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Literature surveillance in pharmacovigilance

Literature Surveillance in Pharmacovigilance; Current Trends, Methods and Challenges
Please join Elizabeth E. Garrard, PharmD, founder and CEO of Garrard Safety Solutions, as she reviews key issues in literature surveillance for Pharmacovigilance.
Objectives:
• Understand the regulatory obligations, best sources and procedures for conducting literature surveillance.
• Appreciate some examples of when a safety signal was detected in the literature and its impact on the lifecycle of a drug.
• Understand when to start and where to look for emerging safety information.
• Setting up your search strategy, how to ensure your search strings are well balanced, recognizing the challenges between precision and sensitivity.
• What is the impact of the new literature monitoring by EMA of a number of substances in selected medical literature to identify suspected adverse reactions with medicines authorized in the European Union. Early insights into successes and issues.
• Discuss current methods that can increase the likelihood of early detection of a safety issue and minimize the issues surrounding.
• Realize the challenges we face including wide differences in quality, accuracy, and completeness in the scientific literature and how best to navigate these differences and maintain proper vigilance.

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Literature surveillance in pharmacovigilance

  1. 1. Literature Surveillance in Pharmacovigilance: Current Trends, Methods and Challenges  Elizabeth Garrard, PharmD.  Garrard Safety Solutions CEO and Founder  Pharmacovigilance Consultant
  2. 2. Disclosure The views and opinions expressed in the following presentation are those of the individual presenter and should not be attributed to Elsevier, the RELX Group, any regulatory authority, or to any of my clients.
  3. 3. Objectives for Today  Understand:  The regulatory obligations, best sources and procedures for conducting literature surveillance.  When a safety signal was detected in the literature and its impact on the lifecycle of a drug.  When to start and where to look for emerging safety information  How to set up your search strategy  What is the impact of the new literature monitoring by EMA?  The current methods that can increase the likelihood of early detection of a safety issue  The challenges we face in quality, accuracy, and completeness in the scientific literature and how best to navigate these differences and maintain proper vigilance.
  4. 4. Why search scientific and medical literature? “Scientific & 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. When we say “Medical Literature” what all is included?  Medical Literature includes:  Published abstracts or  Articles in medical/scientific journals  Unpublished manuscripts involving case reports  Important safety findings or clinical studies including posters, letters to the editors, and associated communication from scientific meetings.
  6. 6. Literature volume keeps growing…... Zhiyong Lu Database 2011;2011:baq036 © The Author(s) 2011. Published by Oxford University Press.
  7. 7. Literature is but one of many sources of information…..
  8. 8. Understanding the Regulatory Obligations Literature Searches in Pharmacovigilance
  9. 9. How are regulatory agencies responding?  Health regulatory authorities (RAs) are intensifying safety regulations and focus on Literature Monitoring in EU and US Marketing authorization holders are expected to maintain awareness of possible publications through a systematic literature review of widely used reference databases (e.g. Medline, Excerpta Medica or Embase) no less frequently than once a week. The quality of the reports is critical for appropriate evaluation of the relationship between the product and adverse events.
  10. 10. LITERATURE:ICH E2D 3.1.2 Literature  Each MAH is expected to regularly screen the worldwide scientific literature by accessing widely used systematic literature reviews or reference databases. The frequency of the literature searches should be according to local requirements or at least every two weeks.  Cases of ADRs from the scientific and medical literature, including relevant published abstracts from meetings and draft manuscripts, might qualify for expedited reporting. A regulatory reporting form with relevant medical information should be provided for each identifiable patient.
  11. 11. LITERATURE: ICH E2D (con’t) 3.1.2 Literature (cont’d)  All company offices are encouraged to be aware of publications in their local journals and to bring them to the attention of the company safety department as appropriate.  The regulatory reporting time clock starts as soon as the MAH has knowledge that the case meets minimum criteria for reportability.  If the product source, brand, or trade name is not specified, the MAH should assume that it was its product, although the report should indicate that the specific brand was not identified.  If multiple products are mentioned in the article, a report should be submitted only by the applicant whose product is suspected. The suspect product is that identified as such by the article's author.
  12. 12. LITERATURE: FDA “Reports of serious, unexpected adverse experiences described in the scientific literature should be submitted for products that have the same active moiety as a product marketed in the United States. This is true even if the excipient, dosage forms, strengths, routes of administration, and indications vary.” “ When a serious, unexpected adverse experience is based on a foreign language article or manuscript, the applicant should translate the publication into English promptly…” Reference: Guidance for Industry: Postmarketing Safety Reporting for Human Drug and Biological Products including Vaccines:
  13. 13. Literature: FDA (con’t) “Serious, unexpected adverse experiences reported in the scientific literature (or in an unpublished scientific paper) that are known to the applicant must be submitted as 15-day reports…Applicants can use literature search services to identify adverse experiences in the scientific literature….” “ If multiple products are mentioned in the article, an Form FDA 3500A should be submitted only by the applicant whose product is the suspect drug. The suspect drug is that identified by the article’s author and is usually mentioned in the article’s title. If the applicant believes that the suspect product is different from the one identified by the author of the article, the applicant should indicate such information in the narrative section of the Form FDA 3500A. Guidance for Industry: Postmarketing Safety Reporting for Human Drug and Biological Products including Vaccines:
  14. 14. LITERATURE: Health Canada “Every MAH is expected to screen the worldwide scientific literature on a regular basis by accessing widely used systematic literature review or reference databases. It is recommended that the frequency of the literature searches be at least every two weeks. A qualified healthcare professional from the MAH should use their clinical judgment to determine the appropriate frequency of literature searches based on the health product marketed by the MAH.” Reference: Guidance Document for Industry: Reporting Adverse Reactions to Marketed Health Products:
  15. 15. LITERATURE:Health Canada (con’t) “For foreign literature reports, all foreign serious, unexpected ARs involving the MAH’s foreign products with the same combination of active ingredients irrespective of variations in the formulation, dosage form, strength , route of administration, or indication, that is also marketed in Canada must be reported to MHPD in accordance with the Regulations.” Reference: Guidance Document for Industry: Reporting Adverse Reactions to Marketed Health Products:
  16. 16. LITERATURE : EMA Reports of suspected adverse reactions from the scientific and medical literature, including relevant published abstracts from meetings and draft manuscripts, should be reviewed and assessed by marketing authorisation holders 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(s) as having at least a possible causal relationship with the suspected adverse reaction should be considered by the concerned marketing authorisation holder(s).” Reference: Guideline on good pharmacovigilance practices (GVP): Module VI-Management and of adverse events to medicinal products:
  17. 17. LITERATURE :EMA (Exclusions) VI.C.2.2 Articles can be excluded from the reporting of ICSRs by the MAH if another company's branded medicinal product is the suspected medicinal product. In the absence of a specified product source or invented name, ownership of the product should be assumed unless ownership can be excluded on the basis of one of the following criteria: medicinal product name active substance name pharmaceutical form, batch number or route of administration. Exclusion based on the primary source country or country of origin of the adverse reaction is possible if the MAH can demonstrate that the suspected medicinal product has never been supplied or marketed in that territory. Reference: Guideline on good pharmacovigilance practices (GVP): Module VI-Management and of adverse events to medicinal products:
  18. 18. LITERATURE REPORTS: EMA (Exclusions)  MAH can exclude from reporting if the following conditions apply:  For ICSRs identified in the scientific and medical literature that originate in a country where a company holds a MA but has never commercialized the medicinal product;  For literature ICSRs which are based on an analysis from a competent authority database within the EU. The reporting requirements remain for those ICSRs which are based on the analysis from a competent authority database outside of the EU.  For literature articles, which present data analyses from publicly available databases or which summarize results from post-authorization studies. (describes adverse reactions in a group of patients or presents data in aggregate or in tables) Reference: Guideline on good pharmacovigilance practices (GVP): Module VI-Management and of adverse events to medicinal products:
  19. 19. Safety Signals that have been detected in the Literature Reference: Pontes H, Clement M, Rollason V. Safety signal detection: the relevance of literature review. Drug Saf. 2014 Jul;37(7):471-9.
  20. 20. LITERATURE: Example #1 Thalidomide-induced Phocomelia (1961) Obstetrician William G. Mc Bride published a letter in the Lancet linking the rare birth defect with the use of thalidomide by pregnant women NOTE: At that time, there was no structure for reporting of ADRs to Regulatory Reference: McBride WG. Thalidomide and congenital abnormalities. Lancet. 1961;278: 1358
  21. 21. LITERATURE: Example # 2 Granulocyte Macrophage Colony- Stimulating Factor and Increased Risk of Viral Replication (1998) Literature search performed to assess safety of use of GM-CSF in the treatment of neutropenia in HIV patients (off label use in US) In vitro data suggested HIV up- regulation by GM-CSF Literature meta analysis showed increased risk of viral replication by the use of GM-CSF in patients with HIV not currently taking antiretrovirals. This type of safety concern would have never been detected by spontaneous reporting.
  22. 22. LITERATURE: Example # 3 Nifedipine and Fatal Aplastic Anemia (1998): Article described a case-control study linking six cases of fatal aplastic anemia with nifedipine Report identified a Type B ADR (bizarre or idiosyncratic, dose independent and unpredictable reaction) Reference: Laporte JR, Ibanez L, Ballarin E, Perez E, Vidal X. Fatal Aplastic anemia associated with nifedipine. Lancet. 1998;352: 619-20
  23. 23. LITERATURE: Example #4 Tamsulosin and ‘Floppy Iris Syndrome” (2005): 15 cases were described in the literature in April, 2005 At the time of publication, none had been reported to the Regulatory Authorities! Reference: Chang DF, Campbell JR,. Intraoperative floppy iris syndrome associated with tamsulosin. J Cataract Refract Surg. 2005;3: 664-73
  24. 24. Literature searching: When to start and where to look?
  25. 25. When to Start and Stop  For the period between submission and granting of a marketing authorization, literature searching should be conducted to identify published articles that provide information that could impact on the risk- benefit assessment of the product under evaluation.  Literature searches should be conducted for all products with a marketing authorization, irrespective of commercial status.  Bottom line: It is expected that literature searching would start on submission of a marketing authorization application and continue while the authorization is active.
  26. 26. What types of new emerging safety information should you be searching for…..  New, unexpected serious and non-serious ICSR reports with a reasonable causal association with the product. AND…..non-ICSR safety information  Pregnancy outcomes (including termination) with no adverse outcomes  Use in pediatric populations  Compassionate supply, named patient use  Lack of efficacy  Asymptomatic overdose, abuse or misuse  Medication error where no adverse events occurred  Important non-clinical safety results
  27. 27. Where to look?  Well recognized scientific and medical journals  Embase  Medline  Excerpta Media  International symposia or local journals  Abstracts from meetings and draft manuscripts
  28. 28. Medical Databases and Search Engines for Literature Screening Database Search Engines Medline Pubmed Embase Quosa BioSys Previews Ovid Cochrane Library ISI Web of Knowledge CINAHL Scopus SEDBASE Google Scholar
  29. 29. Considerations when choosing relevant Databases  Accessibility  Not all free; costs can be high  Coverage  Worldwide or not  Focus  Orientated towards particular medical discipline  Overlap
  30. 30. Considerations when choosing Literature Search Engines  Costs  Free or has access costs associated with it.  Is the user interface easy to navigate or complex?  How dependable and reliable are the outputs?  Can the search engine return de-duplicated results?  Can the user make selections for the most relevant articles and store your selected citations?  Can the user be notified when certain articles of interest are available?
  31. 31. Setting up an effective search strategy that can increase the potential for detecting a safety concern early. Methods and Search Strategies
  32. 32. Methods and Signal Search Strategies  Database/search engine selection  Approach to record retrieval  Establishing a search strategy  Creating a “search string”  Selection of relevant terms or text  Application of limits  Use of automated methods
  33. 33. LITERATURE: Search Strategy Recommendations from CIOMS V & EMA  Target the search to publications that appear in internationally recognized databases  Search at least two suitable databases  Constuct search string with terms likely to solicit relevant information  Utilize consistent and balanced search strategies (INN as keyword for retrieval)  Searches should be scheduled with a frequency appropriate to the drug [& as required by the local RA]  Review search results for ICSRs and non ICSR safety data. Consider separate searches for each.  Make sure local database searches are being conducted
  34. 34. Non-ICSR relevant data  Exposure during pregnancy or lactation (including pregnancies with no adverse outcomes)  Use of the product in pediatric populations, elderly or organ- impaired individuals  Occupational exposure  Lack of therapeutic efficacy  Asymptomatic overdose, abuse, or misuse  Medication error where no adverse events occurred (‘near misses’)  Off-label use  Suspected transmission of infectious agents  Compassionate supply, named-patient use  Clinical trial results/conclusions  Important non-clinical safety results (including in vitro/in vivo laboratory studies)  Information on the risk-benefit  Counterfeit product  Potential Diversion  Other data of interest
  35. 35. Choice of the Search Construction and Search Terms: Precision and Recall  The success of a search can be measured according to precision and recall (also called sensitivity)  Recall is the proportion of records retrieved ("hits") when considering the total number of relevant records that are present in the database.  Precision is the proportion of "hits" that are relevant when considering the number of records that were retrieved.  Good search construction should result in an output with low recall and high precision.
  36. 36. Representative list of possible terms for “adverse” Source: Webinar in 2013 - Searching Adverse Events on Embase: http://www.slideshare.net/rocheam/embase-webinar-ard-25-sep-2013
  37. 37. LITERATURE: Search Construction  Precision and recall- ideal is low recall & high precision  Adding index terms can increase precision and return records that are of relevance to PV – but use with caution  Search term construction is a balancing act- too many “hits” vs omission of relevant records
  38. 38. Creating the search string  Creation of a search string is a very delicate balancing act, as you want to ensure the best recall with the most precision.  Some Examples are below:  MESH.EXACT("generic -- adverse effects") OR MESH.EXACT ("generic -- poisoning") OR MESH.EXACT("generic -- contraindications") OR MESH.EXACT("generic -- toxicity")  OR (truncated generic&2 or generic other or TradeName1 or TradeName2 or other active substance or etc) near/15 ti,ab(adverse or allerg&2 or anomaly or causal or carcinogen&5 or complication&1 or congenital or contraindicat&4 or death&1 or mortality or mutagen&5 or oncogen or overdos&3 or poison&3 or pregnan&2 or reaction&1 or risk&1 or safe&1 or side or disabl&3 or disability or failure or fatal&3 or iatrogen&2 or ineffective or interact&3m or intoxicat&3 or "lack of efficacy" or lethal or error&1 or misuse or morbidity or teratogen&5 or toxic&3 or unexpected or unintended or unintentional or untoward or unwanted or analyphyla&3 or interact&5 or overdos&3 or intoxicat&3 or poison&3 or error&1 or "off label use")
  39. 39. Use of Search Limits  Should be relevant to the search criteria and purpose of the search  Should be applied to produce results for date ranges  Should also retrieve all records added in that period, and not just those initially entered or published during the specified period  Use of publication type limits is not robust for the detection of ICSRs, because an ICSR might be presented within review articles or study publications that are not usually indexed as ‘case reports’.
  40. 40. Examples of the relevance of search limits in Literature Screening Reference: Pontes H, Clement M, Rollason V. Safety signal detection: the relevance of literature review. Drug Saf. 2014 Jul;37(7):471-9.
  41. 41. Automated Methods  Use of literature search automated system that provides  Searches in relevant databases  Ability to set search limits, customize search strings and use free text to find adverse effects  Email alerts  All results stored electronically.  The electronic text files of searches performed and the archive of full text articles are readily available for internal or regulatory inspection.  Examples include Elsevier’s Quosa, Infotrieve, Nerac,
  42. 42. EMA Medical Literature Monitoring (MLM)
  43. 43. EMA Literature Monitoring  The agency decided to monitor a range of substances including herbals and the selection was made based on being active ingredients for products with high numbers of MAHs in the EU  The total number of substance groups to be included in the literature-monitoring service is depending on allocated budget.  The service was fully operational as of 1 September 2015  The European Medicines Agency (EMA) has outsourced the monitoring of literature to a service provider Monitored list URL: http://www.ema.europa.eu/docs/en_GB/document_library/Other/2014/03/WC500163678.pdf http://www.ema.europa.eu/docs/en_GB/document_library/Other/2014/03/WC500163679.pdf
  44. 44. Key principles for why EMA decided to implement MLM  Alleviate the burden on maximum number of MAHs.  Innovative medicinal products should not be covered.  Avoid partial service that would necessitate duplicative efforts by MAHs.  Provide quality controlled literature-monitoring services.  Establish a process so that MAHs can comply with the worldwide regulatory requirements.
  45. 45. Expected Benefits of the EMA Literature Monitoring  The monitoring of medical literature and the entry of relevant information into EudraVigilance will be carried out by EMA in order to:  Enhance the efficiency of adverse reactions reporting;  Provide a simplification for the pharmaceutical industry;  Improve data quality by reducing the number of duplicates;  Contribute to resource savings for the pharmaceutical industry;  Support signal detection activities by national competent authorities and marketing-authorisation holders. Website for list of EMA monitored products: http://www.c3ihc.com/blog/monitoring-medical-literature-eu- changes/
  46. 46. Which MAHs are going to benefit?  The Agency defined a range of active substances including herbal active substances contained in medicinal products for which a high number of marketing authorizations were granted to various MAHs in the EEA  More than 3,500 MAHs in the EEA will benefit from the MLM Service for the 300 substance groups selected by the Agency  More than 640 MAHs in the EEA will benefit from the MLM Service for the 100 herbal substance groups selected by the Agency  The list of MAHs benefitting from the service will be published on the EMA website
  47. 47. What databases are being used by EMA for their Literature Monitoring  Journal/Reference Databases that are monitored by EMA  Embase - a large, comprehensive and widely used, daily updated and indexed biomedical reference database covering literature from EEA and non-EEA countries  EBSCO - covering a wide variety of resources, including Medline Plus, International Pharmaceutical Abstracts (IPA) and The Allied and the Complementary Medicine Database (AMED)  The journals covered by the reference databases are further described in the document “Description of the MLM Journal/Reference databases” published at the EMA website
  48. 48. What specific types of safety information are being sought for MLM The purpose of the screening, review and assessment process is to identify valid Individual Case Safety Reports (ICSRs) related to:  suspected adverse reactions originating from spontaneous reports and solicited reports in humans;  special situations such as use of a medicinal product during pregnancy or breastfeeding, use of a medicinal product in a pediatric or elderly population, reports of off- label use, misuse, abuse, overdose, medication errors and occupational exposure with suspected adverse reactions;  lack of therapeutic efficacy;  suspected adverse reactions related to quality defects or falsified medicinal products;  suspected transmission via a medicinal product of an infectious agent.
  49. 49. MLM Search String http://www.ema.europa.eu/docs/en_GB/document_library/Other/2 015/08/WC500191377.pdf
  50. 50. ICSR Workflow for MLM http://www.ema.europa.eu/ema/index.jsp?curl= pages/regulation/general/general_content_000 633.jsp
  51. 51. MLM : Pharmacovigilance Dream or Nightmare? • MAH is fully responsible for executing literature screening for ICSRs (Yellow and Green area). • MHA must report ICSRs detected on literature from Yellow area. • MAH must not report ICSRs from Blue area. • MAH must incorporate the cases detected by EMA from the Blue area in their safety management systems. • MAH must report the ICSRs that have escaped EMA (by screening the Green area) as QC incidents, not as ICSRs. Reference Elsevier
  52. 52. Ways to avoid having a nightmare!  As soon as possible, find a way to detect your Yellow area, and screen it while EMA is screening the Green area.  Pay regular attention to the Blue area, i.e., those references and sources that never crossed your radar. Do the ICSRs matter? What does your Risk and Signal Detection have to say about them?  Although MLM targets a very narrow set of generic medicinal products, no drug exists isolated in its own universe. Either as a concomitant drug, as part of a drug- drug interaction or as an optional suspect drug, all MAHs will, every once in a while, be referenced in the MLM ICSR List.
  53. 53. ICSR Timelines  ICSRs are created within the following timelines:  Suspected serious adverse reactions originating from the EEA or in third countries immediately and no later than seven calendar days from day zero.  Non-serious adverse reactions originating from the EEA within 21 calendar days from day zero.  The ICSRs related to serious and non-serious adverse reactions are submitted within one calendar day to the concerned NCA in accordance with the reporting requirements of ICSRs as outlined in GVP Module VI  MAH’s can access and download ICSRs from EudraVigilance or a dedicated area of the EudraVigilance website
  54. 54. Follow-up on ICSRs by the Agency  In principle, one attempt to follow-up with the primary author is made for suspected serious adverse reactions based on a risk-based approach  Follow-up is pursued for those ICSRs where outcome is unknown or important clinical information is missing  New information will be added in a follow-up ICSR  All attempts to obtain additional follow-up is documented  MLM website publishes date follow-up is initiated
  55. 55. EMA Fee’s associated with literature monitoring Reference: http://www.ema.eu ropa.eu/docs/en_G B/document_librar y/Other/2015/07/W C500190190.pdf
  56. 56. MLM final thoughts…..  The burden seems to be on the companies now to go the site, probably every working day, as it would not be advisable to have serious ICSRs available to the public before the company.  Non-indexed local journals are excluded from the Agency's monitoring activities and remain under the responsibility of the MAHs.  What about disagreements on causal or expectedness? It’s not clear how the company will handle those cases where they disagree with the causality and/or expectedness.  It is also not clear whether the company can or should do follow up on their own even if the EMA has already done so.  Will the EMA update its database (EudraVigilance) with a company’s version?  It is possible two or more companies may do follow up in addition to the EMA if both market the drug.
  57. 57. Challenges and Common Inspection Findings Of Literature Search and Review
  58. 58. LITERATURE: Challenges in Screening & Review of Articles  Ensuring that the search string is robust enough to capture all relevant hits and not so overly inclusive that you capture irrelevant information.  Data is often presented in tables, without identifiable MSI (% of patients experienced [adverse event])  Case reports present the suspicion of the reporter; often opinion based, not a proven association  Drug reactions may have confounding factors (comorbid illness, patient population, concomitant medications)  Drug reactions may be the result of patient non- compliance, medication error, or other factors
  59. 59. LITERATURE: Challenges in Screening & Review of Articles  Lack of population exposure data  Social Media Bias  Authors may have or not reported the case to the MAH or the regulatory authority  Authors may have first published the single case report followed by the publication of a case series  Authors may have presented the case in conferences and thus the case was published as proceedings of the conference followed by publications in a peer reviewed journal  Authors may have published in local journals followed by publication in a peer reviewed journal  Drug safety reviews may cross refer to the publications of ICSRs or the same case may have been indexed in many databases in a slightly different manner.
  60. 60. LITERATURE: Challenges in Screening & Review of Articles  Published reports have been submitted to a third- party and might lack clarity with respect to drug- event attribution (especially with study reports)  Published papers may not specifically describe or discuss attribution- adverse events are mentioned without much discussion  Spontaneous reports are prompted by a suspicion of drug-related harm/injury (implied causality), while publications containing adverse event data cannot necessarily be categorized as having presumed drug-causality Reference: CIOMS V:
  61. 61. Common Regulatory Inspection Findings Related to Literature  Inadequacies in the construction of, or process used for, literature searching (sources used, adequacy of scope of search with respect to search objective, local literature scanning, language restrictions, lack of QC).  Not all relevant articles that had been newly distributed in the database in the week of search had been identified therefore articles were omitted from literature review (MHRA finding).  Waiting to search the literature at data lock for PSUR instead of searching proactively.  Failure to discuss in PSURs significant safety findings (non-ICSR’s) reported in published literature.  Lack of training to personnel involved in literature searching.  Results of searches are not reproducible and tracked
  62. 62. Major audit findings by MHRA (Apr 2014 – Mar 2015)
  63. 63. In Summary…….  Ensure you select the most relevant publication databases for your product  Systematically monitor publications at a frequency consistent with regulatory obligations.  Systemically monitor all active substances for which you hold MA within the EU (where not listed by the EMA)  Monitor articles published locally in each territory where your product is marketed  Route the results of this activity to the appropriate departments within your company  Understand and comply with the time deadlines that apply to ICSR Literature Screening – even if a third party is completing your screening  Avoid reporting duplicate ICSRs within literature  Describe and analyze any new and significant safety findings in the medicinal products PSUR  Understand and comply with the requirement to immediately notify regulators of new safety information from screening
  64. 64. Further Suggestions:  Anyone involved in literature searches for pharma companies must pay careful attention to this as it evolves. Study the relevant documents, read the SOPs, get into EudraVigilance and understand what is happening.  See which of your drugs are covered and which are not. It is not totally clear how/when they will add products. Check the website every day!  Do not stop doing literature searches even if they seem to be duplicative of the EMA’s searches. See how this plays out and see if both searches pick up the same cases or whether some are missed. Compare your search strings to the EMA’s .  New SOPs and Work Instructions will be needed.  Figure out whether you need to keep doing searches for other HA’s (e.g. FDA).  Figure out your follow up strategy with the authors. Are you willing to wait weeks or more for EMA’s revised ICSRs after follow up?
  65. 65. Elizabeth Garrard, PharmD Garrard Safety Solutions eegarrard@gmail.com
  66. 66. References  Regulation (EU) No 658/2014 of the European Parliament and of the Council of 15 May 2014 on fees payable to the European Medicines Agency for the conduct of pharmacovigilance activities in respect of medicinal products for human use:  − http://ec.europa.eu/health/files/eudralex/vol- 1/reg_2014_658/reg_2014_658_en.pdf  • Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency:  − http://ec.europa.eu/health/files/eudralex/vol- 1/reg_2004_726/reg_2004_726_en.pdf  • Directive 2001/83/EC of the European Parliament and of the Council 6 November 2001 on the community code relating to medicinal products for human use:  − http://ec.europa.eu/health/files/eudralex/vol- 1/dir_2001_83_consol_2012/dir_2001_83_cons_2012_en.pdf
  67. 67. References:  European Medicines Agency, Heads of Medicines Agencies. Guideline on good pharmacovigilance practices (GVP): module VI—management and reporting of adverse reactions to medicinal products.  European Medicines Agency, Heads of Medicines Agencies. DRAFT detailed guide regarding the monitoring of medical literature and the entry of relevant information into the EudraVigilance database by the European Medicines Agency. May 2014  US Food and Drug Administration. 21CFR314.80- Postmarketing reporting of adverse drug experiences.  US Food and Drug Administration. DRAFT Guidance for Industry: Postmarketing Safety Reporting for Human Drug and Biological Products Including Vaccines, March 2001  Council for International Organizations of Medical Sciences (CIOMS), Working Group V:Current Challenges in Pharmacovigilance: Pragmatic Approaches  Health Canada. Guidance Document for Industry- Reporting Adverse Reactions to Marketed Health Products.
  68. 68. References: Pontes H, Clement M, Rollason V. Safety signal detection: the relevance of literature review. Drug Saf. 2014 Jul;37(7):471-9. Ross S. Drug -related adverse events: A readers’ guide to assessing literature reviews and meta- analyses. Arch Int Med. 2001. 161: 1041-45. Shetty KD, Dalal SR. Using information mining of the medical literature to improve drug safety. J Am Med Inform Assoc. 2011; 18: 668-674
  69. 69. Database Sources
  70. 70. Database sources (con’t)
  71. 71. Database sources (con’t)
  72. 72. Database sources (con’t)
  73. 73. | PVblog.elsevier.com

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