Module 2: The crises of new antibiotic development
Russell Lewis, Associate Professor
Infectious Diseases, IRCSS S. Orsola-Malpighi Hospital
Department of Medical and Surgical Sciences
Alma Mater Studiorum
Università di Bologna
source: www.react.org
Bush, K. & Jacoby, G. A. Antimicrobial Agents and Chemotherapy 54, 969–976 (2010).
Priority | Pathogens included |
---|---|
Critical |
Acinetobacter baumannii (Carbapenem-resistant) Pseudomonas aeruginosa (Carbapenem-resistant) Enterbacterales (3rd generation cephalosporin, carbapenem-resistant) |
High |
Enterococcus faecium, vancomycin-resistant Staphylococcus aureus, methicillin-resistant, vancomycin intermediate and resistant Helicobacter pylori, clarithromycin-resistant Campylobacter, fluoroquinolone-resistant Salmonella spp., fluoroquinolone-resistant Neisseria gonorrhoeae, 3rd gen. cephalosporin-resistant, fluoroquinolone-resistant |
Medium |
Streptococcus pneumoniae, penicillin-non-susceptible Haemophilus influenzae, ampicillin-resistant Shigella spp., fluoroquinolone-resistant |
This table does not include Mycobacterium tuberculosis, which was already recognized as a global health priority pathogen
Source:World Health Organization
New antibiotic development is driven by small- or medium-sized enterprises (SMEs), with large pharmaceutical companies continuing to exit the field (currently 4 large Pharma companies)
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 clinical pipeline remains insufficient to tackle the challenge of increasing emergence and spread of antimicrobial resistance.
Update: Antimicrobial Agent Chemother 2022: 10 January 2022
Ideally must target multiple pathways in bacterial species (to avoid rapid resistance development) ...but not human targets
Must be safe...drugs are administered in grams, not mg or μg
Must penetrate and be active in multiple body sites
Must be effective now and in the future against resistant pathogens (i.e. predict future resistance problems)-
you must be looking now for the antibiotic you will use in 2040!
Penicillin culture flasks, 1942. Photo: James Jarche
Since 1970, the only indisputably new antibiotic classes to reach the market are: the oxazolidinones (discovered 1978, launched 2000) and lipopeptides (discovered 1986, launched 2003)
Penicillins → cephalosporins, carbapenems
nalidixic acid → fluoroquinolones
kanamycin → amakacin
glycyclines → tetracyclines
resistance
mechanisms
develop to entire antibiotic classes
United States Food and Drug Administration
EMA
African Medicines Agency
Many other countries have their own processes for drug registration and approval
Costs on average: 1-1.5 billion US dollars
Wouters et al. JAMA 323, 844–853 (2020).
Proving efficacy in humans: The Phase III non-inferiority trial:
A paradoxical problem for antibiotics
Medical Priority: We need new drugs for bad bugs
The superiority of a NEW antibiotics is easily shown in the lab on the basis of MIC testing (potency) or in animal models of infection
Clinical data is the problem- trials must (usually) be designed to avoid superiority
Example: Limb-threatening skin and soft-tissue infection due to MRSA....It is not ethical to randomize to methicillin vs. NEW Antibiotic, must instead compare vancomycin vs. NEW antibiotic
Patients cannot be enrolled in a trial where they are randomized to be treated with an ineffective antibiotic
Instead we must use non-inferiority designs showing similar activity relative to another active agent
"Assessing non-inferiority in a trial is more complex than assessing superiority, in both the design and analysis phases.
Although it is not statistically possible to prove that two treatments are identical, it is possible to determine that a new treatment is not worse than the control treatment by an acceptably small amount, with a given degree of confidence"ce.
Mauri L, D’Agostino RB Sr. Challenges in the Design and Interpretation of Noninferiority Trials.
N Engl J Med 2017; 377:1357–1367.
A
B
C
D
E
F
G
H
New treatment better
active control better
Absolute Risk
Difference=0
(95% confidence intervals)
Δ inferiority margin (e.g., 10%)
Conclusion from trial
1. Superiority concluded
2. Non-inferior but not superior
3. Non-inferior but possibly not inferior
5. Non-inferiority not shown
6. Non-inferiority not shown
7. Non-inferior but inferior
8. Inferiority concluded
Typical antibiotic Phase III trial: prove an antibiotic is not inferior to "active control therapy" and not 10% worse for study outcome
Approved
Approved
Approved
Approved
Rejected
Rejected
Rejected
Rejected
4. Non-inferior but not superior
DPE is the difference in point estimates of response rates for placebo and active therapy. No adjustment is made for the precision of these two estimates.
M1 is a margin less than DPE that is thought to be the largest reliable estimate of the treatment effect that incorporates the uncertainty around the individual
M2 is a margin less than M1 that is proposed as a clinically acceptable margin and reflects the degree of potential loss of efficacy that is acceptable.
Δ
Np-nosocomial pneumonia
cIAI-complciated intraabdominal infections
cUTI- complicated urinary tract infections
Is it feasible to perform a clinical trial for MDR pathogens?
Statistical examples for a nosocomial pneumonia trial
Typical estimate would be 10-15% of patients in ICUs from large academic medical centers have pathogen of interest, but not necessarily MDR pathogens
Implications: Hundreds of enrolling centers required, huge costs, high risk
Huge costs are also incurred post-approval for antibiotics
Pediatric dosing and safety studies,
Pharmacokinetic studies in special populations (i.e. elderly, obese, dialysis)
Pharmacovigelence (safety)
Development and validation of susceptibility testing technology/platforms
Manufacturing and supply chain investments
5-10 years commitment to monitor resistance through antimicrobial surveillance studies..etc, etc....
Costs = Antibiotic Price * Units Sold
Business plan: Sell lots of antibiotics (high use → drive resistance → drug becomes less effective) or charge very high prices
Source: Financial Times
McKenna, M. Nature 584, 338–341 (2020).
Typical patent life: 20 years from discovery
McKenna, M. Nature 584, 338–341 (2020).
The Achaogen story (developer of plazomicin)
NY Times December 25, 2019
Achaogen a company founded in 2002 developed a new aminoglycoside (plazomicin) that was active against WHO-priority Gram-negatives, including carbapenem-resistant Enterbacteriacea (CRE)
Achaogen raised around $500+ million in venture capital and public funds to advance into Phase III trials, not counting non-dilutive support and debt
A phase 3 complicated UTI trial was completed in Dec 2016 demonstrated impressive activity vs. meropenem (EPIC trial)
Allergan and Melinta launched ceftazidime-avibactam and meropenem-vaborbactam in 2015 and 2017 respectively- two beta-lactam antibiotics that cover CRE (competititors to plazomicin)
A Phase 3 trial of plazomicin vs. colistin-standard of care in CRE bloodstream infection was started in 2014 (CARE trial) but this trial was difficult to enroll with 2100 patients screened and 37 randomized over 2.5 years at a cost of 70 million.
Plazomicin was launched in the U.S. in July 2018
Added to the WHO Essential Medicines list
Archaogen filed for Chapter 11 bankruptcy in April 2019
Cipla Pharmaceuticals buys plazomicin for 16 million
McKinnell, J. A. et al. New England Journal of Medicine, 380(8), 791-793.
Patients receiving plazomicin developed less nephrotoxicity:
16.7% vs. 50%
Manufacturer of meropenem-vaborbactam
incentive recommendations
US Biomedical Advanced Research and Development Authority BARDA (1.2 billion dollars to support Phase 2/3 antibiotic development against 21st century threats including drug-resistant bacteria, supports CARB-X)
CARB-X (550 million, Hits to lead Phase 1 product development of therapeutics, diagnostics and preventatives against WHO and CDC priority drug-resistant bacteria)
The Global Antibiotic Research and Development Partnership -GARDP (Produce discovery from discovery to delivery including novel therapeutics, optimizing antibiotics, developing combinations. Focused on WHO priority list).
Novo Holdings REPAIR Impact Fund (165 million investment in lead optimization to Phase I development of therapeutics and diagnostics against WHO priority drug-resistant bacteria
Joint Programming Initiative on Antimicrobial Resistance -JPIAMR (novel therapeutics, diagnostics, surveillance, prevention, stewardship, WHO priority pathogens
Wellcome Trust (175 million drug-resistant infections focused on policy, strengthening evidence for action, clinical trial capabilities and innovative product development including CARB-X
AMR Action Fund. WHO, European Investment Bank, and Wellcome Trust
UK AID (315 million pounds funded through the Global AMR innovation fund and the Fleming Fund to help LMICs tackle AMR).
The German Federal Ministry of Education and Research support of national research programs as well as contributions to international initiatives like CARB-X, GARDP, and JPIAMR.
Bill & Melinda Gates Foundation (124 million targeting drug-resistant infections in low-middle income countries (LMICs), disease surveillance, vaccine development, economic modeling, and CARB-X
U.S. National Institutes of Health (1.4 billion dollars funding basic research, academic industry startup partnerships, and other research and development against bacterial threats, for vaccines, therapeutics and diagnostics
Pull incentives are primarily after regulatory approval and hence only successful products are supported
Netflix is a subscription-based streaming service that allows our members to watch TV shows and movies without commercials on an internet-connected device.
You pay a monthly fee whether or not you watch movies.
How would a Netflix-like pull incentive work for antibiotics?
How would a Netflix-like pull incentive work for antibiotics?
More detail on antibiotic pull incentives being considered by different countries...
Gotham, D. et al. Health Policy 125, 296–306 (2021)
Slide: John Rex, M.D.
We pay firefighters to be available and prepared so they can come to our rescue when we need them
We should pay to have antibiotics ready for resistant infections in hopes that we never need them
Lack of antibiotic availability due to supply chain problems
Increasing frequency of shortages for injectable generic antibiotics contributes to antimicrobial resistance
Shafiq, N. et al. BMJ Global Health 6, e006961 (2021).
Frost et al. Access Barriers to Antibiotics. Center for Disease Dynamics, Economics & Policy (CDDEP), 2019.
Global antibiotic consumption (2000 to 2015). Change in antibiotic consumption rate per 1,000 inhabitants per day.
Antibiotic consumption rate in defined daily doses (DDDs) per 1,000 inhabitants per day by country in 2015
Defined daily dose (DDD) is a standardised index of drug consumption, defined by the WHO, used to compare antibiotic use between different drug classes and dosage forms.
DDD is calculated by multiplying the quantity field by the DDD conversion factor field. For example, the strength of one ciprofloxacin tablet is 500 mg and the DDD is 1 g (500 mg twice daily) for ciprofloxacin. Each 500 mg tablet is equivalent to 0.5 DDD.
Frost et al. CDDEP, 2019.
Frost et al. CDDEP, 2019.
CDDEP Recommendation | Stakeholders | Rationale | |
---|---|---|---|
1 | Encourage R&D of new or improved antibiotics, diagnostic tests, vaccines, alternatives to antibiotics for bacterial infections | Countries, regional collaborators, WHO and other international bodies, pharmaceutical industry, academia | At a global scale, higher investment in novel antibiotics, temperature-stable formulations, and rapid diagnostic tests |
2 | Support the registration of antibiotics in more countries according to clinical need | WHO and other international bodies, national governments, policymakers, regulators, pharmaceutical industry | Efforts at the national, regional, and global levels to support drug registration could reduce the upfront cost of accessing less attractive markets and benefit patients by making life-saving drugs available. Newer drugs coming to market are likely to be introduced by small and medium-size enterprises that may not have the expertise or resources to register in multiple countries. However, this cost should not be a barrier. |
Regulators and policymakers | In many instances, regulations and requirements could be aligned across countries and simplified to reduce costs | ||
Pharmaceutical companies | Plans for registration should be part of the development process. |
CDDEP Recommendation | Stakeholders | Rationale | |
---|---|---|---|
3 | Establish standards of practice and national treatment guidelines. | WHO, countries, experts and their professional associations, hospitals and community care facilities | The WHO should issue a call to action for all professional associations and councils involved in prescribing practices to develop clinical guidelines for treating infectious diseases at all levels of healthcare. |
4 | Generate awareness and educate patients and prescribers. | Non governmental organizations (NGOs), advocacy groups, professional bodies,WHO offices at all levels, health ministries, and local institutions (hospitals, clinics, schools, churches, etc.) | Information about the price and quality of antibiotics approved for use in a country will support rational prescribing and use, as will surveillance data on local antibiotic resistance profiles. NGOs, professional bodies, and advocacy groups can use existing communications channels to educate patients and prescribers about drug quality and rational antibiotic use. Such information will empower consumers who purchase drugs out-of-pocket to demand quality antibiotics while increasing price competition among suppliers and removing poor-quality suppliers from the market. |
CDDEP Recommendation | Stakeholders | Rationale | |
---|---|---|---|
5 | Reduce conflict of interest and incentives that lead to inappropriate antibiotic use. | Regulators, NGOs, doctors, and patients | Conflicts of interest between prescribers and the vendors of pharmaceuticals can be addressed by regulating gifts from drug companies and promoting the enforced or voluntary declaration of such gifts |
CDDEP Recommendation | Stakeholders | Rationale | |
---|---|---|---|
6 | Explore innovative funding of essential antibiotics | UNICEF, WHO, national governments, pharmaceutical manuscfactures | Countries with less purchasing power could pool their resources for procurement under arrangements similar to Gavi (the vaccine alliance) or the Global Fund. UNICEF/WHO might coordinate procurement and distribution. Besides helping LMICs increase their purchasing power, such an arrangement would support quality manufacturers while driving out substandard suppliers. |
See online resources for discussion of these programs
CDDEP Recommendation | Stakeholders | Rationale | |
---|---|---|---|
7 | Ensure the quality of antibiotics, and strengthen pharmaceutical regulatory capacity | WHO, national and regional regulators, countries, pharmaceutical suppliers and manufacturers | WHO support and coordination, national and regional regulators could collaborate to support quality assurance and avoid duplication of effort across countries; Rapid information exchange for pharmacovigilance, information on poor- quality suppliers, and sharing of best practices and innovation will help drive substandard and falsified antibiotics from the market. An international entity, such as the WHO, could provide surveillance, monitoring, and compliance testing for antibiotic quality. Such work would support LMICs' regulatory authorities and also ensure the integrity of the supply chain from the dominant suppliers in India and China. It could also establish standards for generic antibiotics and fixed-dose combinations, which are commonly used in LMICs, and support the industry in self- regulation. |
CDDEP Recommendation | Stakeholders | Rationale | |
---|---|---|---|
8 | Encourage local manufacturing for cost-effective antibiotics. | Countries, regional collaborations, pharmaceutical industry, including drug R&D and manufacturers | Development and diversification of local manufacturers can help ensure the steady supply of essential, quality-assured antibiotics so that countries can meet their own needs. This should be supported through regional collaborations of countries such as the African Union. |