Protocol F1K-MC-EVDPEfficacy and Safety of Drotrecogin Alfa (Activated) in Adult Patients with Septic

ShockPROWESS SHOCKJonathan Janes FRCP MFPMMedical Director- Acute Care

Lilly Research CentreErl Wood Manor, UK

Critical Care Canada Forum 2011 Toronto

Disclosures:

I am an employee and shareholder of Eli Lilly and Company.

Xigris Studies

• Xigris Studies (> 11,000 patients) – EVAA Phase II N= 131– PROWESS Phase III N=1690– ENHANCE Open label N= 2378– ADDRESS Lower risk of death N= 2640– RESOLVE Paediatric study N= 477– XPRESS Heparin study N= 1935– RESPOND Phase II study N= 433

• Potential role of PC as a biomarker to guide Xigris therapy

– PROWESS SHOCK N= 1696

Clinical Trial and Registries – Hospital/ ICU mortalityXigris Control, Adjusted Control,

or Predicted MortalityLilly Clinical PROWESS-Overall 29% 35%

Study PROWESS-≥3 OD 36% 44%

Observational Poland (N=302) 39% 56%

Studies Italy (GiViTI; N=668) 46% 55%

United Kingdom 1 (ICNARC; N=1292) 45% 49% – 58%*

United Kingdom 2 (N=351) 47% 60%

Belgium (N=436) 52% 64%

Global 1 (N=882) 50% 57% -61%*

Spain (N=87) 37% 57%

United States 1 (N=1576) 41% 47%

United States 2 (N=108) 35% 54%

Global 2 (N=unknown) OR: 0.71 95% CI: 0.62-0.82

France (N=1049) 47% 68%* Ranges estimated from relative risk

Xigris Approvals & EU Annual Licence Reassessments

2003 1st Annual Licence Reassessment ENHANCE update

2004 2nd Annual Licence Reassessment PROWESS Long-Term Follow-Up, ENHANCE, ADDRESS

2005 3rd Annual Licence Reassessment ADDRESS Long-Term Follow-Up, RESOLVE

2006 4th Annual Licence Reassessment XPRESS, Agreement to conduct PROWESS-Shock

2007 5-year renewal

2007 5th Annual Licence Reassessment Final PROWESS-SHOCK protocol Reviewed

2008 6th Annual Licence Reassessment SPC updates

2009 7th Annual Licence Reassessment No SPC changes

2010 8th Annual Licence Reassessment No SPC changes

2011 9th Annual Licence Reassessment PROWESS-SHOCK Results

• November 2001 Approval from FDA• August 2002 Approval from EMEA

The small difference in the 28-day mortality of the overall population (26.4% in the Xigris arm versus 24.2% in the placebo arm; n=1680 patients) is not statistically significant. The risk of severe bleeding events, which is the main risk with this product, was 1.2% in the Xigris arm and 1.0% in the placebo arm, suggesting there was no increased harm.

Why did PROWESS SHOCK Results differ from PROWESS? • PROWESS SHOCK was not designed to “re-test” PROWESS, but

rather to test a high disease severity subset reflecting both the labeled indication and how DAA was being used in clinical practice– Advances in standard of care were protocolised– The following may have been contributing factors

PROWESS PROWESS SHOCK

CV Dysfunction 1 hr hypotension or 1 hr of vasopressors (any dose)

Minimum 4 hr , minimum dose of vasopressors

Resuscitation 500 ml fluid in 30 min ≥ 30 mL/kg within +/- 4 hr of vasopressors

Other organ dysfunction 1 or more Shock + hypoperfusion

Infection Known or suspected infection

Evidence of infection receiving IV antimicrobials

Coordinating centre Reviewed sepsis histories within 24 hr

Approved every patient

Placebo mortality 35% (≥2OD, Vasopressor) 24.2%

Why did Lilly Withdraw Xigris?

• Patents enrolled in PROWESS SHOCK largely reflected what would have been considered an indicated population

• The study failed to demonstrate that Xigris improved patient survival and thus calls into question the benefit-risk profile of Xigris and its continued use

Regulatory Guidance on Acceptance of a Single Study for Efficacy

In some instances, clinical evidence consisting of a single, large-scale, adequate and well controlled study or one pivotal trial and additional clinical evidence may be deemed "substantial" [Jan 31,2003]http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/priorit/priordr-eng.php

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000366.jsp&mid=WC0b01ac0580032ec4&jsenabled=true

EMA Guidance• There is no formal requirement to include two or

more pivotal studies in the phase 3 program• In most cases several studies are the most or

only feasible way to confirm usefulness• In the exceptional event of a submission with

only one pivotal study this has to be particularly compelling with regard to: – Internal and external validity– Clinical relevance– Statistical significance– Data quality– Internal consistency

www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm078749.pdf

FDA Guidance on Acceptance of a Single Study for Efficacy

• Limited to situations where a clinically meaningful effect is observed:– Mortality– Permanent morbidity– Prevention of a disease with a potentially serious

outcome• Confirmation of the results in a second trial

would be practically or ethically impossible

FDA Guidance on Acceptance of a Single Study for Efficacy

(1) Large, multicenter clinical trial– No single study site provided an unusually large

fraction of patients– No single investigator or site was responsible for

the favorable effect seen(2) Consistency across study subsets

– Positive effects should be observed across clinically meaningful subsets of patients (age, gender, race, severity of illness)

(3) Statistically very persuasive findings– “In a multicenter study, a very low p-value indicates

that the result is highly inconsistent with the null hypothesis of no treatment effect.”

FDA Guidance on Acceptance of a Single Study for Efficacy

(4) Multiple endpoints involving different events– “In some cases, a single study will include multiple

primary and secondary endpoints, each of which demonstrates a beneficial, but different, event” as with reduction in MI and reduction in need for urgent intervention.

(5) Multiple studies in a single study– A large study can be viewed as two or more studies

by subdividing it and showing that effectiveness is seen in the subdivisions.

Agennix Update on Talactoferrin: 2010

• End-of-Phase II meeting with the U.S. Food & Drug Administration (FDA) to discuss future development plans for talactoferrin in severe sepsis

• The FDA strongly recommended that Agennix conduct two adequate and well-controlled Phase III studies to support a potential Biologic License Application (BLA) submission.

http://www.agennix.com

Other questions?• If 2 trials are required in the future should these be run

in sequence or parallel?– In parallel similar to 1 large trial divided into 2 parts– In sequence, the timeline and cost of Phase 3 may be

prohibitive• What is the value of registry data?

– Suggested a beneficial effect with Xigris yet RCT negative– Suggested a harmful effect of steroids yet commonly used– Is our ability to adjust/predict mortality adequate?

• Implications for other efficacy trials as clinical practice evolves? – Are there instances where we might need to repeat clinical

trials to assure continued efficacy of an intervention?– Regulatory agencies monitor for new or worsening safety

signals, not loss of efficacy

Thank You