The World Health Organization
2019 Antibacterial agents in clinical development: an analysis of the antibacterial clinical development pipeline is the WHO third annual review of the clinical antibacterial pipeline to analyse how the pipeline responds to the WHO priority pathogens list.
This report covers direct-acting small molecules and biological agents that are in development worldwide. It assesses to what extent the pipeline addresses the WHO priority pathogens, Mycobacterium tuberculosis and Clostridioides difficile and to what extent the antibacterial agents are innovative. This report is part of the WHO’s efforts in global research and development (R and D) priority setting to contain antimicrobial resistance.
Key messages:
• The clinical pipeline remains insufficient to tackle the challenge of increasing emergence and spread of antimicrobial resistance.
• It is primarily driven by small- or medium-sized enterprises (SMEs), with large pharmaceutical companies continuing to exit the field.
• Eight new antibacterial agents have been approved since 1 July 2017, but overall, they have limited clinical benefits.
• One new anti-tuberculosis (anti-TB) agent, pretomanid, developed by a not-for-profit organization, has been approved for use within a set drug-combination treatment for MDR TB.
• The current clinical pipeline contains 50 antibiotics and combinations (with a new therapeutic entity) and 10 biologicals, of which 32 antibiotics are active against the WHO priority pathogens:
o Six of these agents fulfil at least one of the innovation criteria; only two of these are active against the critical MDR Gram-negative bacteria.
• More than 40% of the pipeline targeting WHO priority pathogens consists of additional β-lactam and β-lactamase inhibitor (BLI) combinations, with a major gap in activity against metallo-β-lactamase (MBL) producers.
• The anti-TB and C. difficile antibacterial pipeline is more innovative than the WHO priority pathogens pipeline, with more than half of the antibiotics fulfilling all of the innovation criteria.
Market approvals
Since 2017 eight new antibiotics ― including one for the treatment of TB ― have been approved (Table 1). Two, vaborbactam + meropenem and lefamulin, were classified as meeting at least one of the innovation criteria. The other newly approved antibiotics are derivatives of known classes, such as the two tetracycline derivatives eravacycline and omadacycline. Half of the new agents target carbapenem-resistant Enterobacteriaceae (CRE); however, only one is of a new class. New approved antibiotics to treat carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa are absent. Thus, there is a visible mismatch between the few newly approved antibiotics and the WHO priority pathogens list.
Of the two new β-lactam/BLI combinations that have been approved, vaborbactam is a first-in-class BLI that contains a cyclic boronate pharmacophore and relebactam, a diazabicyclooctane (DBO) analogue. Both are active against many CRE isolates, but not against CRE where resistance is due to MBLs such as the New Delhi metallo-β-lactamase (NDM) enzyme.
Pretomanid, which was approved by the US Food and Drug Administration (FDA) in August 2019 for use within a set drug-combination treatment for MDR TB, is the first new TB drug to be developed and registered by a not-for-profit organization, the Global Alliance for TB Drug Development (TB Alliance).
Overall, the newly approved products have limited clinical benefit over existing treatments. The lack of differentiation against existing treatments, their non-inclusion in clinical guidelines and their higher prices in comparison to existing generic treatments make it difficult to predict their place in the treatment landscape. As six of the eight are from existing classes where multiple resistance mechanisms are well established, the possibility of fast emergence of resistance to these new agents is foreseen.
Clinical antibacterial pipeline
As of 1 September 2019, there are 50 antibiotics and combinations (with a new therapeutic entity), and 10 biologicals in the clinical pipeline (Phase 1– 3) targeting the WHO priority pathogens, TB and C. difficile (Fig. 1). Of these 50 antibiotics, 32 target the WHO priority pathogens, and 12 of those have activity against at least one of the critical Gram-negative pathogens (Table 2). There are 12 antibiotics targeting TB and six for the treatment of C. difficile infections.
Of the 32 antibiotics that are being developed and that target the WHO priority pathogens, six fulfil at least one of the four criteria that were used to assess the extent to which agents in the pipeline can be classified as innovative (see criteria under section 2.3.2).
Only two of the antibiotics that meet at least one of the innovation criteria are active against the critical Gram-negative bacteria. On 17 July 2019, Polyphor terminated development of the intravenous form of murepavadin, which was the only potential treatment option against Gram-negative bacteria that fulfilled all four of the innovation criteria, due to concerns over nephrotoxicity observed in Phase 3. Seven of the 12 antibiotics under development for TB meet at least one of the innovation criteria (Table 4).
The current pipeline is dominated by β-lactam/BLI combinations (n = 13, 41% of products targeting WHO priority pathogens). Of the β-lactam/BLI combinations, the majority target extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae, Klebsiella pneumoniae carbapenemase (KPC) and oxacillinase-48 (OXA-48)-producing Enterobacteriaceae. There are only two agents (cefiderocol and durlobactam [ETX-2514] + sulbactam) that are active against MDR A. baumannii and one (cefiderocol) that is active against MDR P. aeruginosa.
Market dynamics and funding situation
Public and philanthropic investment in developing antibacterial agents has increased in recent years, through mechanisms such as the Biomedical Advanced Research and Development Authority (BARDA), Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator (CARB-X), the Replenishing and Enabling the Pipeline for Anti-Infective Resistance (REPAIR) Impact Fund, and the Global Antibiotic Research and Development Partnership (GARDP).
Private investment, however, has further decreased, with large pharmaceutical companies and private venture capital investors abandoning the area. Recognizing the need to ensure that effective antibiotics are available to enable and secure modern medicine (e.g. for patients undergoing chemotherapy or organ transplantation), governments are testing different models to change the value and market dynamics for antibiotics. Current examples include the United States’ revised hospital reimbursement system and the United Kingdom and Sweden’s pilots on alternative antibiotic procurement and payment models. It is important that all these efforts focus on the most useful and innovative products in the clinical and preclinical pipeline. This assessment should help governments in making appropriate decisions in this regard.
The important 'Compliance with legal requirement to report clinical trial results on ClinicalTrials.gov: a cohort study' by Nicholas J DeVito, Seb Bacon and Ben Goldacre in (2020)
The Lancet comments
Background
Failure to report the results of a clinical trial can distort the evidence base for clinical practice, breaches researchers' ethical obligations to participants, and represents an important source of research waste. The Food and Drug Administration Amendments Act (FDAAA) of 2007 now requires sponsors of applicable trials to report their results directly onto ClinicalTrials.gov within 1 year of completion. The first trials covered by the Final Rule of this act became due to report results in January, 2018. In this cohort study, we set out to assess compliance.
Methods
We downloaded data for all registered trials on ClinicalTrials.gov each month from March, 2018, to September, 2019. All cross-sectional analyses in this manuscript were performed on data extracted from ClinicalTrials.gov on Sept 16, 2019; monthly trends analysis used archived data closest to the 15th day of each month from March, 2018, to September, 2019. Our study cohort included all applicable trials due to report results under FDAAA. We excluded all non-applicable trials, those not yet due to report, and those given a certificate allowing for delayed reporting. A trial was considered reported if results had been submitted and were either publicly available, or undergoing quality control review at ClinicalTrials.gov. A trial was considered compliant if these results were submitted within 1 year of the primary completion date, as required by the legislation. We described compliance with the FDAAA 2007 Final Rule, assessed trial characteristics associated with results reporting using logistic regression models, described sponsor-level reporting, examined trends in reporting, and described time-to-report using the Kaplan-Meier method.
Findings
4209 trials were due to report results; 1722 (40·9%; 95% CI 39·4–42·2) did so within the 1-year deadline. 2686 (63·8%; 62·4–65·3) trials had results submitted at any time. Compliance has not improved since July, 2018. Industry sponsors were significantly more likely to be compliant than non-industry, non-US Government sponsors (odds ratio [OR] 3·08 [95% CI 2·52–3·77]), and sponsors running large numbers of trials were significantly more likely to be compliant than smaller sponsors (OR 11·84 [9·36–14·99]). The median delay from primary completion date to submission date was 424 days (95% CI 412–435), 59 days higher than the legal reporting requirement of 1 year.
Interpretation
Compliance with the FDAAA 2007 is poor, and not improving. To our knowledge, this is the first study to fully assess compliance with the Final Rule of the FDAAA 2007. Poor compliance is likely to reflect lack of enforcement by regulators. Effective enforcement and action from sponsors is needed; until then, open public audit of compliance for each individual sponsor may help. We will maintain updated compliance data for each individual sponsor and trial at fdaaa.trialstracker.net.
