Closing the Loop: Towards Claim-Evidence Networks in Clinical Practice

Closing the Loop: Towards Claim-Evidence

Networks in Clinical PracticeAnita de Waard

VP Research Data Collaborations, Elsevier

Clinical CommunicationHas Many Loose Ends…

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• Data2Semantics Project: Linking clinical guidelines to evidence in a linked data form

• Goal: improve speed of integration of research > practice • Issue: citations seem to provide evidence… or do they?

Studies have demonstrated inconsistent results regarding the use of such markers of inflammation as C-reactive protein (CRP), interleukins- 6 (IL-6) and -8, and procalcitonin (PCT) in neutropenic patients with cancer [55–57].

Studies have demonstrated inconsistent results regarding the use of such markers of inflammation as C-reactive protein (CRP), interleukins- 6 (IL-6) and -8, and procalcitonin (PCT) in neutropenic patients with cancer [55–57].

[55]: …PCT and IL-6 are more reliable markers for neutropenia than CRP for predicting bacteremia in patients with febrile

[55]: …PCT and IL-6 are more reliable markers for neutropenia than CRP for predicting bacteremia in patients with febrile

[56] In conclusion, daily measurement of PCT or IL-6 could help identify neutropenic patients with a stable course when the fever lasts >3 d. …, it would reduce adverse events and treatment costs.

[56] In conclusion, daily measurement of PCT or IL-6 could help identify neutropenic patients with a stable course when the fever lasts >3 d. …, it would reduce adverse events and treatment costs.

[57] Our study supports the value of PCT as a reliable tool to predict clinical outcome in febrile neutropenia.

[57] Our study supports the value of PCT as a reliable tool to predict clinical outcome in febrile neutropenia.

Why Is That A Problem? 1. From Trials to Guidelines

Why is that a problem? 2.

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Karen Dineen Wagner, M.D., Ph.D.; Adelaide S. Robb, M.D.; Robert L. Findling, M.D.; Jianqing Jin, Ph.D.; Marcelo M.

Gutierrez, Ph.D. William E. Heydorn, Ph.D.A Randomized, Placebo-Controlled Trial of Citalopram for

the Treatment of Major Depression in Children and Adolescents

Am J Psychiatry 2004;161:1079-1083. 10.1176/appi.ajp.161.6.1079

Karen Dineen Wagner, M.D., Ph.D.; Adelaide S. Robb, M.D.; Robert L. Findling, M.D.; Jianqing Jin, Ph.D.; Marcelo M.

Gutierrez, Ph.D. William E. Heydorn, Ph.D.A Randomized, Placebo-Controlled Trial of Citalopram for

the Treatment of Major Depression in Children and Adolescents

Am J Psychiatry 2004;161:1079-1083. 10.1176/appi.ajp.161.6.1079

Emslie GJ, Ventura D, Korotzer A, Tourkodimitris S. Escitalopram in the treatment of adolescent depression: a

randomized placebo-controlled multisite trial. J Am Acad Child Adolesc Psychiatry. 2009 Jul;48(7):721-9.

Disclosure: Dr. Emslie has received grants from the National Institute of Mental Health, Eli Lilly and Company, Forest

Laboratories, …. Drs. Ventura, Korotzer, and Tourkodimitris are employees of Forest Research Institute.

Emslie GJ, Ventura D, Korotzer A, Tourkodimitris S. Escitalopram in the treatment of adolescent depression: a

randomized placebo-controlled multisite trial. J Am Acad Child Adolesc Psychiatry. 2009 Jul;48(7):721-9.

Disclosure: Dr. Emslie has received grants from the National Institute of Mental Health, Eli Lilly and Company, Forest

Laboratories, …. Drs. Ventura, Korotzer, and Tourkodimitris are employees of Forest Research Institute.

http://clinicaltrials.gov/ct2/show/NCT00107120Emslie Study:

The Safety and Efficacy of Escitalopram in Pediatric Patients With Major Depressive Disorder

Sponsor: Forest LaboratoriesInformation provided by: Forest LaboratoriesClinicalTrials.gov Identifier: NCT00107120

http://clinicaltrials.gov/ct2/show/NCT00107120Emslie Study:

The Safety and Efficacy of Escitalopram in Pediatric Patients With Major Depressive Disorder

Sponsor: Forest LaboratoriesInformation provided by: Forest LaboratoriesClinicalTrials.gov Identifier: NCT00107120

The citalopram trial (Wagner et al., 2004) that formed part of the basis for escitalopram FDA approval was alleged to have been written and submitted by a medical “ghost-writer” on behalf of Forest Laboratories, Inc. [...] Drs. Wagner, Robb, and Findling reported that they had received an initial draft from Dr. Heydorn to which they contributed through several drafts. . Drs. Wagner, Robb, and Findling report that they contributed with Dr. Heydorn to the resubmission and that they were not aware that Dr. Heydorn was working with a commercial writer. Dr. Heydorn did not respond to our request for comment.

The citalopram trial (Wagner et al., 2004) that formed part of the basis for escitalopram FDA approval was alleged to have been written and submitted by a medical “ghost-writer” on behalf of Forest Laboratories, Inc. [...] Drs. Wagner, Robb, and Findling reported that they had received an initial draft from Dr. Heydorn to which they contributed through several drafts. . Drs. Wagner, Robb, and Findling report that they contributed with Dr. Heydorn to the resubmission and that they were not aware that Dr. Heydorn was working with a commercial writer. Dr. Heydorn did not respond to our request for comment.

The research groups that have studied citalopram and escitalopram for pediatric depression in RCTs are not independent groups, with the exception of the von Knorring group from Sweden (von Knorring et al., 2006). However, the RCT by this group was a negative trial. The other principal investigators on the studies analyzed here are co-authors on each others studies (Wagner et al., 2006; Wagner et al., 2004) and one group performed the double blind extension (Findling et al., 2008) of the other group’s RCT (Emslie et al., 2009). From these data, escitalopram and citalopram should not be considered for first-line treatment of adolescent depression, given the lack of replication of positive studies by independent groups. […] Each positive RCT lasted for only 8 weeks duration (Wagner et al., 2004; Emslie et al., 2009), and there was only one 16 week extension (Findling et al., 2008). Hence, the indication for escitalopram for maintenance treatment of adolescent depression is premature. […]While not required for licensing approval, a glaring omission is the lack of head to head trials of escitalopram or citalopram with fluoxetine, the gold-standard treatment for pediatric depression.

The research groups that have studied citalopram and escitalopram for pediatric depression in RCTs are not independent groups, with the exception of the von Knorring group from Sweden (von Knorring et al., 2006). However, the RCT by this group was a negative trial. The other principal investigators on the studies analyzed here are co-authors on each others studies (Wagner et al., 2006; Wagner et al., 2004) and one group performed the double blind extension (Findling et al., 2008) of the other group’s RCT (Emslie et al., 2009). From these data, escitalopram and citalopram should not be considered for first-line treatment of adolescent depression, given the lack of replication of positive studies by independent groups. […] Each positive RCT lasted for only 8 weeks duration (Wagner et al., 2004; Emslie et al., 2009), and there was only one 16 week extension (Findling et al., 2008). Hence, the indication for escitalopram for maintenance treatment of adolescent depression is premature. […]While not required for licensing approval, a glaring omission is the lack of head to head trials of escitalopram or citalopram with fluoxetine, the gold-standard treatment for pediatric depression.

ConclusionIn conclusion, the available evidence does not support first-line treatment of adolescent depression with either escitalopram or citalopram. It is our opinion that the US FDA approval of escitalopram was premature, given the available evidence.

ConclusionIn conclusion, the available evidence does not support first-line treatment of adolescent depression with either escitalopram or citalopram. It is our opinion that the US FDA approval of escitalopram was premature, given the available evidence.

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Lexapro under performing in the under 20 age segment (9%)Lexapro under performing in the under 20 age segment (9%)

So How Do We Connect These Loose Ends?

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So How Do We Connect These Loose Ends?

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Cancer CommonsCancer

Commons

WebsitesWebsites

Scientists Clinical Researchers Physicians Patients

Guidelines Data Case ReportsTrials Treatments Journals

One Example of a Closed Loop:Cancer Commons

© Marty Tenenbaum

ReferenceModels

Another example of a closed loop: the Cochrane Collaboration*

•Our mission is to promote evidence-informed health decision-making by producing high-quality, relevant, accessible systematic reviews and other synthesized research evidence.•Cochrane Reviews are systematic reviews of primary research in human health care and health policy, and are internationally recognised as the highest standard in evidence-based health care.

(*) Thanks to Chris Borgman for reminding me of Cochrane”s!

Trying to find evidence in papers: Big Mechanism

1. Identify epistemic values (v.1 completed):– Problem (Value = 0.25): “Until now, it has been unclear how RAS could affect ASPP2 to

enhance p53 function.”– Hypothesis (Value = 0.5): “It is likely that this possible feedback loop leads to an

amplified pro-apoptotic signal.”– Implication (Value = 0.75): “We show here that ASPP2 is phosphorylated by the

RAS/Raf/MAPK pathway..”– Fact (Value = 1.0): “ASPP2 is a haploinsufficient tumor suppressor [15] [16] and it can

cooperate with p53 to suppress tumour growth in vivo [15].”

• Identify source of statements (in progress):– Result (Source=Author): “Here we show that monoubiquitination decreases the

sensitivity of Ras to GAP–mediated hydrolysis. ”– Others-Result (Source=Citation): “It has recently been shown that oncogenic RAS can

enhance the apoptotic function of p53 via ASPP1 and ASPP2. [2]”

• Identify basis of statements (in progress): 1. Result (Basis=Data): “…we observed two conserved putative MAPK phosphorylation

sites in ASPP1 and ASPP2.”2. Hypothesis (Basis=Reasoning): “If RAS is only temporarily active, as happens in natural

growth conditions, one could hypothesize that ASPP2 would bind active RAS, potentiate its downstream pathways, and MAPK-mediated phosphorylation of ASPP2 would lead to increased binding to p53.”

In Summary: • Having all clinical trials available is GREAT – but it’s

not enough:– Example: guideline does not summarize trials– Example: marketing drugs enables sketchy evidence to look

strong

• What we need: better relations between claims and evidence:– Example: Cancer Commons– Example: Cochrane Collaboration– Example: finding epistemics in text

• Better tools to link to evidence• More cries for evidence!