1 Conflicts of interest Bernard Lo, M.D. September 16, 2010

2 Views of audience Investment company offers fund whose selectors have personal stake in fund going lower. Company also has shorted fund. Should these interests be disclosed? 1. Yes 2. No 3. Not sure

3 Views of audience Should such a fund be banned (even if interests aredisclosed)? 1. Yes 2. No 3. Not sure

My COI disclosure  No relationships with for-profit companies  Chaired 2009 Institute of Medicine report on COIs 4

5 What is a conflict of interest?  Special relationships of trust, dependency  Primary interest in well-being of clients, patients, integrity of research  Secondary interest in personal gain ($, professional advancement)

6 What is a conflict of interest?  Unacceptable risk that primary interest unduly influenced by secondary interest

Points to consider 1. Arrangement may be problematic even if no proof of bias  Hard to tell if bias exists 2. Disclosure necessary but not sufficient  May not know what risks are or how to reduce them 7

Points to consider 4. COI policies should consider Risk of relationship Burdens and unintended adverse effects of policies 8

9 Spiral CT for lung cancer screening  Screened >31,000 high risk persons  F/u Stage 1 cancers who had surgical resection 10 year estimated survival 92%  “Could prevent 80% of deaths from lung cancer”

10 Spiral CT for lung cancer screening  Advocates have pushed states to pay for screening  NY bill would pay only at Cornell

11 Spiral CT for lung cancer screening  $200 million NIH trial comparing CT screening vs. CXR  “Allowing hundreds of thousands to die is unethical”

12 Methodologic concerns  No concurrent control group  Lead time bias  Few patients followed for 5 years  Assume at all persons found to have cancer would die without screening  Ignore false positive scans

13 Financial relationships  $3.6 million from parent company of cigarette manufacturer  Grant to Foundation for Lung Cancer  PI, co-PI as officers  Dean, vice-chair of overseers as directors Claim didn’t know origin of money  Gift announced publicly

14 Financial relationships  Not disclose 10 patents on CT screening in some articles and CME lectures  Claim not relevant  Cornell receives royalties

15 Financial relationships  Not disclose funding as required  To NEJM Would not have published  On American Cancer Society grant Prohibit funding if also tobacco support

16 Points to consider  Voluntary disclosure ineffective  Impetus for public disclosure of payments  Institutions have their own COI  Bright people find loopholes

17 Concerns about COIs  Disagreements and errors inevitable  Due to reasonable differences of opinion, slip, or financial profit?  Disclosure not remove risk of bias

18 Interactions between physicians and industry

19 Academia-industry collaboration to develop new therapies  Antiretrovirals for HIV infection  Pulmonary surfactant  Imatinib, tyrosine kinase inhibitor for CML  Rituximab, MAB against CD20 on B cells

21 Concerns about industry-sponsored clinical trials  Most trials now sponsored by industry  Academic investigators may lack  Access to data  Independent statistical analysis  Drafting of papers by medical writers

22 Concerns about industry-sponsored clinical trials 1. Favorable conclusions

23 Association between funding and conclusions  Investigator ties to manufacturer  3.6 times more likely to find drug effective  Sponsored by manufacturer  4.0 times more likely to find drug effective JAMA 2003; 289: 454 BMJ 2003; 327: 1167

24 Explanations for association  Publication bias against negative trials  Less rigorously designed  Evidence not support this  Manufacturers sponsor trials that are likely to succeed

25 Concerns about industry-sponsored clinical trials 2. Methodologic flaws that favor study drug 3. Not report negative findings

26 Rosiglitazone allegations  Manufacturer failed to release to FDA data showing cardiac risk  Audit of RECORD trial showed 12 endpoints on drug not counted

27 Not report negative findings  Celecoxib  6-month data reported, showed benefit.  12-month data known, no benefit BMJ 2002; 324: 1287 JAMA 2001; 2886: 2398

28 Mission of drug companies  “Drug companies have to continue to be successful businesses… But their primary mission is products that save lives and improve lives.”  “This is an area that’s different from ice cream, bubble gum, and automobiles.”

Responses to conflicts of interest 1. Disclosure  To university Annually With grant submission (new NIH requirements)  To IRB  To research subjects  When submit, present, publish 29

Responses to conflicts of interest 1. Disclosure  To public Required for some companies by legal settlements Voluntary by some companies Some state laws New federal law (in 2013) 30

31 Arguments for disclosure  “Sunshine the best of disinfectants”  May deter questionable behavior  But may also deter desirable behaviors

32 Concerns about disclosure  Not specific or standardized  Categories like “consultant” ambiguous – scientific or marketing?  May be misinterpreted  Discrepancies due to different requirements  Not prevent undue influence or bias  Necessary but limited first step

Responses to conflicts of interest 1. Disclosure 2. Management of relationship 3. Prohibition 33

Clinical trial investigators with significant conflicts of interest  Default or presumption is that may not participate if financial stake in results  Patent, royalties  Stock options  Management position in sponsor 34

Clinical trial investigators with significant conflicts of interest  Exceptions permitted  For safety of participants Inventor of medical device  For validity of study Only lab that can conduct assay 35

Clinical trial investigators with significant conflicts of interest  Limit role of conflicted investigator  Not tasks that others can carry out Recruitment of subjects Data analysis Drafting of manuscript  May not be PI  Alternatively, may end conflicting role 36

Contracts or grants for Industry-sponsored clinical trials  Be willing to justify protocol and conduct of trial  Register with clinicaltrials.gov 37

Contracts or grants for Industry-sponsored clinical trials  Access to complete raw data  Independent statistical analysis  Control decision to publish  May give sponsor draft  Short delay for patent finding 38

39 Concerns about current policies  Responses out of proportion to problems  Overreaction to egregious cases  Unfair suspicion  Burdensome for physicians  Particularly for MDs who act with integrity

Other COI issues  Medical education  Development of practice guidelines  Clinical practice  Institutional COIs 40

41 Take home message  Are policies proportional to problems?  How likely and serious is the risk?  What are the desirable and detrimental consequences of policies?

42 Take home message  Public and press concerns about conflicts of interest