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Drug analytics based on triple linking v1.0
- 1. Drug analytics on Embase Smart data for drug development, repurposing and safety based on triple indexing Ivan Krstic, PhD Senior Product Development Manager Embase July 27th 2016
- 2. 2 Agenda Data analytics based on manually extracted semantic relationships between: – Drug – Disease • Adverse Reaction • Therapy – Drug – Drug • Interactions • Combination • Comparison very valuable for: • Drug repurposing • Drug development • Drug safety
- 4. 4 Indexing for Embase is a manual process performed by trained indexers with a biomedical background, with the exception of articles designated for automatic indexing. Indexers read and analyze the full text of articles in order to identify relevant concepts, and index them with the most specific Emtree terms. Index terms are controlled by the Emtree thesaurus resulting in consistent coverage of concepts that may be expressed in many different ways in the literature. Indexing principles
- 5. 5 Indexing: subheadings Subheadings are Emtree terms that are also used as concept qualifiers for drugs, diseases and devices to refine their meaning, providing a very precise idea of what an article covers. Important Definition Drug subheadings
- 6. 6 Indexing: key subheadings Concept Key Subheading drug adverse drug reaction drug drug combination drug drug comparison drug drug interaction drug drug therapy device adverse device effect device device comparison disease drug therapy disease side effect Nine subheadings are denoted key subheadings. Important Definition
- 7. 7 Indexing: triple-linking Triple-indexing is a three level indexing of the full text of an article, and it consists of: ‒ Concept (drug or device or disease) ‒ Key subheading (relationship) ‒ Linked concept (e.g. stomatitis, hypertension, nausea, etc.) Triple indexing has started in Q1 of 2007 for the drug triples (drug therapy from Q2 of 2009). Devices began in Q2 of 2014. Important Definition Everolimus Adverse drug reaction Stomatitis Manually Extracted Semantic Relationships
- 8. 8 How can the Manually Extracted Semantic Relationships be searched Filter options For each drug, device and disease manually extracted semantic relationships can be identified and filtered (simple search a drug and use drug filter) Search query language 'everolimus'/'drug therapy'/'breast cancer'
- 9. 9 How are the Manually Extracted Semantic Relationships displayed? In individual results
- 10. 10 How are the manually extracted semantic relationships displayed? In filters
- 12. 12 Drug repositioning to treat (rare) diseases Compounds targeted for repositioning have already gone through extensive preclinical testing and have shown safety in their original indication. The key benefits are: Shorter development time Lower development costs - safety profiles of the products will have already been established Higher success rates
- 13. 13 Manually extracted drug-disease relationships for drug repositioning Drug therapy = Used as a drug subheading to identify a drug used to treat disease / indication (including curative, palliative, symptomatic or prophylactic treatment) Everolimus Drug therapy Tumor neuroendocrine 320 Breast cancer 633 Kidney carcinoma 993 Important Definition
- 15. 15 Everolimus (Afinitor®) http://clincancerres.aacrjournals.org/content/16/5/1368 mTOR Signalling in cancer: • Positively regulates cell growth and proliferation • Positively regulates cellular metabolism & adenosine triphosphate (ATP) production • Promotes angiogenesis • Promotes cell growth by negatively regulating degradative processes in cells Mechanism of Action: mTOR inhibitor (inhibits the mammalian target of rapamycin) mTOR inhibitors can be used to block the multiple biologic effects caused by the aberrant activation of mTOR found in several cancer types.
- 16. 16 Everolimus is approved for various conditions • Advanced kidney cancer (US FDA approved in March 2009) • Prevention of organ rejection after renal transplant (April 2010) • Subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS) (October 2010) • Progressive or metastatic pancreatic neuroendocrine tumors not surgically removable (May 2011) • Breast cancer in post-menopausal women with advanced hormone-receptor positive, in conjunction with exemestane (July 2012) • Prevention of organ rejection after liver transplant (Feb 2013 • Progressive, well-differentiated non-functional, neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin (February 2016). Launch Date March 2009 First Full-Year Sales (2010) $243 million Sales in 2015 $1.6 billion
- 17. 17 Semantic relationship between Everolimus and treated indications Everolimus – list of all on-label and off-label use indexed on Embase
- 18. 18 Relation between approval year and records reporting direct relationship between drug and indication Pub. year Kidney cancer Pancreatic neuroendocrine tumor Breast cancer Neuroendocrine tumor Tuberous sclerosis 2016 66 17 43 20 10 2015 84 45 82 39 26 2014 102 29 104 29 15 2013 142 74 139 36 26 2012 170 71 124 81 10 2011 190 12 63 69 11 2010 144 2 60 32 3 2009 114 34 21 2 2008 9 2 2 # of published articles for Everolimus per year Is Tuberous Sclerosis next use to be approved for Everolimus ?
- 19. 19 Relation between approval year and records reporting direct relationship between drug and indication Pub. year Kidney cancer Pancreatic neuroendocrine tumor Breast cancer Neuroendocrine tumor Tuberous sclerosis 2016 66 17 43 20 10 2015 84 45 82 39 26 2014 102 29 104 29 15 2013 142 74 139 36 26 2012 170 71 124 81 10 2011 190 12 63 69 11 2010 144 2 60 32 3 2009 114 34 21 2 2008 9 2 2 # of published articles for Everolimus per year Take-home message: Semantic relationship between drugs and indications can be used to guide drug repositioning strategies.
- 20. Nivolumab
- 21. 21 Nivolumab Indications (approved): • Hodgkin's disease • malignant melanoma • non-small cell lung cancer • renal cell cancer Off-label use: • colorectal cancer • lung cancer • ovary cancer
- 22. 22 Nivolumab for Colorectal cancer in Clinical trials Embase search: 'nivolumab'/'drug therapy'/'colorectal cancer' AND 'nivolumab'/'clinical trial'
- 24. 24 Kadcyla (ado-trastuzumab emtansine) In a clinical trial of women with advanced HER2 positive breast cancer who were already resistant to trastuzumab alone Kadcyla improved median overall survival by 5.8 months (30.9 months vs. 25.1 months) compared to the combination of lapatinib and capecitabine.
- 25. 25 Potential new use for Kadcyla Is there an evidence for a new use?
- 26. New drug combinations for combination drugs
- 27. 27 What is a Drug combination on Embase? Drug combination = Used as a drug subheading for drugs given in combination or concomitantly Everolimus Drug combination Paclitaxel 221 Exemestane 259 Bevacizumab 270 Important Definition
- 28. 28 Drug combinations for new combinations Everolimus is approved for breast cancer in post-menopausal women with advanced hormone-receptor positive, HER2-negative type cancer, in conjunction with exemestane (FDA July 2012)
- 29. 29 New combinations for Everolimus PUBYEAR everolimus- drug combination- exemestane everolimus- drug combination- bevacizumab 2016 14 1 2015 46 17 2014 56 19 2013 73 34 2012 53 54 2011 11 47 2010 2 42 2009 3 36 2008 16 2007 4 Is the combination with bevacizumab next to be approved for the treatment of kidney cancer or colorectal cancer?
- 30. 30 New combinations for Kadcyla New formulation looks promising – combination of trastuzumab emtansine (Kadcyla), paclitaxel, and pertuzumab in clinical trials. Potential new combination with Pertuzumab
- 32. 32 What is a drug-drug interaction on Embase? Drug interaction = alteration of the effects of a drug by reaction with another drug or drugs, with foods or beverages, or with a preexisting medical condition. Used as a drug subheading. Everolimus Drug interaction Erythromycin 26 Rifampicin 28 Ketoconazole 28 Important Definition
- 33. 33 Drug-drug interactions Long list of drug with reported interactions with everolimus – to be listed in the label.
- 35. 35 What is a drug-drug comparison on Embase? Drug comparison = Used as a drug subheading when two or more drugs are compared within the same study. EverolimusDrug comparison Azathioprine 65 Paclitaxel 172 Rapamycin 192 Important Definition
- 36. 36 Seamless access to drug comparison data Analytical capability provides access to information on drug-drug comparison in literature.
- 37. 37 Drug comparison – smooth access to records with clinical efficacy and safety data
- 38. Drug safety
- 39. 39 What is an Adverse drug reaction on Embase? Adverse drug reaction = Used as a drug subheading to identify a drug for which an undesired side effect is reported (when used at therapeutic dose ranges in humans) Fatigue 564 Everolimus Adverse drug reaction Diarrhea 570 Stomatitis 616 Important Definition
- 40. 40 Seamless access to safety signals
- 41. 41 Manually extracted semantic relationships for drug safety Safe and rational use of drug Better risk management Assess causalities
- 42. 42 Everolimus - safety signals per year Smart data available in Embase helps to improve Risk Management (Causality assessment and Signal confirmation)
- 43. 43 Summary Manually extracted semantic relationships can be used to: guide drug repositioning strategies investigate potential for development of combination drugs identify drug-drug interactions collect drug-drug comparison information improve risk management (Causality assessment and Signal confirmation)
- 44. Thank you! Any questions? Ivan Krstic, PhD Senior Product Development Manager Embase i.krstic@elsevier.com