D
Applying the Recommended Approaches

The special needs and vulnerabilities of infants require a clear and complete set of guidelines to assess the safety of infant formulas. Guidelines must also provide an appropriate level of flexibility to address the multitude and diversity of possible new ingredients. It is not realistic or desirable to provide specific recommendations for each potential new ingredient. Thus the committee recommends that the manufacturer or notifier and an expert review panel establish the relative importance of potential adverse effects for each new ingredient and determine the types of preclinical and clinical studies and in-market surveillance needed to accurately assess safety.

The committee was requested to apply the recommended tools and approaches to the specific situation of adding long-chain polyunsaturated fatty acids (LC-PUFAs) to infant formulas and to consider another example of a specific ingredient, if appropriate. Probiotics was selected as the second case study to demonstrate the flexibility of the algorithms when analyzing a “complex” ingredient comprised of a variety of different components that would be contained in a microorganism or microorganism mix. This appendix describes the steps in the committee’s recommended approaches that should be considered when assessing the safety of LC-PUFAs and probiotics.

As discussed in Chapter 1, algorithms diagram the safety assessment process into a step-by-step decision tree. The algorithms presented in Chapters 4 through 7 are provided to summarize the appropriate level of assessment by considering the harm and the potential adverse effects of a new ingredient. The approaches presented in this appendix are not meant to provide all of the information, events, or tests that need to be assessed to ensure safety, but rather to exemplify needed steps in the review process. The corresponding chapters provide more information on specific levels and tests.

The committee emphasizes that the purpose of these case studies is not to make conclusions about the completeness of the information or the safety of the new ingredient, but to point out assessment processes or steps that need to be considered. The algorithms that follow utilize an asterisk (*) with corresponding text underlined to indicate steps that the committee concluded could have been included if the notifier had used the committee’s



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D Applying the Recommended Approaches The special needs and vulnerabilities of infants require a clear and complete set of guidelines to assess the safety of infant formulas. Guidelines must also provide an appropri- ate level of flexibility to address the multitude and diversity of possible new ingredients. It is not realistic or desirable to provide specific recommendations for each potential new ingre- dient. Thus the committee recommends that the manufacturer or notifier and an expert review panel establish the relative importance of potential adverse effects for each new ingredient and determine the types of preclinical and clinical studies and in-market surveil- lance needed to accurately assess safety. The committee was requested to apply the recommended tools and approaches to the specific situation of adding long-chain polyunsaturated fatty acids (LC-PUFAs) to infant formulas and to consider another example of a specific ingredient, if appropriate. Probiotics was selected as the second case study to demonstrate the flexibility of the algorithms when analyzing a “complex” ingredient comprised of a variety of different components that would be contained in a microorganism or microorganism mix. This appendix describes the steps in the committee’s recommended approaches that should be considered when assessing the safety of LC-PUFAs and probiotics. As discussed in Chapter 1, algorithms diagram the safety assessment process into a step- by-step decision tree. The algorithms presented in Chapters 4 through 7 are provided to summarize the appropriate level of assessment by considering the harm and the potential adverse effects of a new ingredient. The approaches presented in this appendix are not meant to provide all of the information, events, or tests that need to be assessed to ensure safety, but rather to exemplify needed steps in the review process. The corresponding chapters provide more information on specific levels and tests. The committee emphasizes that the purpose of these case studies is not to make conclu- sions about the completeness of the information or the safety of the new ingredient, but to point out assessment processes or steps that need to be considered. The algorithms that follow utilize an asterisk (*) with corresponding text underlined to indicate steps that the committee concluded could have been included if the notifier had used the committee’s 186

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187 APPENDIX D recommended algorithms to guide decisions about the type of safety assessments to apply. The asterisk with corresponding text underlined does not imply that the step was not performed or considered by the qualified experts, but that the information was not available for review by the committee. Note that under the proposed recommendation (Chapter 4), the expert panel can choose to include or not include certain tests in the submission. LONG-CHAIN POLYUNSATURATED FATTY ACIDS For the case of LC-PUFAs, the committee applied the information given to the Food and Drug Administration available through the Freedom of Information Act in Generally Recog- nized as Safe (GRAS) Notices 000041 and 000080 to its recommended algorithms, compar- ing the steps taken by the manufacturer, notifier, or expert panel to determine the safety of ARASCO (arachidonic acid-rich single-cell oil) and DHASCO (docosahexaenoic acid-rich single-cell oil) in infant formulas. Figure D-1 provides an overview of the proposed process. The sources of ARASCO and DHASCO have no prior use in foods in the United States, but they are used in infant formulas in Europe. Preclinical Studies As shown in Figure D-2, structure, stability, and solubility characterization studies are an important part of preclinical assessment. Figure D-3 illustrates that level 2 assessments would have been applied in determining the safety of the LC-PUFAs. These in-depth mea- sures of the organ and neurological systems would further investigate abnormalities and/or are theoretically related to structure or function. In this case it appeared that there were some minor effects on organ systems. It is not obvious which of the proposed testing regimes in Chapter 5 were followed. The nonhuman primate studies were limited. These are consid- ered an appropriate model to study changes in general behavior and speed of neural process- ing in response to the addition of LC-PUFAs. Chapter 5 provides more details on structure, stability, and solubility characterization, as well as the committee’s recommendations for level 2 assessments. Clinical Studies As seen in the overview of the proposed clinical guidelines (Figures D-4, D-5, and D-6), it is not clear whether assessments of body composition, immune response, auditory func- tion, and temperament were conducted. Several of these tests (to be determined by expert panels), applied at level 2 or level 3, are especially important to determine the safety of LC- PUFAs because theoretical safety concerns exist. For example, LC-PUFAs affect immune response, and they have been linked to neural development. Chapter 6 provides the com- mittee’s findings and recommendations on body composition and immune, auditory, and temperament assessment. In-Market Surveillance Figure D-7 illustrates the levels of proposed in-market surveillance. Selection of an appropriate type of in-market surveillance should be based on theoretical concerns about the new ingredient and/or results from preclinical and clinical studies. As long as preclinical and clinical studies are properly conducted, adverse outcomes should be rare and it would take a considerable period of time to collect sufficient data in order to reaffirm the GRAS status

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188 INFANT FORMULA: EVALUATING THE SAFETY OF NEW INGREDIENTS PROPOSED PROCESSES 1 New ingredient proposed for infant formula 2 Manufacturer establishes assessment process to determine the safety of ingredients new to infant formula Sidebar A: Preclinical Studies Characterize chemical and physical properties of the new 3 Review of literature ingredient. Conduct preclinical studies to evaluate toxicity - history of safe use and neurological s afety. (See Chapter 5) 4 Sidebar B: Clinical Studies Preclinical Studies (See Sidebar A) Conduct clinical studies to assess symptoms and laboratory indicators for specific organ systems, absorption and metabolism, and developmental and behavioral outcomes. 5 (See Chapter 6) Clinical Studies (See Sidebar B) Sidebar C: In-Market Surveillance Establish expert panel to evaluate in-market monitoring, * Manufacturer selects an expert panel in 6 review submitted evidence,surveillance data, and ongoing consultation with regulatory agency to review * literature reviews. Determine necessary follow-up studies. results and determine safety of new (See Chapter 7) ingredient 7 Manufacturer submits to regulatory agency its demonstration of safety of new 9 ingredient Manufacturer provides answers to questions Regulatory agency raises 8 questions concerning the Y es scientific results, process, or other components? No 10 Regulatory agency has 11 no objection Ensure safety of formula Yes concerning the safety containing new ingredient of new ingredient No No 14 15 12 REGULATORY AGENCY REGULATORY AGENCY DISCONTINUE DOES NOT APPROVE APPROVES INFANT PROCESS INFANT FORMULA WITH FORMULA WITH NEW NEW INGREDIENT INGREDIENT 13 In-Market Surv eillance * (See Sidebar C) FIGURE D-1 Proposed process for evaluating the safety of ingredients new to infant formulas algorithm: Application by using the long-chain polyunsaturated fatty acid Generally Recognized as Safe (GRAS) Notifications 000041 and 000080 as a case study. An asterisk (*) along with the corresponding text underlined indicate steps that were either not apparent or not carried out within the GRAS notifications 000041 and 000080 provided to the committee. In-market assessment should be planned in conjunction with preclinical and clinical testing. This algorithm is modeled after the U.S. Generally Recognized as Safe Notification process; similar schemes can be adapted to other regulatory processes. = a state or condition, = a decision point, = an action, sidebar = an elaboration of recommendation or statement.

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189 APPENDIX D PPROPOSED PRECLINICAL ASSESSMENT 1 New ingredient proposed for infant formula 2 Are the active component or the impurities well known ? AND Yes Is adequate literature available to Sidebar A: Chemical and Physical determ ine their safety? Characterization Structure, Stability, and Solubility 3 - High performance liquid chromatography, Initiate preclinical studies to evaluate toxicity liquid chromatography-mass spectrometry, and No and neuro logical safety (See Figure D-3) thin layer chromatography. - T he stability to temperature, ultraviolet light as well as the solubility properties of the ingredient. * - T he percentage of the unidentifiable mater ials 8 in ingredient. * - T he kind ofsolvents,suspending agents, Chemical and Physical Characterization (See Sidebar A) emulsifiers, or other materials that will be used in a d minister ing the ingredient whether in in vitro or an imal studies. - Ingredient should be stored under conditions that maintain its stability, quality, and purity 9 4 until the subsequent studies are complete. Are chemical and Toxicity Assessment - T hese studies should be repeated with the Yes physical purity assured? (See Sidebar B) ingredient in the solution or matrix that would be fed to the human infants. Sidebar B: Toxicity Assessment 1. Genetic tests 2. Cellular studies 3. Animal toxicity studies - Acute, subchronic, and chronic toxicity - Developmental toxicity - Absorpt ion, distribution, metabolism,,and excretion 4. Organ level studies - Gastrointest inal tract No - Hepatic - Renal - Hematology - Immune - Endocrine - Neurolo gic 5 Any positive test for toxicity or concern for Yes safety? No 6 10 7 DISCONTINUE DISCONTINUE Neurological Safety Assessment PROCESS (See Figure D-3) PROCESS FIGURE D-2 Proposed preclinical assessment algorithm: Application by using the long-chain poly- unsaturated fatty acid Generally Recognized as Safe (GRAS) Notifications 000041 and 000080 as a case study. An asterisk (*) along with the corresponding text underlined indicate steps that were either not apparent or not carried out within the GRAS notifications 000041 and 000080 provided to the committee. = a state or condition, = a decision point, = an action, sidebar = an elaboration of recommendation or statement.

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190 INFANT FORMULA: EVALUATING THE SAFETY OF NEW INGREDIENTS P PROPOSED LEVELS OF PRECLINICAL ASSESSMENT 1 Initiate preclinical studies to evaluate toxicity and neurological safety 2 Any evidence of abnormalities based on previous human data, other preclinical studies, or on Yes theoretical plausible perturbation of a metabolic pathway? No Sidebar A: Level 1 Assessment 7 Standard measures of genetic tests, cellular studies, animal toxicity studies, Lev el 1 Assessment (See Sidebar A) major organ systems, and neurological preclinical screening measures. (See Tables 5-1 through 5-10) Sidebar B: Level 2 Assessment * Detailed measures of genetic tests, 8 3 Any evidence of cellular studies, animal toxicity studies, Lev el 2 Assessment adverse Yes major organ systems, and neurological (See Sidebar B) effect/event? preclinical measures. (See Tables 5-1 through 5-10) No 4 Any evidence of adverse effect/event or concern Yes for safety? No 6 9 5 Continue to clinical Re-evaluate results before DISCONTINUE studies considering clinical trials PROCESS FIGURE D-3 Proposed levels of preclinical assessment algorithm: Application by using the long- chain polyunsaturated fatty acid Generally Recognized as Safe (GRAS) Notifications 000041 and 000080 as a case study. An asterisk (*) along with the corresponding text underlined indicate steps that were either not apparent or not carried out within the GRAS notifications 000041 and 000080 provided to the committee. = a state or condition, = a decision point, = an action, sidebar = an elaboration of recommendation or statement.

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191 APPENDIX D CPROPOSED CLINICAL ASSESSMENT 1 New ingredient proposed for infant formula 2 Initiate clinical studies to evaluate the impact of new ingredient on growth and development Sidebar A: Growth Studies Assess: - Weight velocity * - Length velocity 3 Grow th Studies - Head circumference (See Sidebar A) - Body composition and * Clinical Endpoints (See Sidebar B and Figure D-5) Sidebar B: Clinical Endpoints Assess symptoms and adverse laboratory indicators in the following: - Gastrointestinal tract - Kidney * - Blood - Immunological system 4 - Endocrinological system Abnormal growth or Assess absorption, distribution, adverse effect/event on metabolism, and excretion of Yes specific organ, immune, or ingredient where appropriate endocrine systems Sidebar C: Developmental-Behavioral No Assessment 6 * Assess: - Sensory and motor function * Dev elopmental-Behav ioral Assessment - Cognitive development (See Sidebar C and Figure D-6) - T emperament - Neurological function 7 5 Abnormal function in major DISCONTINUE Yes developmental areas PROCESS No 8 MANUFACT URER/REGULAT ORY AGENCY DET ERMINES INGREDIENT IS SAFE FIGURE D-4 Proposed clinical assessment algorithm: Application by using the long-chain polyun- saturated fatty acid Generally Recognized as Safe (GRAS) Notifications 000041 and 000080 as a case study. An asterisk (*) along with the corresponding text underlined indicate steps that were either not apparent or not carried out within the GRAS notifications 000041 and 000080 provided to the committee. = a state or condition, = a decision point, = an action, sidebar = an elaboration of recommendation or statement.

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192 INFANT FORMULA: EVALUATING THE SAFETY OF NEW INGREDIENTS PROPOSED LEVELS OF CLINICAL ASSESSM ENT OF MAJOR SYSTEMS 1 New ingredient proposed for infant form ul a 2 Sidebar A: Level 1 Assessment Known or theoretical i ndi rect Y es li nk to major organ system s? Major organ systems screening measures in the following: - Gastrointestinal tract No - Liver 6 - Kidney - Blood Adverse effect/event documented - Immune in precli ni cal trials? - Endocrine OR Y es (See Tabl es 6-3, 6-5, 6-6, 6-8, and 6-9) Evi dence of signifi cant individual difference i n susceptibil ity to the ingredient? Sidebar B: Level 2 Assessment No Major organ systems detail ed m easures 7 in the foll owi ng: Lev el 1 Assessment - Gastrointestinal tract (See Sidebar A) - Liver * - Kidney - Blood - Imm une 8 - Endocrine (See Tabl es 6-3, 6-5, 6-6, 6-8, and 6-9) Evi dence of effect/adverse Yes event? 3 * Lev el 2 Assessment (See Sidebar B) 4 No Evi dence of effect/adverse Yes event? No 5 9 Continue to DISCONTINUE neurobehavioral clinical PROCESS studi es FIGURE D-5 Proposed levels of clinical assessment of major organ, immune, and endocrine systems algorithm: Application by using the long-chain polyunsaturated fatty acid LC-PUFA Generally Recog- nized as Safe (GRAS) Notifications 000041 and 000080 as a case study. An asterisk (*) along with the corresponding text underlined indicate steps that were either not apparent or not carried out within the GRAS notifications 000041 and 000080 provided to the committee. = a state or condition, = a decision point, = an action, sidebar = an elaboration of recom- mendation or statement.

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193 APPENDIX D PROPOSED LEVELS OF CLINICAL ASSESSM ENT OF DEVELOPM ENT AND BEHAVIOR 1 New ingredient proposed for infant formula Sidebar A: Developmental-Behavioral Assessment Cri teria for choosing neural -behavioral 2 assessment measures: Known or theoreti cal li nk to - Age appropri ateness Yes neurobehavior? - Predictive value - Sensi tivi ty - Brai n-behavior l inks No - Cross-species general izabil ity - Function speci ficity 7 - Ease of ad ministration Adverse effect/event Study design requirements: documented in preclinical - Adequate stati stical power trial s? - Avoi d over-control of mediator variabl es OR Yes - Use measurement aggregation Evidence of significant - Use repeated measures indi vidual difference in susceptibility to the ingredient? Sidebar B: Level 1 Assessment No Neural and behavioral screening 11 measures admi nistered duri ng a routine Known or theoreti cal well-baby physical exam or through indi rect l ink to other Yes parent reports. (See Tabl e 6-10) organ systems? Sidebar C: Level 2 Assessment No 12 Detai led measures of function in maj or Lev el 1 Assessment child developmental areas. Si ngle (See Sidebars A and B) assessment for each area using one instrument. (See T ables 6-11 through 6-15) Sidebar D: Level 3 Assessment 13 8 Evidence of Lev el 2 Assessment Detai led measures of function in maj or adverse Yes (See Sidebars A and C) child developmental areas on at least two * effect/event? separate occasionsusing two recommended instruments for each area. (See T ables 6-11 through 6-15) 9 3 Evidence of Lev el 3 Assessment * adverse Yes (See Sidebars A and D) effect/event? No 4 Evidence of adverse Yes effect/event? No No 10 5 14 6 MANUFACTURER/REGU MANUFACTURER/REGULATORY DISCONTINUE LATORY AGENCY DISCONTINUE AGENCY DETERMINES PROCESS DETERMINES PROCESS INGREDIENT IS SAFE INGREDIENT IS SAFE FIGURE D-6 Proposed levels of clinical assessment of development and behavior algorithm: Appli- cation by using the long-chain polyunsaturated fatty acid Generally Recognized as Safe (GRAS) Notifications 000041 and 000080 as a case study. NOTE: An asterisk (*) along with the correspond- ing text underlined indicate steps that were either not apparent or not carried out within the GRAS notifications 000041 and 000080 provided to the committee. = a state or condition, = a decision point, = an action, sidebar = an elaboration of recommendation or statement.

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194 INFANT FORMULA: EVALUATING THE SAFETY OF NEW INGREDIENTS PROPOSED IN-MARKET SURVEILLANCE 1 Sidebar A: Indication for Level 3 Marketed formula with new ingredient Assessment Lev el 3 assessment should be considered if there is potential f or harm. For example: 2 1. When action of new ingredient could af f ect: -Slower developing brain regions, Did any of the follow ing exist prior to -Endocrine or neurotransmitter action, and marketing: -Ea rly behavior t hat can impact the q ual i ty of - Evidence for signi ficant individual ongoing parent-child relations. or pop ulatio n differences in 2. Primary care phy sicians identif y changes in susceptib ility to the new ingredient? the in d ividual's growth or other outcomes, - Adverse effect/event reported in Yes such as changes in weight, height, and head prec li n i c al or cli n i c al tri als? circumference percentiles; skin or hair - Scienti fic evi dence linki ng the new changes; muscle atr ophy; mood changes; ingre dient or new ingredient source to anorexia; vomiting; and diarrhea. development of any of the areas of infant func tion (See Chapter 6) ? Sidebar B: Level 3 Assessment The f ollowing issues should be considered in lev el 3 No assessment: - The domains to be inv estigated and the 9 instrume nts to be used wil l vary depending on Lev el 1 Assessment: the organ or functional systems that are most PASSIVE SURVEILLANCE like ly to be affecte d by the ingredient and 1-800 li ne or Internet web site result s from in-market, preclinical, or clinical studies. - Assessment should include times when children 10 make major life transitions, such as ent ry into school, the onset of puberty, high-school Surveill ance data indicates problems graduation, and vocational cho ice. Ev en further in a function area beyond follow-up in adult life m ay be desirable with expectati on based upon previous Yes tr ansitions points, such as post-high-school survey, cl ini cal studi es or population education and vocation status. base rates ? - The location of those inf ants participating in the clinical trials should be tracke d after the trials are over. No 3 Lev el 2 Assessment: * 11 Convene an expert panel (in consultation with Any adverse effect/event the regulatory agency) to review existing reported in l iterature Yes published or proprietary data, submitted published after marketing ? evidence, survei llance data, and ongoing li terature revi ews 4 Is there harm linked to marketed YYes formula with new ingredient? 5 Formula is pulled from No market No 6 Is there potential for harm? No (See Sidebar A) Yes 8 Expert panel makes recommendations to 7 Lev el 3 Assessment: regulatory agency about Initi ate studies at level and type needed 12 long-term safety status of to establi sh safety of formula Conti nue surveil lance formula with new ingredient (See Sidebar B) and whether further long-term follow-up is needed FIGURE D-7 Proposed in-market surveillance algorithm: Application by using the long-chain poly- unsaturated fatty acid Generally Recognized as Safe (GRAS) Notifications 000041 and 000080 as a case study. NOTE: An asterisk (*) along with the corresponding text underlined indicate steps that were either not apparent or not carried out within the GRAS notifications 000041 and 000080 provided to the committee. = a state or condition, = a decision point, = an action, sidebar = an elaboration of recommendation or statement.

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195 APPENDIX D of the ingredient. Chapter 7 provides more details on the committee’s recommendations for in-market surveillance. If needed, a selection of a qualified and unbiased expert panel is important to evaluate surveillance data and ongoing literature reviews to determine if follow- up studies are necessary. PROBIOTICS For the case of probiotics, the committee reviewed GRAS Notice 000049 to analyze the addition of probiotics to infant formula using its recommended algorithms. Figure D-8 provides an overview of the proposed process. Probiotics have a history of safe use in infant formulas in other countries, and a review of the scientific literature showed no significant adverse events linked to these ingredients. Preclinical Studies A probiotic is a complex ingredient (e.g., a microorganism) and thus, stability and solubility studies should be performed with the ingredient in solution, as well as in the matrix that would be fed to human infants (Figure D-9). Each probiotic should be tested separately, as well as in the combination that will be used in the infant formula. This is important because different probiotics may possess different chemical characteristics, nutri- tional contributions, and pharmacological and physiological activities, and they may be derived from novel sources or processes. A comprehensive preclinical level 1 assessment also should be conducted. As shown in Figures D-9 and D-10, preclinical studies are important in assessing the safety of probiotics since changing intestinal flora may lead to production of atypical components in the intes- tines. Chapter 5 provides more details on the committee’s recommendations for preclinical studies. Clinical Studies As seen in the overview of the proposed clinical guidelines (Figures D-11 and D-12), it is important to include appropriate measures of body composition and hepatic and endocrine function. The addition of probiotics could lead to formation of certain molecules at high levels not commonly present in the intestines. This could theoretically affect hepatic and endocrine function and other systems. Finally, clinical studies should include a comprehen- sive level 1 assessment of behavioral and neural screening measures (see Figures D-11, D-12, and D-13). Chapter 6 provides more information about these assessments. In-Market Surveillance Figure D-14 illustrates proposed in-market surveillance guidelines. Assuming that the recommended preclinical and clinical tests using probiotics detected no adverse effects, passive surveillance for in-market monitoring and level 2 long-term follow-up strategies are recommended. Chapter 7 provides more information about the committee’s recommenda- tions on in-market surveillance.

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196 INFANT FORMULA: EVALUATING THE SAFETY OF NEW INGREDIENTS PROPOSED PROCESSES 1 New ingredient proposed for infant formula 2 Manufacturer establishes assessment process to determine the safety of ingredients new to infant formula Sidebar A: Preclinical Studies Characterize chemical and physical properties of the new 3 Review of literature ingredient. Conduct preclinical studies to evaluate toxicity * - history of safe use and neurological safety. (See Chapter 5) 4 Sidebar B: Clinical Studies Preclinical Studies * (See Sidebar A) Conduct clinical studies to assess symptoms and laboratory * indicators for specific organ systems, absorption and metabolism, and developmental and behavioral outcomes . 5 (See Chapter 6) Clinical Studies * (See Sidebar B) Sidebar C: In-Market Surveillance Establish expert panel to evaluate in-market monitoring, * Manufacturer selects an expert panel in 6 review submitted evidence,surveillance data, and ongoing consultation with regulatory agency to review * literature reviews. Determine necessary follow-up studies. results and determine safety of new (See Chapter 7) ingredient 7 Manufacturer submits to regulatory agency its demonstration of safety of new 9 ingredient Manufacturer provides answers to questions Regulatory agency raises 8 questions concerning the Y es scientific results, process, or other components? No 10 Regulatory agency has 11 no objection Ensure safety of formula Yes concerning the safety containing new ingredient of new ingredient No No 15 14 REGULATORY AGENCY DISCONTINUE 12 REGULATORY AGENCY DOES NOT APPROVE PROCESS APPROVES INFANT INFANT FORMULA WITH FORMULA WITH NEW NEW INGREDIENT INGREDIENT 13 In-Market Surv eillance * (See Sidebar C) FIGURE D-8 Proposed process for evaluating the safety of ingredients new to infant formulas algorithm: Application by using the probiotics Generally Recognized as Safe (GRAS) Notification 000049 as a case study. An asterisk (*) along with the corresponding text underlined indicate steps that were either not apparent or not carried out within the GRAS notification 000049 provided to the committee. In-market assessment should be planned in conjunction with preclinical and clinical test- ing. This algorithm is modeled after the U.S. Generally Recognized as Safe Notification process; similar schemes can be adapted to other regulatory processes. = a state or condition, = a decision point, = an action, sidebar = an elaboration of recommendation or statement.

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197 APPENDIX D PROPOSED PRECLINICAL ASSESSM ENT 1 New ingredient proposed for infant formula 2 Are the active component or the impurities well known ? Sidebar A: Chemical and Physical AND Yes Is adequate literature available to Characterization determ ine their safety? Structure, Stability, and Solubility - High performance liquid chromatography, liquid chromatography-mass spectrometry, and 3 thin layer chromatography. Initiate preclinical studies to evaluate toxicity * No - T he stability to temperature, ultraviolet light as and neurological safety (See Figure D-10) well as the solubility properties of the ingredient. - T he percentage of the unidentifiable mater ials in ingredient. * 8 - T he kind of solvents, suspending agents, emulsifiers, or other materials that will be Chemical and Physical Characterization * used in adm inister ing the ingredient whether in (See Sidebar A) in vitro or a nimal studies. - Ingredient should be stored under conditions that maintain its stability, quality, and purity until the subsequent studies are complete. - T hese studies should be repeated with the 9 4 ingredient in the solution or matrix that would Are chemical and Toxicity Assessment * be fed to the human infants. Yes physical purity assured? (See Sidebar B) Sidebar B: Toxicity Assessment 1. Genetic tests 2. Cellular studies 3. Animal toxicity studies - Acute, subchronic, and chronic toxicity - Developmental toxicity * - Absorpt ion, distributi on, metabolism,,and excretion 4. Organ level studies - Gastrointest inal tract - Hepatic No - Renal - Hematology - Immune - Endocrine - Neurologic 5 Any positive test for toxicity or concern for Yes safety? No 6 10 7 DISCONTINUE DISCONTINUE Neurological Safety Assessment * PROCESS (See Figure D-10) PROCESS FIGURE D-9 Proposed preclinical assessment algorithm: Application by using the probiotics Gener- ally Recognized as Safe (GRAS) Notification 000049 as a case study. An asterisk (*) along with the corresponding text underlined indicate steps that were either not apparent or not carried out within the GRAS notification 000049 provided to the committee. Many of the steps of chemical and physical characterization cannot be applied to probiotics. = a state or condition, =a decision point, = an action, sidebar = an elaboration of recommendation or statement.

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198 INFANT FORMULA: EVALUATING THE SAFETY OF NEW INGREDIENTS P PROPOSED LEVELS OF PRECLINICAL ASSESSMENT 1 Initiate preclinical studies to evaluate toxicity and neurological safety 2 Any evidence of abnormalities based on previous human data, other preclinical studies, or on Yes theoretical plausible perturbation of a metabolic pathway? No Sidebar A: Level 1 Assessment 7 Standard measures of genetic tests, cellular studies, animal toxicity studies, Lev el 1 Assessment * * major organ systems, and neurological (See Sidebar A) preclinical screening measures. (See Tables 5-1 through 5-10) Sidebar B: Level 2 Assessment Detailed measures of genetic tests, 8 3 Any evidence of cellular studies, animal toxicity studies, Lev el 2 Assessment adverse Yes major organ systems, and neurological (See Sidebar B) effect/event? preclinical measures. (See Tables 5-1 through 5-10) No 4 Any evidence of adverse effect/event or concern Yes for safety? No 6 9 5 Continue to clinical Re-evaluate results before DISCONTINUE studies considering clinical trials PROCESS FIGURE D-10 Proposed levels of preclinical assessment algorithm: Application by using the probi- otics Generally Recognized as Safe (GRAS) Notification 000049 as a case study. An asterisk (*) along with the corresponding text underlined indicate steps that were either not apparent or not carried out within the GRAS notification 000049 provided to the committee. = a state or condition, = a decision point, = an action, sidebar = an elaboration of recommendation or statement.

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199 APPENDIX D PROPOSED CLINICAL ASSESSMENT 1 New ingredient proposed for infant formula 2 Initiate clinical studies to evaluate the impact of new ingredient on growth and development Sidebar A: Growth Studies Assess: * - Weight velocity - Length velocity 3 Grow th Studies - Head circumference (See Sidebar A) - Body composition and * Clinical Endpoints (See Sidebar B and Figure D-12) Sidebar B: Clinical Endpoints Assess symptoms and adverse laboratory indicators in the following: - Gastrointestinal tract - Kidney * - Blood - Immunological system 4 - Endocrinological system Abnormal growth or Assess absorption, distribution, adverse effect/event on metabolism, and excretion of Yes specific organ, immune, or ingredient where appropriate endocrine systems Sidebar C: Developmental-Behavioral No Assessment 6 Assess: * - Sensory and motor function * Dev elopmental-Behav ioral Assessment - Cognitive development (See Sidebar C and Figure D-13) - T emperament - Neurological function 7 5 Abnormal function in major DISCONTINUE Yes developmental areas PROCESS No 8 MANUFACT URER/REGULAT ORY AGENCY DET ERMINES INGREDIENT IS SAFE FIGURE D-11 Proposed clinical assessment algorithm: Application by using the probiotics Gener- ally Recognized as Safe (GRAS) Notification 000049 as a case study. An asterisk (*) along with the corresponding text underlined indicate steps that were either not apparent or not carried out with- in the GRAS notification 000049 provided to the committee. = a state or condition, = a decision point, = an action, sidebar = an elaboration of recommendation or statement.

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200 INFANT FORMULA: EVALUATING THE SAFETY OF NEW INGREDIENTS PROPOSED LEVELS OF CLINICAL ASSESSM ENT OF MAJOR SYSTEMS 1 New ingredient proposed for infant form ul a 2 Sidebar A: Level 1 Assessment Known or theoretical i ndi rect Y es li nk to major organ system s? Major organ systems screening measures in the following: - Gastrointestinal tract No - Liver 6 * - Kidney - Blood Adverse effect/event documented - Immune in precli ni cal trials? - Endocrine OR Y es (See Tables 6-3, 6-5, 6-6, 6-8, and 6-9) Evi dence of signifi cant individual difference i n susceptibil ity to the ingredient? Sidebar B: Level 2 Assessment No Major organ systems detail ed m easures 7 in the foll owi ng: * Lev el 1 Assessment - Gastrointestinal tract (See Sidebar A) - Liver - Kidney - Blood - Immune 8 - Endocrine Evi dence of (See Tabl es 6-3, 6-5, 6-6, 6-8, and 6-9) adverse Yes effect/event? 3 Lev el 2 Assessment (See Sidebar B) 4 No Evi dence of adverse Yes effect/event? No 5 9 Continue to DISCONTINUE neurobehavioral studi es PROCESS FIGURE D-12 Proposed levels of clinical assessment of major organ, immune, and endocrine sys- tems algorithm: Application by using the probiotics Generally Recognized as Safe (GRAS) Notifica- tion 000049 as a case study. An asterisk (*) along with the corresponding text underlined indicate steps that were either not apparent or not carried out within the GRAS notification 000049 provided to the committee. = a state or condition, = a decision point, = an action, sidebar = an elaboration of recommendation or statement.

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201 APPENDIX D PROPOSED LEVELS OF CLINICAL ASSESSM ENT OF DEVELOPM ENT AND BEHAVIOR 1 New ingredient proposed for infant formula Sidebar A: Developmental-Behavioral Assessment Cri teria for choosing neural -behavioral assessment measures: 2 - Age appropri ateness Known or theoreti cal li nk to - Predictive value Yes neurobehavior? - Sensi tivi ty - Brai n-behavior l inks - Cross-species general izabil ity No - Function speci ficity - Ease of ad ministration 7 Study design requirements: Adverse effect/event - Adequate stati stical power documented in preclinical - Avoi d over-control of mediator variabl es trial s? - Use measurement aggregation OR Yes - Use repeated measures Evidence of significant indi vidual difference in susceptibility to the ingredient? Sidebar B: Level 1 Assessment No * Neural and behavioral screening 11 measures admi nistered duri ng a routine Known or theoreti cal well-baby physical exam or through indi rect l ink to other Yes parent reports. (See Tabl e 6-10) organ systems? Sidebar C: Level 2 Assessment No Detai led measures of function in maj or 12 child developmental areas. Si ngle Lev el 1 Assessment * assessment for each area using one (See Si debars A and B) instrument. (See T ables 6-11 through 6-15) Sidebar D: Level 3 Assessment 13 8 Evidence of Detai led measures of function in maj or Lev el 2 Assessment adverse Yes child developmental areas on at least two (See Sidebars A and C) effect/event? separate occasionsusing two recommended instruments for each area. (See T ables 6-11 through 6-15) 9 3 Evidence of Lev el 3 Assessment adverse Yes (See Sidebars A and D) effect/event? No 4 Evidence of adverse Yes effect/event? No No 10 5 14 6 MANUFACTURER/REGU MANUFACTURER/REGULATORY DISCONTINUE LATORY AGENCY DISCONTINUE AGENCY DETERMINES PROCESS DETERMINES PROCESS INGREDIENT IS SAFE INGREDIENT IS SAFE FIGURE D-13 Proposed levels of clinical assessment of development and behavior algorithm: Appli- cation by using the probiotics Generally Recognized as Safe (GRAS) Notification 000049 as a case study. An asterisk (*) along with the corresponding text underlined indicate steps that were either not apparent or not carried out within the GRAS notification 000049 provided to the committee. = a state or condition, = a decision point, = an action, sidebar = an elaboration of recommendation or statement.

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202 INFANT FORMULA: EVALUATING THE SAFETY OF NEW INGREDIENTS PROPOSED IN-MARKET SURVEILLANCE 1 Sidebar A: Indication for Level 3 Marketed formula with new ingredient Assessment Lev el 3 assessment should be considered if there is potential f or harm. For example: 2 1. When action of new ingredient could af f ect: -Slower developing brain regions, Did any of the follow ing exist prior to -Endocrine or neurotransmitter action, and marketing: -Ea rly behavior t hat can impact the q ual i ty of - Evidence for signi ficant individual or ongoing parent-child relations. populatio n differences in suscepti bility 2. Primary care phy sicians identif y changes in to the new ingredient? the in d ividual's growth or other outcomes, - Adverse effect/event reported in Yes such as changes in weight, height, and head prec li n i c al or cli n i c al tri als? circumference percentiles; skin or hair - Scienti fic evi dence linki ng the new changes; muscle atr ophy; mood changes; ingre dient or new ingredient source to anorexia; vomiting; and diarrhea. development of any of the areas of infant func tion (See Chapter 6) ? Sidebar B: Level 3 Assessment The f ollowing issues should be considered in lev el 3 No assessment: - The domains to be inv estigated and the 9 instrume nts to be used wil l vary depending on Lev el 1 Assessment: the organ or functional systems that are most PASSIVE SURVEILLANCE * like ly to be affecte d by the ingredient and 1-800 li ne or Internet web site result s from in-market, preclinical, or clinical studies. - Assessment should include times when children 10 make major life transitions, such as ent ry into school, the onset of pube rty, high-school Surveill ance data indicates problems graduation, and vocational cho ice. Ev en further in a function area beyond follow-up in adult life m ay be desirable with expectati on based upon previous Yes tr ansitions points, such as post-high-school survey, cl ini cal studi es, or population education and vocation status. base rates ? - The location of those inf ants participating in the clinical trials should be tracke d after the trials are over. No 3 Lev el 2 Assessment: 11 Convene an expert panel (in consultation with Any adverse effect/event the regulatory agency) to review existing reported in l iterature Yes published or proprietary data, submitted published after marketing ? evidence, survei llance data, and ongoing li terature revi ews 4 Is there harm linked to marketed YYes formula with new ingredient? 5 Formula is pulled from No market No 6 Is there potential for harm? No (See Sidebar A) Yes 8 Expert panel makes recommendations to 7 Lev el 3 Assessment: regulatory agency about Initi ate studies at level and type needed 12 long-term safety status of to establi sh safety of formula Conti nue surveil lance formula with new ingredient (See Sidebar B) and whether further long-term follow-up is needed FIGURE D-14 Proposed in-market surveillance algorithm: Application by using the probiotics Gen- erally Recognized as Safe (GRAS) Notification 000049 as a case study. An asterisk (*) along with the corresponding text underlined indicate steps that were either not apparent or not carried out with- in the GRAS notification 000049 provided to the committee. = a state or condition, = a decision point, = an action, sidebar = an elaboration of recommendation or statement.

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203 APPENDIX D SUMMARY These two case studies demonstrate the flexibility and utility of the proposed processes. They also indicate an important potential role for expert panels in determining the types and levels of assessment to ensure the safety of two very different ingredients. Their application also shows the importance of standardized elements and frameworks when considering the safety of new ingredients added to infant formulas.