01-02-mar-ds-challenges in the development of new antibiotics in the 21st century

7/27/2019 01-02-MAR-DS-Challenges in the Development of New Antibiotics in the 21st Century

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Challenges in the development

of new antibiotics in the 21st

Century

Roadblocks and Opportunities

David M. Shlaes MD PhD

www.antiinfectivesconsulting.comhttp://antibiotics-theperfectstorm.blogspot.com/
http://www.antiinfectivesconsulting.com/http://www.antiinfectivesconsulting.com/


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Disclaimers

I make my living by consulting Large PhRMA

Biotech

Academics

Active member of IDSA.

I am NOT a statistician!

Mostly working on antibiotics, occasionally

antiviral drugs. A recent client list can be found on my website.

The views I present today are my own.


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Outline Resistance is global.

We need a pipeline of new antibiotics active againstresistant pathogens.

Companies continue to abandon the field.

FDA is releasing guidance requiring infeasibletrial designs.

The FDA must provide feasible guidance.

Pharmacometrics is one way forward.

The US antibiotic market share is decreasing. It will soon make sense to ignore the US.

Novel trial designs are needed.


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FDA Antibiotic Approvals 1983-2012

Boucher, H at Pew charitable Trust Meeting


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The Perfect Storm

Antibiotic discoveryis hard!The ROI is average

at best.The regulatoryenvironment (US) ishostile.


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Consolidation within the pharmaceutical industry 1980-2003.

2003 PharmaceuticalCompany Number of originalcompanies since 1980

Aventis1

Bristol-Meyers-SquibbGlaxo Smith KlineNovartisPfizer

Wyeth2

Total

17

8127

12

14

70

1. Now Sanofi-Aventis2. Now Pfizer


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Large PhRMA Actively PursuingAntibiotics R&D 2011

Astra-Zeneca

GSK

Sanofi-Aventis (Novartis)

(Merck)


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Synercid - 1999

Linezolid 1999

Daptomycin 2003

10-14 years will

seem short ifthings dontchange.


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FDA vs. EU

FDA Guidance for each

indication.

Establishes ownbreakpoints can conflictwith CLSI, EUCAST.

Good communicationpossible and encouraged.

No link between regulatoryprocess and price.

May change withMedicare

EMEA

General guidance lots ofroom for novel approaches.

Communicationencouraged but difficultformal process bothsponsor and CHMP

obliged by decisions. Most sponsors use

individual countryagencies forcommunication.

Breakpoint - Individualcountries decide

New process exists toallow EUCAST review ofproposed breakpoints forEMEA.

Regulatory decisions linkedto pricing by individual

countries.


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The Low Point

At the 2010 ICAAC, Mark Goldberger,former Director ODE IV at FDA, stated thatour letter, Shlaes and Moellering, entitled,

The FDA and the End of Antibiotics, 2002,was the low point in FDA-industry relationson antibiotics.

Little did he know . . .


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The Ketek Scandal David M Shlaes, Robert C Moellering. Telithromycin and the FDA: implications for the

future. Feb 2008 The Lancet Infectious Diseases, Vol. 8 No. 2 pp 83-85.

In 2006, US marketing approval for telithromycin (Ketek) for otitis, sinusitisand ABECOPD was withdrawn.

Rare but serious liver tox.

They had not proven efficacy via placebo-controlled trials as is now required butwas not required when S-A developed the drug.

In the wake of the Ketek scandal of 2006, congress piled-on on the FDA

demanding answers as to how such a drug could have possibly beenapproved.

The results of this unnecessary scandal have been

a loss of critical FDA personnel and a subsequent lack of leadership atthe FDA.

consistent interference in FDAs efforts in the critical area of clinicaltrials for new antibiotics (GAO report)

constant and unpredictable waffling by the FDA along with an antibioticapproval record that will leave our critical antibiotic pipeline in imminentdanger for at least the next decade.


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The Basis of Non-Inferiority

A non-inferiority trial ASSUMES that the controlantibiotic (directly or indirectly) has been shownto be superior to placebo.

The treatment effect = control placebo. The NI margin can never be greater than the

treatment effect.

To justify their NI margins, the FDA has useddata from the pre-antibiotic era, or has usedmodern data where treatment has beeninadequate, to determine a treatment effect.


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Non-Inferiority Trials and Bio-Creep

Study 1: abxA vs placebo = 20% = 8%

= 8% = 8%

Study 2: abxA vs abxBStudy 3:abxBvs abx

Study 4: abxC vs abxD(now equal to placebo)RaveEcanOttsMeda

Placebo = 60% effective

100

80

40

Approval based on a +/- 10% delta

We have always known about possible biocreep. CHMP

John Bradley, UCSD


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15


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FDA Discounting

To calculate the NI margin once theyhave defined a treatment effect the FDAthen estimates the 95% confidenceinterval around this effect and selects thelower bound.

They then apply an arbitrary discount to besure that the NI margin does not exceed atreatment effect. (???)

In this way a treatment effect of 50%always leads to an NI margin of 10%.


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Indication

Cure

Rate

90% Power

10% delta

90% Power

15% delta

CAP (Total Number for 2 Studies)

70% evaluability

85% 1532 688

Skin (Total Number for 2 Studies)

60% evaluability80% 2248 1000

IAI (Total Number for 2 Studies)


HAP (Total Number for 1 Study)


TOTAL 8326 3714

80% Power

10% delta

80% Power

15% delta

TOTAL 6226 2770

Tigecycline example

Decreasing from 90% to 80% power doubles the risk of a false negative result

when the agent is actually not inferior (thanks to M. Wible)


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Multiple Indications and Multiple Trials:

Implications for Program-wise Error Rate

.025 .18 .58 .90

15 10 -5 0 5 10

A total of 300evaluable patients (150 each arm) are needed to

have a 90% chance to declare non-inferiority based on a 15%

margin and a control cure rate of 80%.

If the approval is based on 2 independent trials, the chance of

approving a drug that is truly 10% inferior than the control is

01-02-mar-ds-challenges in the development of new antibiotics in the 21st century

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