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Incentives at the Intersection of Drug Development and Complementary Diagnostics

In the field of diagnostics and antibiotic development, said John Billington (Head of Commercial Pipeline & Health Security, Policy & Advocacy, GSK), there is a struggle to define the value proposition. Misalignment exists between the true value for patients in the marketplace and the reimbursement value; this misalignment makes for a “broken marketplace” for antibiotics and market weaknesses for diagnostics. Policy opportunities or incentives to correct these market inefficiencies are needed, said Billington. Speakers in this session explored incentives and disincentives for the development of rapid diagnostics and new antibiotics and discussed innovative approaches to foster innovation at the intersection

of complementary diagnostics and drug development. In this discussion, Billington said, “incentives” may be defined as key elements that will result in a more robust marketplace for diagnostics and antibiotics together. He noted that because of differences in the value propositions and market characterization of diagnostics and antibiotics, there may be divergence in the kinds of incentives that are appropriate for each type of product.

PANEL DISCUSSION

Case Study: Partnership Between bioMérieux and Entasis Therapeutics

Clinical trials for therapeutics are long, costly, and risk failure, said Valérie Raymond-Schwartzmann (Companion Diagnostics Senior Program Director, bioMérieux). Partnerships between diagnostic and therapeutic companies can help optimize clinical trials by enabling the selection of the right patient population, saving time and cost, and limiting unnecessary patient drug exposure. In addition to increasing the probability of clinical trial success, if the drug and diagnostic reach the marketplace, the partnership can help ensure that patients receive the best course of treatment. A personalized medicine approach that combines diagnostics and therapeutics, explained Raymond-Schwartzmann, could help ensure the most appropriate choice of drug given to a patient increases the chances of a positive outcome, while reducing the risk of undesirable side effects; this in turn leads to safer drug adoption and prescription practices.

The diagnostic-therapy combination has key benefits for patients, pharmaceutical companies, and diagnostics companies, she said. Patients experience quicker selection of the optimal therapy, improved outcomes, reduced side effects, and a deeper understanding of the disease and medical decision. Pharmaceutical companies gain an increased probability of clinical trial success, safer drug prescription practices that protect drug efficacy and prevent misuse, and the opportunity to get a premium reimbursement because a higher medical value is being delivered to patients. For diagnostics companies, there is increased recognition of their medical value and opportunities for collaboration on market access, medical education and promotion, and reimbursement.

Raymond-Schwartzmann described the BIOFIRE® Pneumonia Panel (BPP) as an FDA-cleared and CE-marked multiplex PCR system that integrates sample preparation, amplification, detection, and analysis into one closed system, and requires two minutes of hands-on time with results available within one hour (Buchan et al., 2020). It is a comprehensive panel with multiple targets, including bacteria, viruses, and resistance markers. It is intended for use in diagnosing direct-from-sample lower respiratory tract infections and uses samples from sputum or bronchoalveolar lavage.

It can be used in outpatient, inpatient, or emergency department settings. Next, she described how the BPP could be used to optimize a clinical trial for a new antibiotic (Figure 4-1). Potential subjects for the trial would be hospitalized adults with respiratory symptoms; Raymond-Schwartzmann noted that infections could be caused by different pathogens with similar clinical symptoms. With a drug targeted at Acinetobacter baumannii, it would be critical to identify which patients were infected with this specific pathogen. The BPP can be used to quickly screen patients, and those with a positive result are enrolled. Raymond-Schwartzmann observed that if only one patient was enrolled out of every 6 to 10 patients screened, screening would help a large proportion of patients avoid exposure to an unnecessary treatment.

Alita Miller (Chief Scientific Officer, Entasis Therapeutics) shared an example of how BPP was incorporated into a clinical trial comparing the safety and efficacy of sulbactam-durlobactam (SUL-DUR) vs. colistin for the treatment of carbapenem-resistant Acinetobacter calcoaceticus-baumannii complex (ABC) infections. The Acinetobacter Treatment Trial Against Colistin (ATTACK) trial¹ was a global Phase 3 study that enrolled 183 patients from 16 countries.² The study had two parts. In Part A, patients with documented ABC infections were randomized to receive either SUL-DUR or colistin, with a primary endpoint of all-cause mortality at day 28. In Part B, patients who were not eligible for Part A because their infection was colistin resistant or because they were intolerant to colistin, were given SUL-DUR. The data showed that SUL-DUR was non-inferior to colistin for all-cause mortality and was statistically significantly less nephrotoxic.

BPP was used in ATTACK to enable early identification of ABC in respiratory samples from patients being evaluated for enrollment eligibility, said Miller. Although the BPP test can detect multiple viral or bacterial pathogens, only positive results for ABC were considered or documented for enrollment purposes in ATTACK. All 83 sites were given the device and encouraged to use it, but it was not required. The study protocol required each patient to have a respiratory sample processed for standard culture in a lab. Patients who met all other enrollment criteria and had a positive ABC result on the BPP test were enrolled in the study while awaiting culture results; if the culture was negative, the patient was withdrawn from the trial. Of the 83 sites, 73.5 percent used BPP to evaluate pneumonia patients,

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¹ See https://clinicaltrials.gov/ct2/show/NCT03894046 (accessed January 31, 2023).

² Results from the ATTACK study are expected to be published in the second half of 2023 but were not yet public at the time of the workshop. See https://investors.entasistx.com/news-releases/news-release-details/entasis-therapeutics-initiates-global-phase-3-pivotal-trial (accessed January 25, 2023).

and a total of 422 BPP tests were performed for ATTACK. Of these, 123 patients tested positive for ABC on the BPP, and 106 of these were also culture positive for ABC.

This trial represents the first successful competition of a clinical trial to evaluate pathogen-directed therapy for a drug resistant gram-negative infection, said Miller, and a key component of that success was the ability to make enrollment decisions within 48 hours using a rapid test. Most sites that were provided with the test used it, and 70 percent of patients were able to be excluded from enrollment by using the BPP. Further, there was a high correlation between the rapid test and culture results. Miller said that these data suggest the enrollment of pathogen-directed clinical trials can greatly benefit from the use of a rapid diagnostic test, and personalized antibacterial therapy can lead to better patient outcomes.

Biotechnology Perspective

Despite the need for new antibiotics, there are challenges when it comes to financing clinical trials, obtaining FDA approval, and moving a new antibiotic onto the market, said Gregory Frank (Director, Global Public Policy, Merck). Many antibiotic companies, particularly small biotechnology companies, have entered the market and faced intense challenges that often left them in bankruptcy or having to sell off the company. Frank noted that these examples speak to the need for collaboration between antibiotic and diagnostic developers to share the risks associated with antibiotic development and increase the chances of success, as seen in the BPP/ATTACK example discussed above. There are incentives available to support antibiotic development, said Frank, but it is unknown how effectively these incentives link support for antibiotic development with support for complementary susceptibility testing. Billington added that in addition to risk-sharing among companies, a third party (e.g., the government) could play an important part in collaboration and sharing risk.

Biomedical Advanced Research and Development Authority Perspective

Kim Sciarretta (DRIVe Launch Office Branch Chief, Biomedical Advanced Research and Development Authority (BARDA)) focused her remarks on three areas: preparation for emerging threats, the clinical value of products, and the role of BARDA in catalyzing innovation in this area.

Preparedness

As a preparedness and response organization, BARDA focuses on responding to current threats as well as developing the flexibility and agility

for responding to future threats, said Sciarretta. One way in which BARDA pursues this goal is by considering antibiotics and diagnostics that target more than just one pathogen. This could take the form of platform-type diagnostics that are multiplex or that can rapidly adapt to new pathogens. Another area of focus is on the host-response in disease. For example, sepsis is a host dysregulation and organ dysfunction that occurs because of infection. Monitoring and targeting the host response through diagnostics and therapeutics may be an appropriate means to address AMR threats. Sciarretta noted that close to 80 percent of sepsis cases arise outside of the hospital setting, and she emphasized the importance of early identification and mitigation in multiple types of settings (Novosad et al., 2016).

Role of BARDA

BARDA’s mission is to secure the nation from threats, such as pandemics and emerging infections, through advanced development of medical countermeasures. This mission, said Sciarretta, enables BARDA to establish public-private partnerships, which have led to 64 FDA approvals, licensures, and clearances to date (BARDA, 2022). BARDA’s 2022-2026 strategic plan contains a prominent commitment to combat antimicrobial resistance through approaches including reinvigorating the antibiotic pipeline and catalyzing innovation across the medical countermeasure pipeline.³

Sciaretta said that BARDA is more than a funding agency and is available to provide wraparound support and expertise in any stage of the product development cycle, including regulatory approval. Funding is provided by BARDA through several mechanisms, including

• BARDA Broad Agency Announcement:⁴ focused on topics that align with BARDA’s strategic plan, including the antibacterials division and diagnostics division;
• DRIVe EZ-BAA:⁵ rapid turnaround, smaller dollar value funds aimed at de-risking innovative and promising technologies;
• Project BioShield:⁶ supporting advanced development and procurement of products.

In addition to funding, BARDA has an accelerator network to support entrepreneurs and early technology development as well as strategic

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³ See https://medicalcountermeasures.gov/barda/strategic-plan/ (accessed January 27, 2023).

⁴ See https://medicalcountermeasures.gov/barda/barda-baa/ (accessed January 27, 2023).

⁵ See https://drive.hhs.gov/partner.html (accessed January 27, 2023).

⁶ See https://www.medicalcountermeasures.gov/barda/cbrn/project-bioshield (accessed January 27, 2023).

public–private partnerships such as CARB-X. Finally, BARDA recently established a ventures program in which BARDA can take an equity stance in financing companies to provide a unique means of funding and support to technologies that are relevant to BARDA’s mission.

DISCUSSION

Challenges of partnerships

Raymond-Schwartzmann said that one challenge in collaboration is finding the right time to form a given partnership. If an agreement is made too early in the drug development process, there is the risk that the drug may fail before trials begin. If an agreement is made too late in the drug development process, the diagnostics company might not be able to develop a test in time. Raymond-Schwartzmann suggested that the right time to begin discussions is during Phase II, and both parties should anticipate that it will take time to agree on the details of the collaboration. During the development process, the drug and the diagnostic follow separate pathways, but those pathways will have to link up at some point. Regulatory approval for each product type depends on the success and approval of the other, and each may need support from the other to collect the right evidence. Miller added that an additional challenge from the perspective of the pharmaceutical company can be the cost of diagnostic. In the case of the SUL-DUR drug to combat Acinetobacter, it was not feasible to launch the drug with the BPP advanced diagnostic device due to cost, she said. Although the device and drug are very effective, Acinetobacter infection is rare in the United States.

Incentives

Given the potential benefits of co-developing drugs and diagnostics, Billington asked panelists to discuss specific types of incentives that might work in this context. Frank replied that the first step would be to assess existing incentives for antibiotic development and examine whether, and to what extent, they support co-development. With existing structures and funding streams in place, Frank noted “there is a conversation to be had” with funders about what they are doing and what more could be done. He emphasized that it may be difficult to adjust existing funding programs, but this would still be easier than establishing a new incentive program solely dedicated to co-development. In terms of market incentives, Frank suggested that one approach could be a temporary add-on reimbursement for a new susceptibility test that, if crafted properly, could support more rapid uptake of susceptibility testing and help de-risk the process of bringing these diagnostic products to market. J. Patel added that test developers need help obtaining characterized isolates, so the CDC Antibiotic Resistance

Isolate Bank is a valuable resource. R. Patel added that another resource for isolates is the Antibacterial Resistance Leadership Group Biorepository.⁷

Financial benefit of collaboration

In terms of the financial benefit of co-development, Miller said that ability to complete the trial quickly was invaluable. The ATTACK trial was expensive, in part due to the cost of the diagnostic, but the BPP allowed a design that rapidly excluded most screened patients and focused on those with Acinetobacter infection. For a small company, being able to do the trial quickly and efficiently was critical. Frank added that the cost of enrolling patients in an antibiotic trial may be close to one million dollars, which is not a sustainable price for small or large companies. The more collaboration encouraged between diagnostics and pharmaceutical companies to de-risk the process and make trials more efficient, the better.

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⁷ See https://arlg.org/laboratory-center-strain-access/ (accessed January 25, 2023).