SCOPE OF EXPLANATORY NOTE GMO APs submitted after the IR came into force IR requires a systematic review (SR) covering the 10 years before the submission of the GMO AP GMO APs submitted before the IR came into force Complement GMO APs with relevant findings published in the scientific literature during the regulatory review process 4
SCOPE OF EXPLANATORY NOTE Annual PMEM reports European Commission’s authorisations require to actively screen relevant scientific publications Renewal APs EFSA GMO Panel (2015) requires to search all scientific databases relevant for the three main areas of the risk assessment in a comprehensive and structured manner, in order to retrieve new scientific information relevant to the safety of the GMO for market renewal 5
AIM OF EXPLANATORY NOTE Observations Applicants have undertaken literature searches to various degrees of rigour Lack of clarity on how to address the SR requirement of the IR 6
AIM OF EXPLANATORY NOTE Aim To clarify the scope and methodology for literature searching To give recommendations on how to conduct, report systematic/extensive literature searches, and present the results of any scoping reviews To complement EFSA (2010) on the application of SR methodology to food/feed safety assessments to support decision making, with GMO-specific guidance 7
INTENDED USERS OF EXPLANATORY NOTE Applicants To provide a more rigorous and standardised/harmonised approach to literature searching To perform more consistent and sensitive literature searches, and improve reporting To minimise biases (such as publication bias) Risk assessors and regulators To provide guidance on how to check/appraise systematic/extensive literature searches 8
STRATEGY OF EXPLANATORY NOTE Scoping reviews Systematic/extensive literature searches GMO APs submitted after the IR came into GMO APs submitted force before the IR came into force Annual PMEM reports Renewal APs 9
STRATEGY OF EXPLANATORY NOTE Scoping reviews GMO APs submitted after the IR came into force IR requires a SR Not always useful/necessary to perform SR IR allows for derogation Reasoned justification required Outcome of scoping review can determine whether it is useful to perform SR and for which topics 10
STRUCTURE OF EXPLANATORY NOTE Framework consisting of five successive steps Identifying review questions and clarifying their purpose 1. (Section 3.1) Searching for/identifying relevant studies (Section 3.2) 2. Selecting studies (Section 3.3) 3. Extracting high level data of the relevant studies (Section 4. 3.4 – only applicable to scoping reviews) Summarising and reporting the data, and considering the 5. implications of findings (Section 3.5) 11
STRUCTURE OF EXPLANATORY NOTE Appendices A – Categories of information/data requirements B – Search strategy examples (#4) C – Examples of web-based databases that can contain relevant information supporting the risk assessment of GMOs D – Requirements for undertaking scoping reviews applicable to systematic/extensive literature searchers 12
1. IDENTIFY REVIEW QUESTIONS/CLARIFY THEIR PURPOSE Problem to address should be specified in the form of clear, unambiguous and structured questions Link to GMO risk assessment context Review questions should be broken down into their key elements to guide the development of search terms and structure the search: Structured questions (e.g. PICO, PECO) 1. Information/data requirements outlined in relevant 2. GMO Panel guidance documents, EFSA explanatory notes and IR (see Appendix A) 13
1. IDENTIFY REVIEW QUESTIONS/CLARIFY THEIR PURPOSE Structured questions (e.g. PICO, PECO) 1. “ Does either the GMO and derived food/feed products, or the intended trait(s), have adverse effects on human and animal health and the environment? ” P = population [human/animal health/environment] I/E = intervention/exposure [GMO, derived food/feed products, intended trait(s)] C = comparator O = outcome [adverse effects] 14
1. IDENTIFY REVIEW QUESTIONS/CLARIFY THEIR PURPOSE Information/data requirements outlined in 2. relevant GMO Panel GDs, EFSA explanatory notes and IR (see Appendix A) Examples Protein expression data 90-day feeding studies in rodents Laboratory/greenhouse feeding bioassays with representative non-target organisms … 15
2. SEARCH FOR/IDENTIFY RELEVANT STUDIES Literature searching involves: Developing a search strategy 1. Identifying information sources to search 2. 16
2. SEARCH FOR/IDENTIFY RELEVANT STUDIES Developing a search strategy 1. Approaches to develop searches Single search strategy Series of focused search strategies Search strings (link to key elements of review questions) See Appendix B Search terms • Search functions • Search operators • 17
2. SEARCH FOR/IDENTIFY RELEVANT STUDIES Developing a search strategy 1. Language Time period Reference study searches List of reference studies Results of searches with reference studies Appraisal (EFSA critical appraisal tool [CAT]) 18
2. SEARCH FOR/IDENTIFY RELEVANT STUDIES Identifying sources of scientific literature 2. Electronic bibliographic databases Mandatory At least two multi-disciplinary databases for complementarity (e.g. Web of Science Core Collection, Scopus, CAB Abstracts, Medline) Optional Searching more specialist/subject-specific databases (e.g. Agricola) 19
2. SEARCH FOR/IDENTIFY RELEVANT STUDIES Identifying sources of scientific literature 2. Internet searches (limit publication bias) Mandatory Internet pages of relevant key organisations involved in GMO risk assessment (e.g. FDA, USDA, US EPA) 20
2. SEARCH FOR/IDENTIFY RELEVANT STUDIES Identifying sources of scientific literature 2. Internet searches (limit publication bias) Optional Scientific literature that is not indexed in electronic bibliographic databases via general search engines such as Google scholar (check first 200-300 hits) Web-based databases known to contain information specifically on effects of GMOs (examples given in Appendix C) 21
2. SEARCH FOR/IDENTIFY RELEVANT STUDIES Identifying sources of scientific literature 2. Manual searches Mandatory Checking reference list from recent relevant reviews, methodological publications and scientific opinions Optional Hand-searching key journals or assessing journal contents pages Citation searching 22
3. SELECT STUDIES Determining “ relevance ” Set eligibility/inclusion criteria to determine relevance of the retrieved studies Table 1 gives examples of eligibility/inclusion criteria Reliability of relevant studies is assessed later in the process 23
3. SELECT STUDIES 24
3. SELECT STUDIES 25
3. SELECT STUDIES Process (2 stages) Rapid assessment based on title-abstract-keywords 1. Detailed assessment of full-text documents 2. Quality assurance Relevant screening performed by more than 1 reviewer Ensure inter-reviewer agreement Resolve disagreement 26
3. SELECT STUDIES Classification of studies retrieved Relevant studies To summarise and consider those for reliability Non-relevant studies Give reason(s) for exclusion based on eligibility/inclusion criteria Unobtainable studies & studies with unclear relevance Describe (unsuccessful) methods used to try to obtain a copy of the study Give justification of why relevance cannot be definitively determined 27
4. EXTRACT HIGH LEVEL DATA OF RELEVANT STUDIES Data extraction [only for scoping reviews] Purpose Enable applicants to describe the overall volume, strength and direction of the studies Possible variables Authorship, year of publication, source, title of the study, objective of the study, experimental design, main results, conclusion, protection goal considered, applicable category of information/data requirement, whether adverse effects are reported on human/animal health and/or the environment, … 28
5. SUMMARISE AND REPORT Summarising and reporting the data Search methods and outcomes Results of study selection process See template tables 2 to 5 Narrative synthesis/summary of relevant studies, describing their overall volume, strength and direction [only applicable to scoping reviews] See template tables 6 29
5. SUMMARISE AND REPORT Considering implications of the findings Value of undertaking SR [only applicable to scoping reviews] Implications for risk assessment To assess the reliability and implications for the risk assessment of all relevant studies retrieved after detailed assessment of full-text documents for relevance: ordered by category of information/data requirement(s) (see template Table 7) 30
TRANSITION PHASE Applicability of the explanatory note Six months after publication date of the note New submissions submitted after 10 OCT 2017 Except for: Extensive/systematic literature searchers previously submitted to EFSA that do not comply with minimum quality standards Updates of extensive/systematic literature searchers previously submitted to EFSA 31
COMPLETENESS CHECKLIST EFSA’s completeness checklist To be completed by applicants To ensure adequate reporting to facilitate appraisal and reproducibility How? Appendix to EFSA’s updated submission guidance on applications for authorisation of GM plants under Regulation (EC) No 1829/2003 Attached to GMO Panel/EFSA questions asking for updated or revised literature searches 32
FUTURE UPDATES OF EXPLANATORY NOTE Explanatory note may/will be revised : when experience is gained in its application in view of any amendments to the IR 33
ACKNOWLEDGEMENTS Thank you for your attention EFSA wishes to thank the following for the support provided to this scientific output: Elisa Aiassa, Fernando Álvarez, Hermann Broll, Giacomo De Sanctis, Antonio Fernandez Dumont, Andrea Gennaro, Anna Lanzoni, Nikoletta Papadopoulou, Konstantinos Paraskevopoulos and Matthew Ramon, and experts of the GMO Panel standing Working Groups on Molecular Characterisation, Food/Feed, and Environmental Risk Assessment for inspiring discussions that helped to develop the explanatory note to the guidance 34
STAY CONNECTED! Subscribe to www.efsa.europa.eu/en/news/newsletters www.efsa.europa.eu/en/rss Engage with careers www.efsa.europa.eu/en/engage/careers Follow us on Twitter @efsa_eu @plants_efsa @methods_efsa 35
Guidelines on possible derogation of existing requirements for applications of GM food and feed at low levels submitted under Regulation (EC) No 1829/2003 Anna Lanzoni 8 th GMO Network Meeting 23 May 2017
ROADMAP Introduction The mandate on GMO Low Level Presence (LLP) Project plan and schedule Stakeholders engagement EU Member States consultation The draft guidance: key points Q&A 2
ROADMAP Introduction The mandate on GMO Low Level Presence (LLP) Project plan and schedule Stakeholders engagement EU Member States consultation The draft guidance: key points Q&A 3
THE MANDATE ON GMO LOW LEVEL PRESENCE (LLP) Mandate from European Commission Mandate on possible derogation of existing requirements for applications of GM foods and feeds at low levels submitted under regulation (EC) No 1829/2003 Received by EFSA in 2014 Clarification requested to EC Accepted by EFSA in 2015 (EFSA-Q-2015-00432) 4
LLP PROJECT PLAN AND SCHEDULE 2 May-13 June 2017 28 Oct – 9 Dec 2016 (6-week) ( 6-week) Sept 2017 EU MS Public consultation consultation GMO Panel July 2015 Guidance Sept 2016 Apr 2017 1 st draft 2 nd draft guidance guidance Josep Casacuberta Yann Devos Adinda De Schrijver Antonio Fernandez Achim Gathmann LLPWG Anna Lanzoni – Task leader Mikolaj Gralak Claudia Paoletti Elsa Nielsen Konstantinos Paraskevopoulos Francesco Visioli - Chair Hearing expert: Thomas Frenzel Jean-Michel Wal 5
ROADMAP Introduction The mandate on GMO Low Level Presence (LLP) Project plan and schedule Stakeholders engagement EU Member States consultation The draft guidance: key points Q&A 6
STAKEHOLDERS ENGAGEMENT Two-step approach Dedicated EU Member States Consultation 28 October - 9 December 2016 Public Consultation ongoing, ending 13 June 2017 7
EU MS CONSULTATION EFSA LLP WG The process EFSA Focal Advisory Forum Points MS Competent EFSA Focal Authorities under Points 1829/2003 8
EU MS CONSULTATION The tools 9
EU MS CONSULTATION The outcome 240 comments summarised replies will be provided in a Technical report with those from Public Consultation 10
EU MS CONSULTATION Main comments Readibility Scientific contents reassurance on the appropriateness on most EFSA proposals relevant scientific points raised Risk management issues EC involvement Threshold Scope (“large size” fruit/vegetables) Asynchronicity/asimmetry & mutual recognition 11
ROADMAP Introduction The mandate on GMO Low Level Presence (LLP) Project plan and schedule Stakeholders engagement EU Member States consultation The draft guidance - key points Q&A 12
DRAFT GUIDANCE – IMPROVED READIBILITY VS V1 Improved instructions for use Not a stand-alone document! This document is intended to assist applicants … by indicating which technical requirements of Annex II of Regulation (EU) No 503/2013 are necessary and which are not, in this case providing justification, in order to conclude on the safety of a GMO in a LLP application This document supports Regulation (EU) No 503/2013 and it is not intended to serve as a stand-alone guidance See: 3.1 Introduction 13
NOT A STAND-ALONE DOCUMENT 14
DRAFT GUIDANCE - SCOPE GMO at maximum 0.9% per ingredient point of entry consumer GMO at >0.9% per ingredient : not in the remit of this guidance e.g. GM fruits and vegetables constituting either a full portion or part of a consumed portion, resulting in an exposure of consumers (or animals) higher than 0.9% to that GMO See: 1.2 Interpretation of the Terms of Reference 15
DRAFT GUIDANCE - DEFINITIONS LLP application : covers a request for the authorisation of a GMO present at a level of maximum 0.9% per ingredient in any food and/or feed, submitted under Regulation (EC) 1829/2003 LLP GMO : the GMO subject of the LLP application LLP Ingredient : the mixture of the LLP GMO and the same plant species and/or derived product, at the predefined proportion of a maximum of 0.9% and 99.1% respectively See: 1.2 Interpretation of the Terms of Reference 16
DRAFT GUIDANCE - SCIENTIFIC DRIVERS Stand-alone dossier Comprehensive characterisation of the transformation event (intended trait) Fit-for purpose assessment driven by: low exposure under acute/chronic scenarios 17
MAIN “DEROGATIONS” FROM REGULATION (EU) 503/2013 – AT A GLANCE Molecular characterisation Expression of the insert • Singles: only edible parts Stacks: not routinely needed RNAi off targets • Not necessary Comparative assessment ONLY for output traits, hypothesis-driven situations, de novo compounds • Targeted compositional analysis, not full list of OECD consensus docs compounds • No equivalence test necessary • Greenhouse/field trials acceptable • # sites • No agronomic and phenotypic characteristics assessment on a routine basis • Codex-aligned studies acceptable • Food Feed Assessment No 90-day studies • No endogenous allergens measurements on a routine basis • No nutritional assessment • 18
IN ADDITION Environmental Risk Assessment: case-specific varying depending on the biology of the plant species, the intended trait(s), the potential receiving environments, and interactions among all three 19
FOCUS ON COMPARATIVE ANALYSIS Not mandatory on a routine basis Since in LLP situations the level of exposure of consumers and animals to the LLP GMO is defined to be at a maximum 0.9% per ingredient, not all differences in comparative analysis endpoints between the LLP GMO and the plant (and/or derived product) constituting the remaining part of the ingredient may be relevant Why? Which difference might be relevant in LLP? See 3.2.3.3 Comparative analysis 20
FOCUS ON COMPARATIVE ANALYSIS The level of an endogenous compound in a LLP ingredient is determined by: the level of such endogenous compound in the LLP GMO (and/or derived product) the level of such endogenous compound in the plant (and/or derived product) constituting the remaining part of the ingredient. The ratio between these two levels determines the extent to which the level of the compound of the LLP GMO impacts the overall level of that compound in the LLP ingredient See 3.2.3.3 Comparative analysis 21
FOCUS ON COMPARATIVE ANALYSIS LLP GMO remaining part of the ingredient LLP ingredient endogenous compound + = Case 1 Case 2 Case 3 22
FOCUS ON COMPARATIVE ANALYSIS Table 1: Impact of variations in the levels of an endogenous compound in a LLP GMO on the level of the same compound in a LLP ingredient. Level of a compound in LLP GMO/ Level of the compound in LLP ingredient/ level of the compound in the level of the compound in the ingredient ingredient without the LLP GMO without the LLP GMO 0 0.991 Case 3 0.001 0.991009 0.01 0.99109 0.1 0.9919 Case 1 1 1 10 1.081 20 1.171 50 1.441 90 1.801 Case 2 100 1.891 200 2.791 See 3.2.3.3 Comparative analysis 23
FOCUS ON COMPARATIVE ANALYSIS On the basis of the current knowledge, the GMO Panel is of the opinion that variations in the level of compound(s) in LLP GMOs are generally not large enough to impact on the nutritional or safety characteristics of the LLP ingredient POSSIBLE EXCEPTIONS GMOs with output traits developed to improve nutrition GMOs expected to show compositional changes on the basis of precedent investigations See 3.2.3.3 Comparative analysis 24
FOCUS ON COMPARATIVE ANALYSIS Therefore : No comparative assessment on a routine basis Compositional analysis only if: the intended trait targets the composition of the LLP GMO (output trait) a hypothesis for a relevant compositional change can be formulated based on available information from the hazard identification (e.g. unintended compositional changes anticipated by the precedent analyses) compounds are de novo produced in the LLP GMO No comparative analysis of agronomic/phenotypic characteristics See 3.2.3.3 Comparative analysis 25
FOCUS ON COMPARATIVE ANALYSIS Implementation Targeted compositional analysis No full list of OECD consensus doc compounds Conditions maximising expected change(s), based on available knowledge field trials, greenhouse studies Equivalence test not considered necessary See 3.2.3.3 Comparative analysis 26
FOCUS ON COMPARATIVE ANALYSIS Comparative assessment studies performed under non-EU regulatory frames: applicability in LLP applications studies conducted in accordance with Codex (Codex Alimentarius, 2009) could support the assessment studies not aligned to requirements of Codex are not considered appropriate by the GMO Panel. See 3.2.3.3 Comparative analysis 27
FOCUS ON TOXICOLOGY Testing of whole genetically modified food and feed (Regulation [EU] No 503/2013; Annex II. II, 1.4.4 subsections 1.4.4.1-1.4.4.3) the GMO Panel considers that a 90-day feeding study is not needed to corroborate information on the toxicological characteristics of the whole LLP GM food and feed in rodents and/or to reduce the remaining uncertainties, considering the limited exposure to the LLP GMO See 3.2.3.4 Toxicology 28
FOCUS ON ALLERGENICITY The assessment of the allergenicity of food or feed from the LLP GMO should be conducted in the case changes in the levels of endogenous allergens are expected in the LLP GMO, possibly impacting the allergenicity of the LLP ingredient In such situations, relevant identified endogenous allergens should be analysed and the assessment should indicate whether the GMO could impact the allergenicity of the LLP ingredient See 3.2.3.5 Allergenicity 29
FOCUS ON NUTRITIONAL ASSESSMENT Considering that the scope of LLP applications is limited to a level of maximum 0.9% of a LLP GMO per ingredient a nutritional assessment is not considered necessary on a routine basis, unless relevant changes in the levels of food and feed constituents from the LLP GMO are expected See 3.2.3.6 Nutritional assessment 30
CUMULATIVE RISK ASSESSMENT In the case of multiple LLP applications for LLP GMOs showing similar traits, the possible cumulative contribution from the various LLP GMOs to the ingredient should be taken into consideration in the risk assessment the relative contribution to the ingredient of each of these taken into account to allow an estimation of their total contribution via the addition of the respective trait-related constituent(s) Case-by-case, on the basis of compositional analysis outcome See 3.2.5.3 Cumulative risk assessment 31
Thank you Questions? 32
STAY CONNECTED! Subscribe to www.efsa.europa.eu/en/news/newsletters www.efsa.europa.eu/en/rss Engage with careers www.efsa.europa.eu/en/engage/careers Follow us on Twitter @efsa_eu @plants_efsa @methods_efsa 33
Allergenicity guidelines (EFSA-Q-2014-00547) Antonio Fernandez Dumont 8 th GMO Network Meeting 23 May 2017
Allergenicity guidelines • Self-task activity (initiated by EFSA) - Non-IgE-mediated immune adverse reactions to foods - In vitro protein digestibility - Endogenous allergenicity • Stakeholders engagement - EFSA Workshop (June 2015) - Public consultation (July-September 2016) - EFSA Info Session (November 2016) - «Focus group» interactive consultation body 2
Allergenicity guidelines Non-IgE-mediated immune adverse reactions to foods • Risk Assessment to focus on celiac disease - Clear cause-effect relationship • Risk assessment considerations - Stepwise approach • Annex A - Additional considerations - Examples 3
Allergenicity guidelines 4
Recommend
More recommend
