical trial designs that were practically and financially infeasible would kill our antibiotic pipeline.  Apparently, Europe has yet to learn this lesson.  I am referring to the EMA’s requirement that plazomicin and omadacycline undertake trial commitments that would have been financially infeasible given current market conditions.  These drugs were both pulled from consideration and are not marketed in Europe. While one might argue over the value of these particular drugs in the treatment of patients, it is clear that EMA’s action was yet another nail in the coffin of investment in antibacterial research and resulted in a loss of access to these drugs for countries that might have wanted to have them available. 

# Reprinted with permission of the author. Dr. Shlaes' original blog post can be found here.