Drug Company Funding of Clinical Psychiatric Research

Related to Outcomes

Drug Company Funding of Clinical Psychiatric Research

Related to Outcomes

Robert Kelly, MD

Beth Israel Medical Center

New York, New York

Co-authorsCo-authors

Lisa J. Cohen, PhD

Randye J. Semple, PhD

Philip Bialer, MD

Alison Bodenheimer, BA

Elana Neustadter, BA

Arkady Barenboim, MD, PhD

Igor Galynker, MD, PhD

AcknowledgementsAcknowledgements

Ramin Mojtabai, MD, PhDTheresa Perlis, PhDAdam Cohen, MDKatherine DuHamel, PhDDaniel Eisenberg, MDMatthew Steinfeld, BA

Financial InterestsFinancial Interests

I have no significant financial or other relationship with the manufacturer of any product or service I intend to discuss

--Robert Kelly

Focus on Conflicts of InterestFocus on Conflicts of Interest Increasing Media & Public Attention

“Spitzer Sues a Drug Maker, Saying It Hid Negative Data”

– The New York Times, June 3, 2004

“What does the eight-hundred-pound gorilla do? Anything it wants to.”

– Angell, New York Review of Books, July 4, 2004

“Worrisome Ailment In Medicine: Misleading Journal Articles”

– Wall Street Journal, May 5, 2005

Focus on Conflicts of InterestFocus on Conflicts of Interest

Pressure on Policy-makersPublic reaction to media coverage

Political pressure to fix problems

Individual incidents raise public outcry

Resulting in need for action

Evidence LimitedEvidence Limited

Anecdotes

Speculation

Studies of Funding vs Outcomes

Analyses of Methods/Reporting

Previous Work of Interest-Bekelman et al. 2003

Previous Work of Interest-Bekelman et al. 2003

Reviewed studies of sponsorship-outcome association

Compared new medication to placebo or medication in use.

Four studies used blinded outcome raters Outcome: New drug favorable? Sponsorship assessed as industry vs non-

industry rather than related to drug studied.

Previous Work of Interest-Heres et al. 2006

Previous Work of Interest-Heres et al. 2006

Head-to-head comparisons of second-generation antipsychotic medications (N = 21)

Blinded outcome ratersOutcomes favored study sponsorAnalysis of Methods/ReportingRecommendations

GoalsGoals Examine sponsorship-outcome

associationFocus: Sponsorship-drug relationshipPublished clinical psychiatric studiesBroad range of original/regular articlesBlinded outcome ratersControl for potential confounds

Measure extent of pharmaceutical company sponsorship

Assess how these phenomena have changed over time

Selection of ArticlesSelection of Articles Original/regular articles Four leading psychiatric journals

AGP = Archives of General Psychiatry

AJP = American Journal of Psychiatry

JCP = Journal of Clinical Psychiatry

JCPP = Journal of Clinical Psychopharmacology Two years (N = 850)

1992

2002

Selection of ArticlesSelection of Articles Excluded articles

abstracts did not name any drug used in treatment (n=528)not dealing with issues directly related to treatment (n=19)whose abstracts mention a drug company or brand name (n=1)previously seen by any of the reviewers (n=0)whose sponsors could not be properly categorized (n=1)

Study sample: 301 articles mentioning 542 drugs

Outcome Rating ConsiderationsOutcome Rating Considerations

Goal: Measure influenceBehaviorOpinionTrained raters + guidelines

ChoicesMeasure (e.g., Favorable or not)Operationalized vs. subjectiveBlinded vs. unblindedSelection criteria

Outcome RatingOutcome Rating

Two raters Drug outcomes: Favorable vs. not

favorable Detailed rating guidelines Subjective approach Blind with respect to knowledge of sponsor Only abstracts viewed Results compared and disagreements

resolved by discussion.

Sponsorship RatingSponsorship Rating Four categories:

Same company sponsorship (S)Competing company sponsorship (C)Mixed sponsorship (M)Non-pharmaceutical sponsorship (N)

Sponsorship type

Sponsors olanzapine risperidone

None N N

Janssen C S

Lilly S C

Janssen + Lilly M M

Research QuestionsResearch Questions1. Drug company sponsored studies

increased?2. Favorable outcomes increased?3. Same company favorable outcomes >

non-pharmaceutical?4. Competing company favorable

outcomes < non-pharmaceutical?5. Mixed sponsorship outcomes different

than non-pharmaceutical?

Drug Company SponsorshipDrug Company Sponsorship

25

57***

0

20

40

60

80

100

Percent

Year

1992

2002

* = p < 0.05** = p < 0.01*** = p < 0.001

Favorable OutcomesFavorable Outcomes

52 50

0

20

40

60

80

100

Percent

Year

1992

2002

* = p < 0.05** = p < 0.01*** = p < 0.001

Favorable Outcomes byType of Sponsorship

Favorable Outcomes byType of Sponsorship

78***

48***

28***

0

20

40

60

80

100

Percent

Sponsorship

Same Co

Non-pharm

Comp Co

* = p < 0.05** = p < 0.01*** = p < 0.001

Favorable Outcomes byType of Sponsorship

Favorable Outcomes byType of Sponsorship

78*

50

30*

78***

46**

28***

0

10

20

30

40

50

60

70

80

90

100

Percent

1992 2002

Same Co

Non-pharm

Comp Co

* = p < 0.05** = p < 0.01*** = p < 0.001

Favorable Outcomes byType of Sponsorship

Favorable Outcomes byType of Sponsorship

91*

54

33*

75*

42

29*

87***

58***

22***

64**

3835*

0102030405060708090

100

Percent

AGP AJP JCP JCPP

Same Co

Non-pharm

Comp Co

* = p < 0.05** = p < 0.01*** = p < 0.001

Control for ConfoundsControl for Confounds Example: Ice cream consumption +

death by drowningPositively correlatedIce cream eating precedes drowning=> Ice cream risk factor for drowning!

Possible confoundsTemperatureWeatherSeasonProximity to water

No significant correlation after control

Possible ConfoundsPossible Confounds Year Journal Drug studied Time since FDA drug approval Diagnosis Sample size Study design variables

Placebo comparisonDouble-blind, single-blind, open-label, or case series/chart reviewUse of comparison drugUse of non-drug comparison treatment

Logistic RegressionLogistic Regression N = 205 (1 drug/article; missing values) TFDA related to outcome (p=0.01) Sponsorship related to outcome

(p=0.001) Favorable outcomes for same company

sponsorship> competing company sponsorship (OR=0.07, p<0.001)> mixed sponsorship (OR=0.14, p=0.02)> non-pharmaceutical sponsorship (OR=0.19, p=0.004)

LimitationsLimitations

Potential confounds not consideredSelective fundingSelective publication–Easterbrook, Lancet 1991

Warranted vs. unwarranted influence

Influence warranted when drug companies encourage doctors to make the right decisions.

Why Sponsorship-Outcomes Relationship?Why Sponsorship-Outcomes Relationship? Safer, 2002; Heres, 2006 Method Modifictions

Dosing schedulesStudy endpointsStudy time framesMeasurement scalesStatistical proceduresInclusion/exclusion criteria

Reporting ModificationsHighlighting findings favorable to sponsorEditorializing in the abstract

Restrictive Approach DrawbacksRestrictive Approach Drawbacks

“We desperately need new medications for substance abuse treatment, so we should encourage the pharmaceutical companies to invest.”—Petros Levounis, MD, Director of The Addiction Institute of New York

“Although scandals, real or perceived, have a short lifetime, unmet health needs persist.”—Thomas P. Stossel, MD, NEJM 2005

Treatment Without Side-EffectsTreatment Without Side-Effects Registration of clinical trials Conflict of interest transparency Dual sponsorship encouragement Study design/reporting modifications education

Articles– Safer, 2002– Heres, 2006– Lewis & Warlow, 2004– Montori, 2004

Newsletters– Carlat Psychiatry Report

Most important lesson: Outcomes depend on research question asked

Courtroom AnalogyCourtroom Analogy Plaintiff & Defendant = Competing

Pharmaceutical Companies Jury = General Practitioners and

Psychiatrists in Clinical Practice Judge = Leading Experts