Understanding Modern Non-inferiority Trial Designs in Antibiotic Development

This article discusses the significance of non-inferiority designs in advancing antibiotic development to combat multidrug-resistant bacteria. It emphasizes the importance of distinguishing between UDR, MDR, and XDR bacterial categories in trial design, highlighting challenges in selecting comparators and conducting studies on MDR/XDR isolates. The article underscores the critical role of innovative trial designs in addressing antibiotic resistance and the complexities of recruiting patients for such studies.

• Antibiotic development
• Non-inferiority trials
• Multidrug-resistant bacteria
• Trial design
• Antibiotic resistance

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1. Rex JH, Talbot GH, Goldberger MJ, Eisenstein BI, Echols RM, Tomayko JF, Dudley MN, Dane A Progress in the fight against multidrug-resistant bacteria 2005-2016: Modern non-inferiority trial designs enable antibiotic development in advance of epidemic bacterial resistance. Clinical Infectious Diseases, 2017. https://doi.org/10.1093/cid/cix246 Three intertwined key ideas: UDR, superiority vs. non-inferiority, and the public health consequences of only using superiority designs Rex-Talbot 2017 CID - Modern noninferiority designs (three key ideas) 1

2. 1. Nomenclature: UDR vs. MDR/XDR Useful categories of bacteria: WT: Wild-type. May well now be pretty rare UDR: Usual Drug Resistance1 MDR: Multi-drug resistance XDR: Extensive multi-drug resistance This is a continuum with implications for trial design UDR: Many easy choices. Easy to choose a blinded comparator. MDR: Harder may need 2nd-line drug.2 Single comparator is harder XDR: Needs a difficult or unusual drug.2 Comparator must be ad hoc. Today s UDR pathogen can be tomorrow s MDR (& vice versa) Consider S. aureus: It s been UDR, then MDR.3 MRSA is now UDR If an organism is S(usceptible) to the novel test agent Response is independent of being UDR, MDR, or XDR to other drugs Or, perhaps RDR (rare DR)? 1This may or may not be the same thing as wild-type. See McDonnell, Rex, et al, Efficient Delivery of Investigational Antibacterial Agents via Sustainable Clinical Trial Networks, Clin Infect Dis (in press), 2016. 2Or combination of drugs. 3When MRSA emerged after the introduction of penicillin, it was the nightmare MDR bug. Vancomycin made it UDR. Rex-Talbot 2017 CID - Modern noninferiority designs (three key ideas) 2

3. PK-PD1: UDR vs. MDR/XDR is irrelevant Resistance to OTHER drugs should not matter It s all about the activity of the NEW drug UDR XDR Activity of NEW DRUG is independent of being UDR, MDR, or XDR to other drugs. Frequency Common Rare Standard comparator Easy Hard NEW DRUG S S S Approved Drug #1 S S S? Approved Drug #2 S S R With adequate PK, efficacy vs. UDR predicts efficacy2 in MDR or XDR. Approved Drug #3 S S R Approved Drug #4 S R R Approved Drug #5 R R R 1PK-PD: Pharmacokinetic-Pharmacodynamic correlations. 2Efficacy against the infection, that is the antibiotic can t reverse the underlying disease that may have put the patient at risk for the infection. Rex-Talbot 2017 CID - Modern noninferiority designs (three key ideas) 3

4. Why does this matter? In addition to the problem with selecting a comparator, it s much harder to do prospective, randomized, registration-quality studies of infections due to MDR/XDR isolates than due to UDR isolates At least twice as slow and twice as costly Patients must present at a study site as referral is hard Sites work hard to make MDR and XDR rare! No site wants to be a Center of MDR/XDR Excellence! Chasing MDR/XDR is very frustrating: Lasagna s Law1 in action Achaogen: Pivotal trial in CRE was not possible (R)are DR: And, we want MDR/XDR rates to be low!! If it s easy to recruit MDR/XDR, something is very wrong 1Louis Lasagna: The incidence of patient availability sharply decreases when a clinical trial begins and returns to its original level as soon as the trial is completed. http://www.pmean.com/11/lasagna.html Rex-Talbot 2017 CID - Modern noninferiority designs (three key ideas) 4

5. 2. Superiority vs. Noninferiority Trial design 101: There are 2 types of trials Superiority: Show that A is better than B Noninferiority (NI): Show that A B Superiority studies are preferred Very clear result, fewer quality issues But, new antibiotics are usually studied using NI comparisons vs. existing agents in the UDR setting Typical registration program: 2-4 NI studies Why? Rex-Talbot 2017 CID - Modern noninferiority designs (three key ideas) 5

6. 2. Superiority vs. Noninferiority1 Untreated infections are lethal! So New antibiotic trials must (usually) be designed to avoid superiority Must NOT enroll if resistance is known/likely to TEST or comparator. Very unlikely to see superior efficacy over a fully dosed modern comparator when pathogen is susceptible to same Very hard (rare) to be superior on toxicity (short-term dosing) MDR/XDR are rare, we hope! Superiority is a high-stakes gamble for a novel agent If your primary aim is superiority and the study fails, you cannot retreat to a claim of noninferiority. But if you see superiority in a NI study, you can claim that result We can tie together Ideas #1 and #2 with a recent example 1Rex-Talbot et al. Progress in the fight against multidrug-resistant bacteria 2005-2016: Modern noninferiority trial designs enable antibiotic development in advance of epidemic bacterial resistance. Clin Infect Dis, 2017. Rex-Talbot 2017 CID - Modern noninferiority designs (three key ideas) 6

7. 3. The public health consequences of only using superiority designs to advance new antibiotics Rex-Talbot 2017 CID - Modern noninferiority designs (three key ideas) 7

8. Example: Plazomicin and CRE CRE = Carbapenem-resistant Enterobacteriaceae Plazomicin vs. colistin- based SOC1 for CRE 28-day all-cause mortality 8/20 10/20 4/17 2/17 8/20 2/17 Figure adapted from slide 24 the Jan 2017 Achaogen corporate presentation. Downloaded 24 Feb 2017 from http://files.shareholder.com/downloads/AMDA- 2JY46Z/3956962155x0x922829/80C50E00-4B27-4F84-B13F- 55DE31AABA28/AKAO-Corporate-Deck-January-2017.pdf 1SOC = Standard of Care Rex-Talbot 2017 CID - Modern noninferiority designs (three key ideas) 8

9. Example: Plazomicin and CRE CRE = Carbapenem-resistant Enterobacteriaceae Plazomicin vs. colistin- based SOC for CRE Superiority is shown in this very small study because 28-day all-cause mortality 8/20 10/20 4/17 2/17 8/20 2/17 Figure adapted from slide 24 the Jan 2017 Achaogen corporate presentation. Downloaded 24 Feb 2017 from http://files.shareholder.com/downloads/AMDA- 2JY46Z/3956962155x0x922829/80C50E00-4B27-4F84-B13F- 55DE31AABA28/AKAO-Corporate-Deck-January-2017.pdf Rex-Talbot 2017 CID - Modern noninferiority designs (three key ideas) 9

10. Example: Plazomicin and CRE CRE = Carbapenem-resistant Enterobacteriaceae Plazomicin vs. colistin- based SOC for CRE Superiority is shown in this very small study because 28-day all-cause mortality 8/20 10/20 4/17 2/17 8/20 2/17 ~6 people died on (due to) SOC Figure adapted from slide 24 the Jan 2017 Achaogen corporate presentation. Downloaded 24 Feb 2017 from http://files.shareholder.com/downloads/AMDA- 2JY46Z/3956962155x0x922829/80C50E00-4B27-4F84-B13F- 55DE31AABA28/AKAO-Corporate-Deck-January-2017.pdf Rex-Talbot 2017 CID - Modern noninferiority designs (three key ideas) 10

11. Example: Plazomicin and CRE CRE = Carbapenem-resistant Enterobacteriaceae Plazomicin vs. colistin- based SOC for CRE Superiority is shown in this very small study because We are glad to have clarity on colistin s relative inefficacy but this is a steep price! As colistin is displaced as SOC, future drugs should not be able to plan on similar data 28-day all-cause mortality 8/20 10/20 4/17 2/17 8/20 2/17 ~6 people died on (due to) SOC Figure adapted from slide 24 the Jan 2017 Achaogen corporate presentation. Downloaded 24 Feb 2017 from http://files.shareholder.com/downloads/AMDA- 2JY46Z/3956962155x0x922829/80C50E00-4B27-4F84-B13F- 55DE31AABA28/AKAO-Corporate-Deck-January-2017.pdf Rex-Talbot 2017 CID - Modern noninferiority designs (three key ideas) 11

12. Summary Non-inferiority trial designs are a necessary and essential part of antibiotic development Modern design NI studies conducted in the UDR setting vs. a high-quality comparator produce reliable data Using NI studies in this way permits new agents to be developed prior to epidemic spread of resistance Superiority designs are a valid tool but the ability to use them depends on existence of a public health problem with grim implications As new agents with activity against MDR/XDR pathogens are introduced, superiority designs will hopefully be difficult (or impossible to implement) Rex-Talbot 2017 CID - Modern noninferiority designs (three key ideas) 12