Using Problem Formulation to Develop a Regulatory ERA. Hanoi, 27 th June Mónica García Alonso Estel Consult Ltd.

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1 Hanoi, 27 th June 2011 Estel Consult Ltd.

2 Using problem formulation in environmental risk assessments for regulatory dossiers Basic concepts Examples

3 Considerations for the preparation of high quality ERAs for regulatory dossiers A good regulatory dossier must contain the information necessary to allow an efficient review of the risk assessment conducted A good risk assessment is one that provides sufficient high quality information and analysis so that risk managers can make decisions

4 Environmental Risk Assessment Key principles The risk assessment is NOT a tool to prove safety It is a tool to gather information and analyse it so... decisions can be made It needs to have a clear purpose: What are the key concerns? What information needs to be gathered to address those concerns? What is the legislative framework and what are the data requirements? It needs to be presented in a clear and logical way Technology developers know the product under assessment well but they need to make evaluators familiar with the product so the risk assessment is understandable and decisions can be made It needs to be transparent Explaining the methods used Outlining the assumptions made and highlighting uncertainties Supporting conclusions with relevant information Guiding the evaluator through the thought process

5 Problem formulation provides a methodology that allows the organization of the risk assessment in a logical way In this step of the risk assessment is where the protection goals are clearly outlined It provides a summary of relevant available information Facilitates an initial risk characterization to establish: If the risk characterization can be completed with available information If more information has to be generated If more information needs to be generated, problem formulation allows the development of a clear analysis plan With clear hypothesis that can be tested in well designed studies Using relevant endpoints

6 PROBLEM FORMULATION PROTECTION GOALS COMPILATION OF RELEVANT INFORMATION INITIAL RISK CHARACTERIZATION CONCLUSION OR DEVELOPMENT OF ANALYSIS PLAN

7 PROTECTION GOALS A good definition of the protection goals facilitates the preparation of the risk assessment Applicants follow the guidelines and data requirements established by regulatory authorities, therefore it is key to have a clear understanding of the protection goals and the key questions that the regulatory dossier needs to address. A good understanding of the country regulation is essential Familiarity with the key questions and data requirements Familiarity with the format expected Fit for purpose Decision making

8 PROTECTION GOALS: Using Problem Formulation to Develop a Regulatory Dossier Protection goals are often formulated in very broad terms and they need to be translated into more operational goals for the risk assessment. These operational protection goals can then be translated to hypothesis that can be tested. GENERIC PROTECTION GOAL OPERATIONAL PROTECTION GOAL TESTABLE HYPOTHESIS

9 EXAMPLES: Using Problem Formulation to Develop a Generic protection goal Operational protection goal Testable hypothesis Protection of agricultural production Protection of agricultural production Protection of human and animal health The GM crop must not have adverse effects on organisms that play an important role in the agroecosystem The GM crop must not be more persistent than the conventional crop in natural environments The GM crop must not be more toxic to humans or animals than the conventional counterpart Product x is not toxic to bees Product x is not more weedy than its conventional counterpart Product x is not toxic to humans

10 PROBLEM FORMULATION PROTECTION GOALS COMPILATION OF RELEVANT INFORMATION INITIAL RISK CHARACTERIZATION CONCLUSION OR DEVELOPMENT OF ANALYSIS PLAN

11 COMPILATION OF RELEVANT INFORMATION Once the protection goals and key questions are established, the next step is to find relevant information already available There are different sources of information: Information obtained during the development of the product Information gathered during the commercialization of the product in other countries Information generated by researchers and published in peer reviewed papers or public documents ANY INFORMATION INCLUDED IN A REGULATORY DOSSIER MUST BE VERIFIABLE

12 COMPILATION OF RELEVANT INFORMATION Information generated by applicants must be supported with good quality reports Information from publications or public documents: Must include only reliable information obtained using valid methods Must be accompanied by references that can be found and checked by reviewers

13 Environmental Risk Assessment Basic Concepts The environmental risk assessment for GM plants is conducted using a comparative approach Compares the new plant (GM plant) with its conventional counterpart

14 Basic concepts The assumption is that the conventional crop (recipient) is well known and has been previously cultivated. Also that the crop has been previously used for food and feed so there is a history of previous exposure and history of safe use. There are a number of basic concepts that derive from this: FAMILIARITY SUBSTANTIAL EQUIVALENCE HISTORY OF SAFE USE PREVIOUS EXPOSURE COMPARATIVE ASSESSMENT

15 COMPARATIVE ASSESSMENT Uses the conventional crop as a base line Assumes that: Using Problem Formulation to Develop a The conventional crop is well known (familiarity) The conventional crop is considered safe (history of previous safe use) The conventional crop has been used in the same way before (history of previous exposure for humans, animals and the environment) Focuses on identifying differences between the GM plant and its conventional counterpart that could result in adverse effects. A difference is not necessarily indicative of an adverse effect!

16 COMPARATIVE ASSESSMENT Most regulatory packages contain information on: MOLECULAR CHARACTERIZATION COMPOSITIONAL ANALYSES AGRONOMIC COMPARISON

17 COMPARATIVE ASSESSMENT Provides a weight of evidence approach to establish whether the genetic modification has yielded the expected results or if unintended differences have occurred If no unintended differences are detected, it can be assumed that interactions between the GM plant and the environment will be comparable to interactions between the conventional plant and the environment (except for insecticidal traits, where interactions with some arthropods will be different and will have to be assessed) WEIGHT OF EVIDENCE MOLECULAR CHARACTERIZATION COMPOSITIONAL ANALYSES AGRONOMIC COMPARISON

18 COMPILING RELEVANT INFORMATION Information on the conventional crop is key To establish base line data To establish if the differences observed in the GM crop are of biological relevance Studies where the GM crop and the conventional crop are compared under the same conditions provide useful information for the comparative assessment For GM crops that produce novel proteins, information about those proteins and their previous use in other crops is useful to establish whether there is a history of safe use or if a more in depth evaluation will be needed

19 COMPILING RELEVANT INFORMATION Data available on the novel proteins are relevant to identify potential hazard Expression data is useful to establish potential exposure In summary Using Problem Formulation to Develop a There are many sources of information, but only reliable and verifiable information should be considered in regulatory dossiers Protection goals drive the risk assessment and establish what information must be compiled There is a lot of information, but do we need it all??? Only information that allows clarification for the specific questions we are trying to address is necessary. In this step of the risk assessment information already available is considered

20 PROBLEM FORMULATION PROTECTION GOALS COMPILATION OF RELEVANT INFORMATION INITIAL RISK CHARACTERIZATION CONCLUSION OR DEVELOPMENT OF ANALYSIS PLAN

21 Regulatory Dossier INITIAL RISK CHARACTERIZATION Once the relevant information has been compiled the risk assessor must establish if the information is enough to conduct a risk characterization Risk = f (Hazard, Exposure) If it can be established with reasonable certainty that the hazard is very low or the exposure is very low, the risk can be considered low and the risk characterization can be concluded at this step If the risk assessor concludes that more information is needed, the assessment continues and an analysis plan is developed

22 INITIAL RISK CHARACTERIZATION: EXAMPLE Generic protection goal Operational protection goal Testable hypothesis Scenario 1 Protection of agricultural production Available information shows that: The GM crop must not have adverse effects on organisms that play an important role in the agroecosystem Product x is not toxic to bees The only difference of biological relevance between the GM and conventional crop is the intended protein (comparative assessment) The GM crop has been previously commercialized in other countries and no adverse effects on bees have ever been reported (the hazard is low) The protein is not expressed in tissues that bees will be exposed to (low exposure) The risk to bees can be considered low

23 INITIAL RISK CHARACTERIZATION: EXAMPLE Generic protection goal Operational protection goal Testable hypothesis Protection of agricultural production The GM crop must not have adverse effects on organisms that play an important role in the agroecosystem Product x is not toxic to bees Scenario 2: Available information shows that: The protein is known to be toxic to insects of many orders and could be toxic to hymenoptera The protein is expressed in pollen The assessment must continue to characterize the risk to bees in more detail

24 Environmental Risk Assessment PROBLEM FORMULATION PROTECTION GOALS In some cases, the risk characterization can be completed with available information. The assessment stops here. CONCLUSION COMPILATION OF RELEVANT INFORMATION INITIAL RISK CHARACTERIZATION OR DEVELOPMENT OF ANALYSIS PLAN In some cases, the risk characterization must continue until more data is generated. Exposure assessment Hazard assessment Risk characterization

25 Environmental Risk Assessment PROBLEM FORMULATION Risk characterization completed? Yes No Exposure assessment Hazard assessment Assessment completed Continue assessment Risk characterization

26 PROBLEM FORMULATION PROTECTION GOALS COMPILATION OF RELEVANT INFORMATION INITIAL RISK CHARACTERIZATION CONCLUSION OR DEVELOPMENT OF ANALYSIS PLAN

27 DEVELOPMENT OF ANALYSIS PLAN When the risk assessor, after analysing all the available information, concludes that more data must be obtained, problem formulation provides a good method to generate these data in a logical and effective way Formulation of testable hypothesis Relevant assessment and measurement endpoints Design of studies that allow the measurement of chosen endpoints Tiered assessment

28 DEVELOPMENT OF ANALYSIS PLAN: EXAMPLE Testable hypothesis Measurement endpoint Study Product x is not toxic to bees Mortality after exposure to known amounts of x (LC 50 o NOAEC) Acute bee toxicity study (following IOBC guidelines) In this case the risk assessment would compare the value obtained for the mortality endpoint (LC 50 o NOAEC) with the measured exposure Risk = f (Hazard, Exposure)

29 SUMMARY Using Problem Formulation to Develop a Problem formulation is a useful method for the logic and effective preparation of risk assessments, so: Applicants can prepare regulatory dossiers where The process followed in the risk assessment is logic and transparent The information provided is reliable and verifiable Regulators can make decisions