Literature monitoring for pharmacovigilance – outsourcing or in house solution
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• A brief introduction about relevance of literature screening for P V. • Challenges of literature screening in general. • Benefits and risks of completely outsourcing literature screening for PV. • Business case elements that need to take into consideration when deciding on outsourcing or in-sourcing PV literature screening.
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Literature monitoring for pharmacovigilance – outsourcing or in house solution
- 1. 1 Literature Monitoring for Pharmacovigilance – Outsourcing or In-house Solution Júlio dos Anjos Senior Software Development Manager September 13th, 2017 linkedin.com/in/janjos
- 2. 2 Summary • Scientific and medical literature is a relevant source of safety information • Literature screening for single adverse drug reactions may indeed: – improve patient safety – impact the life cycle of a drug • MAHs are facing a number of challenges with regard to literature management for pharmacovigilance • Outsourcing pharmacovigilance and investment in software solution may support pharmaceutical companies in handling the challenges with literature management for pharmacovigilance. • Using software solutions allow you to have oversight on your CRO and outsource (part of) the workload
- 3. 3 Preventing Adverse Drug Reactions Improves Public Health • 5 % of all hospital admission in EU are related to adverse drug reactions • 28% of patients visit emergency department of hospital due to adverse events • Averse drug reactions are the 5th most common cause of death of hospitalized patients. • Nearly 197,000 death per year due to adverse drug reactions • Costs 75 Billion US Dollars per year - Lazarou J et al. Incidence of ADRs in hospitalized patients. JAMA 1998, 279 (15) 1200-1205 - Classen DC et al. ADRs in hospitalized patients: excess length of stay, extra costs, and attributable mortality. Obstet. Gyncol Surv 1997, 52 (5):291-292 - Ahmad SR: Adverse drug event monitoring at FDA. J Gen Intern Med 2003, 18 (1): 57-60.
- 4. 4 Why search scientific and medical literature? ‘…Scientific and medical literature is a significant source of information for the monitoring of the safety profile and of the risk benefit balance of medicinal products, particularly in relation to the detection of new safety signals or emerging safety issues… Reference: Guideline on good pharmacovigilance practices (GVP): Module VI-Management and reporting of adverse events to medicinal products
- 5. 5 Role of Literature in Pharmacovigilance • Screening scientific & medical literature to identify single adverse drug reactions or special situations • Systematic review of scientific & medical literature for aggregated reporting (PSURs, PBRERs, DSUR). • Screening literature for signal detection and assessment of validated signals.
- 6. 6 Literature is the 4th largest source of AE reporting Adverse events reported in literature can have a high impact — major drug recalls (e.g., Vioxx, Baycol) were initiated by published adverse reactions. Often overlaps with reports from health professionals FDA Adverse Event Reporting System (FAERS) Quarterly Data Files, Q2 and Q3 2013 Reported adverse events by report source, Q2 & Q3 2013 N = 34,469 unique events Overlap of adverse events sourced from literature by reporting sources, Q2 & Q3 2013 N = 4,691 unique events
- 7. 7 Safety information from spontaneous and literature adverse reactions reports may differ Klose J, Fröhling S, Kroth E, Dobmeyer T, Nolting A. Safety information from spontaneous and literature adverse reactions reports: a comparison. Ther Innov Regul Sci. 2013;47:248–55. Extracted from Table 4 Drug Substance System Organ Class Literature Cases (%) Spontaneous Cases (%) % Difference Acetylsalicylic Acid Nervous System Disorders 25.6 8 17.6 Gastrointestinal Disorders 8.4 25.4 17.0 Fentanyl Injury, poisoning, complications 35.9 7.5 28.3 Alendronic acid Gastrointestinal disorders 4.6 21.0 16.5 Injury, poisoning, complications 28.3 5.4 22.9 Tamsulosin Injury, poisoning, complications 50 4.1 45.9 Etoposide Congenital, familial, genetic 0 24.3 24.3
- 8. 8 Literature as source of ADRs: Thalidomide and congenital birth defects (1961) McBride WG. Thalidomide and congenital abnormalities. Lancet. 1961;278:1358
- 9. 9 Signal from literature: Tamsulosin and ‘Floppy Iris Syndrome’ (2005) • Intraoperative floppy iris syndrome occurred in approximately 2% of a cataract surgery population • Appeared to be caused by tamsulosin, a systemic sympathetic alpha-1A antagonist • Chang et al. mention 15 patients with IFIS • At the time of publication, none had been reported to the Regulatory Authorities! Intraoperative floppy iris syndrome associated with tamsulosin Chang D.F., Campbell J.R. Journal of Cataract and Refractive Surgery 2005 31:4 (664-673) Cited by: 285
- 10. 10 2016 Annual Report on Eudravigilance: Increase in signals from scientific literature http://www.ema.europa.eu/docs/en_GB/document_library/Report/2017/03/WC500224056.pdf
- 11. Challenges in literature screening for pharmacovigilance
- 12. 12 What are the biggest challenges with Literature Screening? Differences in Regulations Building an Ideal Search Strategy Large Volume of Scientific Literature Inspections/Audits Monitoring Local Language Journals Implementing EMA MLM Results
- 13. 13 What are the biggest challenges with Literature Screening? Differences in Regulations Building an Ideal Search Strategy Large Volume of Scientific Literature Inspections/Audits Monitoring Local Language Journals Implementing EMA MLM Results
- 14. 14 Guidelines for literature screening may differ between authorities
- 15. 15 • Regularly screen worldwide scientific literature by assessing widely used systematic literature reviews or reference databases • Frequency: according to local/national requirements or at least every two weeks • Scientific and medical literature – Including relevant published meeting & conference abstracts – Including draft manuscripts (Article in press & Article in Process) • Reporting Rules – One form per identifiable patient – Report Source: publication reference – Copy of article might be required (differs between local authorities)
- 16. 16 • Serious, unexpected adverse experiences reported in scientific literature (or in any unpublished scientific paper) that are known to the applicant must be submitted within 15 days. • Reports of serious, unexpected adverse experiences described in scientific literature should be submitted for products with the same active substance as a product marketing in the US. This is true even if the excipient, dosage forms, strengths, routes of administration and indications vary. • Serious unexpected adverse experiences based on a foreign language article or manuscript should be translated by the applicant into English promptly.
- 17. 17 • Reports of suspected adverse reactions from scientific and medical literature, including relevant published abstracts from meetings and draft manuscripts, should be reviewed and assessed by MAHs to identify and record ICSRs originating from spontaneous reports, or non-interventional post-authorisation studies • If multiple medicinal products are mentioned in the publication, only those which are identified by the publication’s author as having at least a possible causal relationship with the suspected adverse reaction should be considered by the concerned MAHs’
- 18. 18 Guidance by authorities shows a lack of harmonization EMA FDA CIOMS ICH Frequency of screening literature At least weekly Not specified Monthly According to local requirements or at least bi-weekly Which Literature to screen? Scientific and medical literature Scientific literature Discusses all terminology used by different Regulators Worldwide literature Reporting requirements Serious and non- serious Serious and unexpected Expedited reporting being discussed Day 0 is when Medical safety information is identified Exclusions No Yes Not applicable Brand or trade name
- 19. 19 Challenges in literature screening: When to start? When do you start your literature surveillance of a new medicinal product? A. After the submission of the application for marketing authorization B. After the regulatory approval of the marketing authorization C. After the marketing of an authorized medicinal product
- 20. 20 Challenges in literature screening: When to start? The correct answer is A… A.On submission of the application for marketing authorization B.After the regulatory approval of the marketing authorization C.After the marketing of an authorized medicinal product It is expected that literature screening should start on submission of a marketing authorization application and should continue while authorization is active.
- 21. 21 What are the biggest challenges with Literature Screening? Differences in Regulations Building an Ideal Search Strategy Large Volume of Scientific Literature Inspections/Audits Monitoring Local Language Journals Implementing EMA MLM Results
- 22. 22 Challenges in Literature screening for PV: Increasing amount of scientific literature Data retrieved from www.Embase.com 0 5 10 15 20 25 30 35 1975 1980 1985 1990 1995 2000 2005 2010 2011 2012 2013 2014 2015 2016 Number of records in Embase per Year (in millions)
- 23. 23 What are your options? Read all literature – Impossible Use an A&I database • Read all PubMed – Impossible • Read all Embase – Impossible Remaining option: • Find and read only relevant records from literature databases • Read the articles these records represent
- 24. 24 Searching for safety-relevant information Optimize your search strategies by… • Choosing the best source databases and search engines • Creating the best possible search strategy and search terms • Using the right search limits • Using defined review criteria
- 25. 25 Choosing the best source database • Search well recognized scientific and medical journals • Screening of well recognized medical databases – Embase – Medline – Cochrane Library – CINAHL – Other relevant databases • Conference abstracts, draft manuscripts • Local Language Journals
- 26. 26 Choice of source databases and Search Engines • Databases differ in accessibility, coverage & overlap • No single database has full sensitivity for literature screening • Periodic literature search and review should be performed in multiple, carefully selected databases
- 27. 27 Building an ideal search strategy • Precision: How many of the records in the result set are relevant to my need (and, as a consequence, how many are not relevant). • Recall: From all records that are relevant to our need, how many are present in the search result, and how many, if any, are relevant, but the search formula failed to capture. • In PV we want a Recall of 100%: NO RECORDS indicating that an ADR is present in the article, are missed by the search formula • Precision will impact productivity: Low values mean too much noise is coming in: irrelevant records to review. But it can’t be increased at the cost of Recall.
- 28. 28 Choice of search strategy • In case of a very large number of results from the search strategy, MAHs may prepare two different search strategies and run these parallel on a weekly basis: • One for ICSR detection • One for PSUR detection • Search strategy for ICSR detection can exclude records for pharmaceutical forms or routes of administration that are not approved for that MAH
- 29. 29 What are the biggest challenges with Literature Screening? Differences in Regulations Building an Ideal Search Strategy Large Volume of Scientific Literature Inspections/Audits Monitoring Local Language Journals Implementing EMA MLM Results
- 30. 30 Challenge: Inspections and Audit Preparedness • Increased attention of regulators for literature screening since introduction of GVP modules in 2012 • Proportion of major and minor findings related to literature screening has increased since 2012 But it is not only about ‘not missing’ articles: – List of journals & reference databases – SOP(s) – Search strategy – Integration of EMA MLM results in your companies workflow – Local language journals – Oversight CRO/Service Providers – Traceability
- 31. 31 It’s ideal to capture an exportable audit trail as you review literature…
- 32. 32 What are the biggest challenges with Literature Screening? Differences in Regulations Building an Ideal Search Strategy Large Volume of Scientific Literature Inspections/Audits Monitoring Local Language Journals Implementing EMA MLM Results
- 33. 33 Monitoring Local Language Journals – most time- consuming uncertainty in PV Literature Management Customer’s Challenges “Many local journals are not included in international databases, so we have to monitor them separately” “Without a database, I have to read the articles one by one, manually. I am always concerned that there is a risk of missing relevant content.” “Time consuming” Regulations ‘… monitor scientific and medical publications in local journals in countries where medicinal products have a marketing authorization …’
- 34. 34 Challenge: Monitoring Local Language Journals List of Local Language Journals • Do you know where to look to identify all relevant local language journals? • Are you sure the company’s list of local language journals is exhaustive?
- 35. 35 What are the biggest challenges with Literature Screening? Differences in Regulations Building an Ideal Search Strategy Large Volume of Scientific Literature Inspections/Audits Monitoring Local Language Journals Implementing EMA MLM Results
- 36. 36 Challenge: EMA Medical Literature Monitoring • EMA MLM Service: 300 active substances, 100 herbals • Since launch (July, 2015) 115,550 literature references reviewed by EMA • In total 1,464 Adverse Drug Reactions were identified, involving 756 individual patients http://www.ema.europa.eu/docs/en_GB/document_library/Other/2015/05/WC500186732.pdf
- 37. 37 A significant workload remains for MAHs • MAHs should still fulfill reporting requirements outside EU • MAHs are still responsible for literature screening for aggregated safety reporting • MAHs are still responsible for monitoring scientific and medical publications in local language journals • MAHs need to integrate the dataflow resulting from the EMA MLM Service into their existing workflow for literature management and ICSR-management
- 38. Outsourcing Literature Monitoring for PV
- 39. 39 When does outsourcing help? • In times of high workload, and no additional in- house resources are available on short term • When companies need to be flexible due to varying workloads • Outsourcing approach of ‘pay as you go’ allows you to respond fully to regulatory obligations, without the need of retaining a full pharmacovigilance team on the payroll • The benefits of outsourcing include reduced costs because less effort is needed for staff recruitment, management and training • With stricter regulatory requirements, the hiring of experienced safety personnel has become highly competitive
- 40. 40 Most commonly outsourced drugs safety activities https://www.ashfieldhealthcare.com/wp-content/uploads/2015/06/Safety-on-a-Budget.pdf
- 41. 41 What kind of Literature Services do CRO’s Provide? • Screening Literature for Identification of Individual Case Safety Reports (ICSRs) and Special Situations • Targeted Literature Screening For Safety Assessments And Benefit Risk Analysis But also: • Entry of identified cases onto a validated safety database • Full medical review of ICSRs • Regulatory reporting of ICSRs • Signal Detection and Benefit risk analysis • Medical Assessment of safety issues
- 42. 42 Conditions & Challenges for outsourcing Literature Management for PV • Do you have oversight over the CRO activities? • How much time do you spend on reconciling the data? • Do you know how the CRO validates/optimizes the search strategy?
- 43. In-house Software Solutions for Literature Management Challenges
- 44. 44 Software solutions: In-house solution to solve challenges with literature management • In-house software solutions provide oversight on reviewers • Increase of efficiency (reduction of costs) due to automated deduplication & generating ICSRs from the tool • Improve the Quality & Compliance of the whole literature review process as: – A software solution structures data-flow >> decreased risk of missing information. – Increased oversight on the workload and possibility to manage/structure the workload – Increased oversight on CRO activities
- 45. 45 Literature monitoring solutions: Decrease risk of missing information without redundant reviewing Make sure all relevant articles are captured • Capture data from most comprehensive source of journals/ conference abstracts • Develop custom search strategies to find all relevant data Avoid redundant reviews of the same input • Save time and avoid redundant reviewing with automatic deduplication of articles Save time and stay current • Stay current and work more efficiently with automated article curation process
- 46. 46 Literature management solutions: improve workflow management and regulatory compliance Track review process in case of audit • Demonstrate procedures done correctly and on time with traceable review process Improve article pipeline management • Identify most relevant articles with text mining • Ensure appropriate personnel receive/ review required data with alert system Capture metrics behind article reviews • Calculate efficiency and ensure strict quality control by capturing metrics
- 47. 47 Empowering rapid, transparent literature surveillance and case triage A browser-based tool that saves time and money by centralizing and automating the literature review and triage process
- 48. 48 Overview: record statistics Dashboard — Improved oversight and efficiency Clear overview of record trends, incoming alerts, productivity and backlogs Average review time/article at each stage Article backlog per agent
- 49. 49 Integrating a CRO with Literature Monitoring Platform Case Input Case Processing Case Output Literature Databases EMA MLM Data Local Language Journals Search Strategies Literature Monitoring Platform Literature Review Performed by CRO MAH Potential ICSR Cases E2B XML Export PSUR/DSUR Lists Performance monitoring
- 50. 50 Summary • Scientific and medical literature is a relevant source of safety information • Literature screening for single adverse drug reactions may indeed: – improve patient safety – impact the life cycle of a drug • MAHs are facing a number of challenges with regard to literature management for pharmacovigilance • Outsourcing pharmacovigilance and investment in software solution may support pharmaceutical companies in handling the challenges with literature management for pharmacovigilance. • Using software solutions allow you to have oversight on your CRO and outsource (part of) the workload
- 51. 51 Our mission in pharmacovigilance Elsevier provides the solutions necessary for Pharmacovigilance and drug safety groups to be more efficient, stay compliant and mitigate risks. Thank you! Any questions? Júlio dos Anjos Senior Software Development Manager j.dosanjos@elsevier.com