Investigator-Initiated Studies:Two Stories from the NIH

Michael S Lauer, MD, FACC, FAHADirector, Division of Cardiovascular Sciences

NHLBI/NIHJanuary 11, 2012

Disclosures: None

First Story: Occluded Artery after MI

2http://www.circulation.or.kr/info/case/200904/fig1.gif http://www.indiastudychannel.com/attachments/Resources/82666-221135-Coronary%20Angiogram.jpg

Observational Findings

3 Lamas GA et al. Circulation 1995;92:1101-9

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006

9/30/99OAT Starts

6/15/98-8/02/99OAT Pilot enrollment

12/30/05OAT Recruitment

CompletedTotal: 2166

07/2001TOSCA-2

begins

08/2002OAT-EP begins

12/2003OAT-NUC

begins

AHA

6/1/19981st NHLBI submission

3/1/19992nd NHLBI submission

NHLBI Workshop on Coronary

Revascularization

1st OAT Steering

Committee

151 409 485 523 382 196

Enrolled patients per year

20

OAT Timeline

Many thanks to Dr. Judith Hochman

Investigator-Cited Problems

Funding Slow to obtain, pilot work unfunded Inadequate once there Private partnerships difficult

Sites Only 320 of 925 agreed (pro-PCI bias) Only 217 of 320 enrolled at least 1 patient Rate 0.25 patients/site/month Only 488 patients from 85 US sites

5 Many thanks to Dr. Judith Hochman

More Problems

Regulatory burdens IRB redundancies and requirements Site monitoring, HIPAA

Bias against withholding available treatment Physicians (91% of refusals)

Strongly held beliefs Loss of procedural revenues

Patients (want the best technology)

6 Many thanks to Dr. Judith Hochman

Physician Bias and “Ethics”

When researchers tried to organize a randomized study of the benefits of angioplasty for patients who had suffered a heart attack three days or more before, they ran into a problem. Many doctors were so convinced of the value of this procedure…that they thought it would be unethical to assign any patients to the control group, which would get all the best medicines for this condition but not the artery-reopening procedure.

But the researchers persisted, with heavy support from the National Heart, Lung, and Blood Institute. After four years of work examining 2,166 patients, they came to an unexpected conclusion….

7 Boston Globe, December 9, 2006

The Findings and Response

8

ACC/AHA STEMI Guideline: “PCI of a totally occluded infarct artery greater than 24 hours after STEMI is not recommended in asymptomatic patients…[who] do not have evidence of severe ischemia.”

Hochman JS. N Engl J Med 2006;355:2395-407Antman EM et al. JACC 2008;51:210-47

A More Recent Story

9Ridker PM. J Throm Haemost 2009;7(S 1):332-9Ridker PM et al. N Engl J Med 2008;359:2195-207

The Proposal

2008: “LAP” process

2009-2010: Grant reviews

Early - mid 2011: Council Revision (not a CRP

trial), funding

10 Ridker PM. J Throm Haemost 2009;7(S 1):332-9

Insights from These Stories

Government-funded trials Encourage investigator-initiated studies Extensive vetting process prior to review Effectiveness and efficacy

Challenges Lengthy process Resistant clinical community Manage conflicts of interest Responsible delivery of “public goods”

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