Feature

Q&A: New model could improve antibiotic development

Brad Spellberg
Brad Spellberg

Although the current approach to incentivizing antibiotic development has led to the creation of effective treatments, the pipeline has collapsed numerous times, leaving clinicians stranded against increasingly resistant infections, according to an article published the Annals of Internal Medicine.

To combat increasing drug resistance, Brad Spellberg, MD, chief medical officer at the Los Angeles County-University of Southern California Medical Center and professor of clinical medicine at USC’s Keck School of Medicine, and colleagues are proposing a new model known as the Developing Antibiotics for Resistant Targets (DART) Board, which shifts the focus of antibiotic development to pathogens that are most likely to or have already developed extreme antibiotic resistance.

Spellberg discussed the DART Board with Healio Primary Care, and how it would improve antibiotic development. – by Erin Michael

Q: Many of the newest antibiotics offer the same coverage as previously approved drugs. What is the best way to use economic incentives to develop antibiotics for which we are in greatest need?

Pill Bottles 
Although the current approach to incentivizing antibiotic development has led to the creation of effective treatments, the pipeline has collapsed numerous times, leaving clinicians stranded against increasingly resistant infections, according to an article published the Annals of Internal Medicine.
Source: Shutterstock

A: The first point is, the best way is to use incentives to develop drugs for which we are in the greatest need, not to develop me-too drugs that don’t differentiate from others already on the market.

As far as how to do that, there needs to be guidance regarding what the current and projected needs are, and that guidance must be dynamic. Unmet needs change over time, both because new drugs come on to the market resolving prior needs, and because new resistance emerges, creating new unmet needs. We need to have some process by which a list of prioritized unmet needs is created and regularly updated to determine which pathogen targets incentives should be deployed against.

Q: Tell us how the DART Board works, and what it could mean for antibiotic development.

A: The DART Board is our proposed solution to the above problem. DART would have experts on it who understand what clinician and patient needs are for new antibiotics, in real time, and projecting forward for the coming decade. This would be based on current patterns of resistance being encountered in hospitals at the bedside, the currently available antibiotic armamentarium with which to treat those infections, and also a thorough understanding of what is currently in the pipeline.

It is very dismaying when lawyers, economists and policy people tell experts in infectious diseases what drugs we need to take care of our patients. We are the experts, at the front lines, at the bedside. We know our needs. The amount of disinformation that comes from those who do not understand the practice of medicine is dismaying. We need to have a voice in what the unmet needs are, to guide incentive deployment for new therapies. The DART Board would meet regularly and would regularly update a list of priority targets for incentives. That list would have to be imbued with the authority to target/limit deployment of publicly funded incentives. It would supersede the list in the GAIN Act, which has numerous pathogens on it that do not reflect unmet need for new antibiotics. Other pathogen lists out there, such as the CDC list and WHO list, have no authority to delimit incentive deployment, are not regularly updated, have no transparent process established for updating, and also have pathogens on them that do not reflect current unmet needs for new antibiotics.

Q: What changes would you make to the regulatory mechanisms that govern clinical trials of antibiotics targeting XDR organisms and why?

A: One of the great paradoxes of antibiotics is that just being safe and effective is not enough to declare them an appropriate treatment for an infection. Broad-spectrum agents that can kill highly resistant bacteria should not be used to treat pathogens for which many other antibiotics are available. For example, piperacillin-tazobactam and fluoroquinolones have activity against Pseudomonas aeruginosa and other resistant gram-negative bacteria. They are effective for treating infections caused by streptococci and staphylococci, for which we have many other agents. But they should not be used for such infections, because we need to preserve them for patients who truly need them, and who do not have multiple other options.

Ironically, FDA pathways to approval are typically based on treating nonresistant bacteria causing common bacterial syndromes, such as urinary tract infections and abdominal infections. Those are the pathways most recently approved new antibiotics have taken. Which means powerful new agents to treat carbapenem-resistant Enterobacteriaceae received FDA indications to treat nonresistant, regular old Escherichia. coli causing pyelonephritis or appendicitis. That is wrong. Since the FDA label limits corporate marketing, we are forcing companies to market new antibiotics for inappropriate use, and actually precluding them legally from marketing the drugs for appropriate use. It’s completely topsy-turvy. We need to have clinical trial pathways that allow important new antibiotics to be studied in a manner aligned with clinical need, which will result in a label aligned with clinical need, which will limit marketing in a manner aligned with clinical need. We have suggested ways to do this in the article, including Bayesian multi-body site, pathogen-specific trials, and platform trials.

Reference:

Spellberg B, et al. Ann Intern Med. 2019;doi:10.7326/M19-1893.

Disclosures: Spellberg reports receiving consulting fees from Acuryx, Alexion, Bayer, Cempra, Forge, GlaxoSmithKline, Merck, Paratek, Peptilogics, Pfizer, Shionogi, Synthetic Biologics and Tetraphase, and equity from BioAIM, ExBaq, Motif, MycoMed, NovaDigm Therapeutics and Synthetic Biologics outside the submitted work. Please see study for all other authors’ relevant financial disclosures.

Brad Spellberg
Brad Spellberg

Although the current approach to incentivizing antibiotic development has led to the creation of effective treatments, the pipeline has collapsed numerous times, leaving clinicians stranded against increasingly resistant infections, according to an article published the Annals of Internal Medicine.

To combat increasing drug resistance, Brad Spellberg, MD, chief medical officer at the Los Angeles County-University of Southern California Medical Center and professor of clinical medicine at USC’s Keck School of Medicine, and colleagues are proposing a new model known as the Developing Antibiotics for Resistant Targets (DART) Board, which shifts the focus of antibiotic development to pathogens that are most likely to or have already developed extreme antibiotic resistance.

Spellberg discussed the DART Board with Healio Primary Care, and how it would improve antibiotic development. – by Erin Michael

Q: Many of the newest antibiotics offer the same coverage as previously approved drugs. What is the best way to use economic incentives to develop antibiotics for which we are in greatest need?

Pill Bottles 
Although the current approach to incentivizing antibiotic development has led to the creation of effective treatments, the pipeline has collapsed numerous times, leaving clinicians stranded against increasingly resistant infections, according to an article published the Annals of Internal Medicine.
Source: Shutterstock

A: The first point is, the best way is to use incentives to develop drugs for which we are in the greatest need, not to develop me-too drugs that don’t differentiate from others already on the market.

As far as how to do that, there needs to be guidance regarding what the current and projected needs are, and that guidance must be dynamic. Unmet needs change over time, both because new drugs come on to the market resolving prior needs, and because new resistance emerges, creating new unmet needs. We need to have some process by which a list of prioritized unmet needs is created and regularly updated to determine which pathogen targets incentives should be deployed against.

Q: Tell us how the DART Board works, and what it could mean for antibiotic development.

A: The DART Board is our proposed solution to the above problem. DART would have experts on it who understand what clinician and patient needs are for new antibiotics, in real time, and projecting forward for the coming decade. This would be based on current patterns of resistance being encountered in hospitals at the bedside, the currently available antibiotic armamentarium with which to treat those infections, and also a thorough understanding of what is currently in the pipeline.

It is very dismaying when lawyers, economists and policy people tell experts in infectious diseases what drugs we need to take care of our patients. We are the experts, at the front lines, at the bedside. We know our needs. The amount of disinformation that comes from those who do not understand the practice of medicine is dismaying. We need to have a voice in what the unmet needs are, to guide incentive deployment for new therapies. The DART Board would meet regularly and would regularly update a list of priority targets for incentives. That list would have to be imbued with the authority to target/limit deployment of publicly funded incentives. It would supersede the list in the GAIN Act, which has numerous pathogens on it that do not reflect unmet need for new antibiotics. Other pathogen lists out there, such as the CDC list and WHO list, have no authority to delimit incentive deployment, are not regularly updated, have no transparent process established for updating, and also have pathogens on them that do not reflect current unmet needs for new antibiotics.

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Q: What changes would you make to the regulatory mechanisms that govern clinical trials of antibiotics targeting XDR organisms and why?

A: One of the great paradoxes of antibiotics is that just being safe and effective is not enough to declare them an appropriate treatment for an infection. Broad-spectrum agents that can kill highly resistant bacteria should not be used to treat pathogens for which many other antibiotics are available. For example, piperacillin-tazobactam and fluoroquinolones have activity against Pseudomonas aeruginosa and other resistant gram-negative bacteria. They are effective for treating infections caused by streptococci and staphylococci, for which we have many other agents. But they should not be used for such infections, because we need to preserve them for patients who truly need them, and who do not have multiple other options.

Ironically, FDA pathways to approval are typically based on treating nonresistant bacteria causing common bacterial syndromes, such as urinary tract infections and abdominal infections. Those are the pathways most recently approved new antibiotics have taken. Which means powerful new agents to treat carbapenem-resistant Enterobacteriaceae received FDA indications to treat nonresistant, regular old Escherichia. coli causing pyelonephritis or appendicitis. That is wrong. Since the FDA label limits corporate marketing, we are forcing companies to market new antibiotics for inappropriate use, and actually precluding them legally from marketing the drugs for appropriate use. It’s completely topsy-turvy. We need to have clinical trial pathways that allow important new antibiotics to be studied in a manner aligned with clinical need, which will result in a label aligned with clinical need, which will limit marketing in a manner aligned with clinical need. We have suggested ways to do this in the article, including Bayesian multi-body site, pathogen-specific trials, and platform trials.

Reference:

Spellberg B, et al. Ann Intern Med. 2019;doi:10.7326/M19-1893.

Disclosures: Spellberg reports receiving consulting fees from Acuryx, Alexion, Bayer, Cempra, Forge, GlaxoSmithKline, Merck, Paratek, Peptilogics, Pfizer, Shionogi, Synthetic Biologics and Tetraphase, and equity from BioAIM, ExBaq, Motif, MycoMed, NovaDigm Therapeutics and Synthetic Biologics outside the submitted work. Please see study for all other authors’ relevant financial disclosures.