Letters
Agency for arsenic in drinking water. The proposed action limit is based on quantitative risk assessment using data on lung and bladder cancer cases from southwestern Taiwan. The increasing evidence for arsenic health effects at low-to-moderate arsenic levels, including both cancer and noncancer end points,2-5 should be considered to evaluate the adequacy of 10 μg/L as the action level for apple juice. For rice, the FDA’s risk assessment is ongoing; an action level has yet to be proposed. As we discussed, in addition to establishing standards for juice, rice, and other foods, adequate monitoring systems are needed for arsenic species in food. Finally, on September 30, 2013, the FDA withdrew the approvals of roxarsone, arsanilic acid, and carbarsone, which are arsenic-based animal drugs.6 Thus, people who eat poultry may be less likely to be exposed to dietary arsenic. Nitarsone, however, is still approved. Ana Navas-Acien, MD, PhD Keeve Nachman, PhD, MHS Author Affiliations: Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (Navas-Acien, Nachman); Department of Epidemiology, Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (Navas-Acien); Department of Health Policy and Management, Johns Hopkins Center for Livable Future, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (Nachman). Corresponding Author: Ana Navas-Acien, MD, PhD, Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St, Office W7513D, Baltimore, MD 21205 ([email protected]). Conflict of Interest Disclosures: None reported. 1. US Food and Drug Administration. Supporting document for action level for arsenic in apple juice. http://www.fda.gov/Food/GuidanceRegulation /GuidanceDocumentsRegulatoryInformation/ChemicalContaminantsMetals -NaturalToxinsPesticides/ucm360023.htm. Accessed November 25, 2013. 2. Sohel N, Persson LA, Rahman M, et al. Arsenic in drinking water and adult mortality: a population-based cohort study in rural Bangladesh. Epidemiology. 2009;20(6):824-830. 3. Chen Y, Graziano JH, Parvez F, et al. Arsenic exposure from drinking water and mortality from cardiovascular disease in Bangladesh: prospective cohort study. BMJ. 2011;342:d2431. 4. García-Esquinas E, Pollán M, Umans JG, et al. Arsenic exposure and cancer mortality in a US-based prospective cohort: the Strong Heart Study. Cancer Epidemiol Biomarkers Prev. 2013;22(11):1944-1953. 5. Moon KA, Guallar E, Umans JG, et al. Association between low to moderate arsenic exposure and incident cardiovascular disease: a prospective cohort study [published online September 24, 2013]. Ann Intern Med. doi:10.7326/0003-4819-159-10-201311190-00719. 6. US Food and Drug Administration. FDA response to citizen petition on arsenic-based animal drugs. http://www.fda.gov/AnimalVeterinary/SafetyHealth /ProductSafetyInformation/ucm370568.htm. Accessed November 25, 2013.
Conflicts of Interest in Approvals of Food Additives To the Editor In concluding that financial conflicts of interest are ubiquitous in the conduct of “generally recognized as safe” (GRAS) determinations, Neltner et al1 fundamentally misunderstand the legal framework that governs the use of substances in food. The authors draw on principles regarding conflicts of interest that were articulated by the Institute of Medicine in the context of medical education, research, and practice. Nowhere do the authors explain why it is approprijamainternalmedicine.com
ate to apply those principles in the context of a GRAS determination by a food manufacturer. It is not appropriate. In conducting a GRAS determination, a food manufacturer is not recommending a course of therapy to a patient or rendering an opinion on whether the Food and Drug Administration (FDA) should approve a drug. Rather, the manufacturer is exercising a responsibility explicitly conferred by the Federal Food, Drug, and Cosmetic Act. That law authorizes a manufacturer to determine whether the proposed use of a substance in food is GRAS (ie, whether the proposed use of the substance is safe and whether there exists general recognition among qualified experts of such safety). There is no question on whose behalf the manufacturer is acting. If the manufacturer errs in its GRAS determination, the manufacturer is subject to substantial civil and criminal liability. In some instances, it may be desirable for a manufacturer to convene a panel of experts to assess whether there exists general recognition of safety. Even in those instances, the ultimate responsibility for a GRAS determination rests with the manufacturer. A manufacturer therefore has strong incentives to seek out the most highly qualified food toxicologists (not food technologists) and other appropriately qualified experts to help the manufacturer determine whether there exists general recognition of safety among such experts. In the end, what the authors appear to object to is the fact that Congress chose to establish the GRAS statutory provision that charges manufacturers with the responsibility of determining when it applies. In the more than 50 years since the law was enacted, that choice has proven wise. Manufacturers have adhered to the law and regulations in order to facilitate innovations that have contributed to the production of safe, nutritious, and affordable food, and the FDA has been left free to focus its limited resources on matters that merit the agency’s attention. Leon Bruner, DVM, PhD Author Affiliation: Science and Regulatory Affairs, The Grocery Manufacturers Association, Washington, DC. Corresponding Author: Leon Bruner, DVM, PhD, Senior Vice President for Scientific and Regulatory Affairs, Grocery Manufacturers Association, 1350 I St NW, Ste 300, Washington, DC 20005 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Neltner TG, Alger HM, O’Reilly JT, Krimsky S, Bero LA, Maffini MV. Conflicts of interest in approvals of additives to food determined to be generally recognized as safe: out of balance. JAMA Intern Med. 2013;173(22):2032-2036.
To the Editor The article by Neltner et al1 raises concerns about the integrity of the “Generally Recognized as Safe” (GRAS) process. The United States has the most robust assessment of food ingredient safety in the world. The current GRAS process relies on scientific expert consensus, publicly available information, and clinical data. GRAS ingredients have been consumed for decades, and none has compromised public health. Under the current self-affirmation GRAS process, expert reviewers are selected for their academic credentials and experience as specified in the statutes,2 promulgated in 1997 and JAMA Internal Medicine February 2014 Volume 174, Number 2
Copyright 2014 American Medical Association. All rights reserved.
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Letters
consistent with the Food and Drug Administration procedures.3 These experts carefully scrutinize “new” food ingredients to determine if there is reasonable certainty the ingredient is not harmful under the “intended conditions of use.” This process includes a plethora of quality evidence, which undergoes extensive, independent review by these experts. Public health and food safety depends on these experts, who come from prestigious universities, research institutions, government agencies, and nonprofit organizations. Without their expertise, we could compromise food safety through empaneling less-experienced reviewers. In efforts to assure public health and the safety of the food supply, reviewers sometimes reject manufacturer data on an ingredient as being inadequate and deficient, and ingredient sponsors often withdraw their submissions until they can meet the high standards required. Experts must document any relationship with the manufacturer or producer to obviate any potential bias. However, the Institute of Medicine acknowledges that a potential conflict of interest “does not mean that a decision itself will be biased.”4 We agree that improved transparency of the current GRAS process may reassure regulatory agencies and the public. However, transparency should not come at the expense of food safety and public health or challenge the integrity and character of experts that serve on GRAS panels. Financial conflict should be minimized, although addressing such conflicts alone will not completely eliminate bias. The current GRAS self-affirmation process is not broken. The US food supply is one of the safest in the world. The public and regulatory agencies should be grateful for the diligence and commitment of all those who contribute to keeping it that way. Roger Clemens, DrPH David Schmidt Author Affiliations: International Center for Regulatory Science, University of Southern California School of Pharmacy, Los Angeles (Clemens); International Food Information Council, Washington, DC (Schmidt). Corresponding Author: David Schmidt, International Food Information Council, 1100 Connecticut Ave NW, Ste 430, Washington, DC 20036 (schmidt @ific.org). Conflict of Interest Disclosures: Dr Clemens is a consultant to Spherix Consulting. Dr Schmidt is president and chief executive officer of the International Food Information Council, which receives financial support from the food, beverage, and agricultural industries. 1. Neltner TG, Alger HM, O’Reilly JT, Krimsky S, Bero LA, Maffini MV. Conflicts of interest in approvals of additives to food determined to be generally recognized as safe: out of balance. JAMA Intern Med. 2013;173(22):2032-2036. 2. US Food & Drug Administration, Federal Food, Drug, & Cosmetic (FD&C) Act, §201(s): “Chapter II—Definitions.” http://www.fda.gov/RegulatoryInformation /Legislation/FederalFoodDrugandCosmeticActFDCAct /FDCActChaptersIandIIShortTitleandDefinitions/ucm086297.htm. Accessed September 6, 2013.
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careful an individual is, conflicts may compromise a scientist’s objective analysis consciously or unconsciously, potentially resulting in a poor decision.1 Clemens and Schmidt also assert, without substantiation, that transparency and conflicts of interest standards may “compromise food safety through empaneling lessexperienced reviewers.” If true that too few competent scientists are without serious conflicts, perhaps the close-knit network that makes many of the determinations about additives to food “Generally Recognized as Safe” (GRAS) has become stagnant and needs to grow. Finally, Clemens and Schmidt claim that the United States “has the most robust assessment of food safety in the world” despite (1) more than 1000 chemicals being added to food without the Food and Drug Administration’s (FDA’s) knowledge2; (2) no other developed country allowing a company to add a chemical to a food product without government approval3; and (3) Europe completing a comprehensive review of previous safety decisions. In contrast, the FDA rarely looks back.4 Bruner dismisses the IOM’s science-based framework as inappropriate by claiming that Congress allowed food manufacturers to make GRAS determinations when it passed the Food Additives Amendment of 1958.5 However, conflicts of interest exist, regardless of whether an action is legal. The IOM framework is an appropriate tool to evaluate both medical and food safety issues; both involve professional judgment in making health and safety decisions that impact the public in tangible ways. Also flawed is Bruner’s rationale that there is sufficient civil and criminal liability to prevent a food manufacturer’s economic self-interest from unduly influencing an employee’s or consultant’s scientific judgment. The FDA acknowledged the limits of these liabilities when it stated the following6(p3): [c]urrently, the legal system does not ensure the optimum level of safety for foods because consumers who become ill often do not know the reason for, or source of, their illness. Even in cases where consumers are aware that their illness was contracted from a specific food, it is often difficult to determine who is ultimately responsible for their illness, since the particular source of contamination is not known in many circumstances. As currently conducted, GRAS determinations undermine the integrity of the regulatory process and raise questions about whether the FDA can ensure the safety of the food supply. Conflicts of interest should be minimized and disclosed. Thomas G. Neltner, JD Maricel V. Maffini, PhD Author Affiliations: Natural Resources Defense Council, Washington, DC.
3. 21 CFR §170.35.
Corresponding Author: Maricel V. Maffini, PhD, Natural Resources Defense Council, 1152 15th St NW, Ste 300, Washington, DC 20005 ([email protected]).
4. Lo B, Field MJ, eds; Committee on Conflict of Interest in Medical Research, Education, and Practice, Board of Health Sciences Policy, Institute of Medicine of the National Academies. Conflict of Interest in Medical Research, Education, and Practice. Washington, DC: National Academies Press; 2009.
Conflict of Interest Disclosures: The authors are employees of the Natural Resources Defense Council. At the time the study was conducted, the authors were employees of The Pew Charitable Trusts, which supported the work. The authors’ current work is also funded by The Pew Charitable Trusts.
In Reply Clemens and Schmidt imply that a conflict of interest is synonymous with a lack of scientific integrity. The Institute of Medicine (IOM) report concluded that no matter how
1. Lo B, Field MJ, eds; Committee on Conflict of Interest in Medical Research, Education, and Practice, Board of Health Sciences Policy, Institute of Medicine of the National Academies. Conflict of Interest in Medical Research, Education, and Practice. Washington, DC: National Academies Press; 2009.
JAMA Internal Medicine February 2014 Volume 174, Number 2
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a University of Birmingham User on 05/31/2015
jamainternalmedicine.com
Agency for arsenic in drinking water. The proposed action limit is based on quantitative risk assessment using data on lung and bladder cancer cases from southwestern Taiwan. The increasing evidence for arsenic health effects at low-to-moderate arsenic levels, including both cancer and noncancer end points,2-5 should be considered to evaluate the adequacy of 10 μg/L as the action level for apple juice. For rice, the FDA’s risk assessment is ongoing; an action level has yet to be proposed. As we discussed, in addition to establishing standards for juice, rice, and other foods, adequate monitoring systems are needed for arsenic species in food. Finally, on September 30, 2013, the FDA withdrew the approvals of roxarsone, arsanilic acid, and carbarsone, which are arsenic-based animal drugs.6 Thus, people who eat poultry may be less likely to be exposed to dietary arsenic. Nitarsone, however, is still approved. Ana Navas-Acien, MD, PhD Keeve Nachman, PhD, MHS Author Affiliations: Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (Navas-Acien, Nachman); Department of Epidemiology, Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (Navas-Acien); Department of Health Policy and Management, Johns Hopkins Center for Livable Future, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (Nachman). Corresponding Author: Ana Navas-Acien, MD, PhD, Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St, Office W7513D, Baltimore, MD 21205 ([email protected]). Conflict of Interest Disclosures: None reported. 1. US Food and Drug Administration. Supporting document for action level for arsenic in apple juice. http://www.fda.gov/Food/GuidanceRegulation /GuidanceDocumentsRegulatoryInformation/ChemicalContaminantsMetals -NaturalToxinsPesticides/ucm360023.htm. Accessed November 25, 2013. 2. Sohel N, Persson LA, Rahman M, et al. Arsenic in drinking water and adult mortality: a population-based cohort study in rural Bangladesh. Epidemiology. 2009;20(6):824-830. 3. Chen Y, Graziano JH, Parvez F, et al. Arsenic exposure from drinking water and mortality from cardiovascular disease in Bangladesh: prospective cohort study. BMJ. 2011;342:d2431. 4. García-Esquinas E, Pollán M, Umans JG, et al. Arsenic exposure and cancer mortality in a US-based prospective cohort: the Strong Heart Study. Cancer Epidemiol Biomarkers Prev. 2013;22(11):1944-1953. 5. Moon KA, Guallar E, Umans JG, et al. Association between low to moderate arsenic exposure and incident cardiovascular disease: a prospective cohort study [published online September 24, 2013]. Ann Intern Med. doi:10.7326/0003-4819-159-10-201311190-00719. 6. US Food and Drug Administration. FDA response to citizen petition on arsenic-based animal drugs. http://www.fda.gov/AnimalVeterinary/SafetyHealth /ProductSafetyInformation/ucm370568.htm. Accessed November 25, 2013.
Conflicts of Interest in Approvals of Food Additives To the Editor In concluding that financial conflicts of interest are ubiquitous in the conduct of “generally recognized as safe” (GRAS) determinations, Neltner et al1 fundamentally misunderstand the legal framework that governs the use of substances in food. The authors draw on principles regarding conflicts of interest that were articulated by the Institute of Medicine in the context of medical education, research, and practice. Nowhere do the authors explain why it is approprijamainternalmedicine.com
ate to apply those principles in the context of a GRAS determination by a food manufacturer. It is not appropriate. In conducting a GRAS determination, a food manufacturer is not recommending a course of therapy to a patient or rendering an opinion on whether the Food and Drug Administration (FDA) should approve a drug. Rather, the manufacturer is exercising a responsibility explicitly conferred by the Federal Food, Drug, and Cosmetic Act. That law authorizes a manufacturer to determine whether the proposed use of a substance in food is GRAS (ie, whether the proposed use of the substance is safe and whether there exists general recognition among qualified experts of such safety). There is no question on whose behalf the manufacturer is acting. If the manufacturer errs in its GRAS determination, the manufacturer is subject to substantial civil and criminal liability. In some instances, it may be desirable for a manufacturer to convene a panel of experts to assess whether there exists general recognition of safety. Even in those instances, the ultimate responsibility for a GRAS determination rests with the manufacturer. A manufacturer therefore has strong incentives to seek out the most highly qualified food toxicologists (not food technologists) and other appropriately qualified experts to help the manufacturer determine whether there exists general recognition of safety among such experts. In the end, what the authors appear to object to is the fact that Congress chose to establish the GRAS statutory provision that charges manufacturers with the responsibility of determining when it applies. In the more than 50 years since the law was enacted, that choice has proven wise. Manufacturers have adhered to the law and regulations in order to facilitate innovations that have contributed to the production of safe, nutritious, and affordable food, and the FDA has been left free to focus its limited resources on matters that merit the agency’s attention. Leon Bruner, DVM, PhD Author Affiliation: Science and Regulatory Affairs, The Grocery Manufacturers Association, Washington, DC. Corresponding Author: Leon Bruner, DVM, PhD, Senior Vice President for Scientific and Regulatory Affairs, Grocery Manufacturers Association, 1350 I St NW, Ste 300, Washington, DC 20005 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Neltner TG, Alger HM, O’Reilly JT, Krimsky S, Bero LA, Maffini MV. Conflicts of interest in approvals of additives to food determined to be generally recognized as safe: out of balance. JAMA Intern Med. 2013;173(22):2032-2036.
To the Editor The article by Neltner et al1 raises concerns about the integrity of the “Generally Recognized as Safe” (GRAS) process. The United States has the most robust assessment of food ingredient safety in the world. The current GRAS process relies on scientific expert consensus, publicly available information, and clinical data. GRAS ingredients have been consumed for decades, and none has compromised public health. Under the current self-affirmation GRAS process, expert reviewers are selected for their academic credentials and experience as specified in the statutes,2 promulgated in 1997 and JAMA Internal Medicine February 2014 Volume 174, Number 2
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a University of Birmingham User on 05/31/2015
299
Letters
consistent with the Food and Drug Administration procedures.3 These experts carefully scrutinize “new” food ingredients to determine if there is reasonable certainty the ingredient is not harmful under the “intended conditions of use.” This process includes a plethora of quality evidence, which undergoes extensive, independent review by these experts. Public health and food safety depends on these experts, who come from prestigious universities, research institutions, government agencies, and nonprofit organizations. Without their expertise, we could compromise food safety through empaneling less-experienced reviewers. In efforts to assure public health and the safety of the food supply, reviewers sometimes reject manufacturer data on an ingredient as being inadequate and deficient, and ingredient sponsors often withdraw their submissions until they can meet the high standards required. Experts must document any relationship with the manufacturer or producer to obviate any potential bias. However, the Institute of Medicine acknowledges that a potential conflict of interest “does not mean that a decision itself will be biased.”4 We agree that improved transparency of the current GRAS process may reassure regulatory agencies and the public. However, transparency should not come at the expense of food safety and public health or challenge the integrity and character of experts that serve on GRAS panels. Financial conflict should be minimized, although addressing such conflicts alone will not completely eliminate bias. The current GRAS self-affirmation process is not broken. The US food supply is one of the safest in the world. The public and regulatory agencies should be grateful for the diligence and commitment of all those who contribute to keeping it that way. Roger Clemens, DrPH David Schmidt Author Affiliations: International Center for Regulatory Science, University of Southern California School of Pharmacy, Los Angeles (Clemens); International Food Information Council, Washington, DC (Schmidt). Corresponding Author: David Schmidt, International Food Information Council, 1100 Connecticut Ave NW, Ste 430, Washington, DC 20036 (schmidt @ific.org). Conflict of Interest Disclosures: Dr Clemens is a consultant to Spherix Consulting. Dr Schmidt is president and chief executive officer of the International Food Information Council, which receives financial support from the food, beverage, and agricultural industries. 1. Neltner TG, Alger HM, O’Reilly JT, Krimsky S, Bero LA, Maffini MV. Conflicts of interest in approvals of additives to food determined to be generally recognized as safe: out of balance. JAMA Intern Med. 2013;173(22):2032-2036. 2. US Food & Drug Administration, Federal Food, Drug, & Cosmetic (FD&C) Act, §201(s): “Chapter II—Definitions.” http://www.fda.gov/RegulatoryInformation /Legislation/FederalFoodDrugandCosmeticActFDCAct /FDCActChaptersIandIIShortTitleandDefinitions/ucm086297.htm. Accessed September 6, 2013.
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careful an individual is, conflicts may compromise a scientist’s objective analysis consciously or unconsciously, potentially resulting in a poor decision.1 Clemens and Schmidt also assert, without substantiation, that transparency and conflicts of interest standards may “compromise food safety through empaneling lessexperienced reviewers.” If true that too few competent scientists are without serious conflicts, perhaps the close-knit network that makes many of the determinations about additives to food “Generally Recognized as Safe” (GRAS) has become stagnant and needs to grow. Finally, Clemens and Schmidt claim that the United States “has the most robust assessment of food safety in the world” despite (1) more than 1000 chemicals being added to food without the Food and Drug Administration’s (FDA’s) knowledge2; (2) no other developed country allowing a company to add a chemical to a food product without government approval3; and (3) Europe completing a comprehensive review of previous safety decisions. In contrast, the FDA rarely looks back.4 Bruner dismisses the IOM’s science-based framework as inappropriate by claiming that Congress allowed food manufacturers to make GRAS determinations when it passed the Food Additives Amendment of 1958.5 However, conflicts of interest exist, regardless of whether an action is legal. The IOM framework is an appropriate tool to evaluate both medical and food safety issues; both involve professional judgment in making health and safety decisions that impact the public in tangible ways. Also flawed is Bruner’s rationale that there is sufficient civil and criminal liability to prevent a food manufacturer’s economic self-interest from unduly influencing an employee’s or consultant’s scientific judgment. The FDA acknowledged the limits of these liabilities when it stated the following6(p3): [c]urrently, the legal system does not ensure the optimum level of safety for foods because consumers who become ill often do not know the reason for, or source of, their illness. Even in cases where consumers are aware that their illness was contracted from a specific food, it is often difficult to determine who is ultimately responsible for their illness, since the particular source of contamination is not known in many circumstances. As currently conducted, GRAS determinations undermine the integrity of the regulatory process and raise questions about whether the FDA can ensure the safety of the food supply. Conflicts of interest should be minimized and disclosed. Thomas G. Neltner, JD Maricel V. Maffini, PhD Author Affiliations: Natural Resources Defense Council, Washington, DC.
3. 21 CFR §170.35.
Corresponding Author: Maricel V. Maffini, PhD, Natural Resources Defense Council, 1152 15th St NW, Ste 300, Washington, DC 20005 ([email protected]).
4. Lo B, Field MJ, eds; Committee on Conflict of Interest in Medical Research, Education, and Practice, Board of Health Sciences Policy, Institute of Medicine of the National Academies. Conflict of Interest in Medical Research, Education, and Practice. Washington, DC: National Academies Press; 2009.
Conflict of Interest Disclosures: The authors are employees of the Natural Resources Defense Council. At the time the study was conducted, the authors were employees of The Pew Charitable Trusts, which supported the work. The authors’ current work is also funded by The Pew Charitable Trusts.
In Reply Clemens and Schmidt imply that a conflict of interest is synonymous with a lack of scientific integrity. The Institute of Medicine (IOM) report concluded that no matter how
1. Lo B, Field MJ, eds; Committee on Conflict of Interest in Medical Research, Education, and Practice, Board of Health Sciences Policy, Institute of Medicine of the National Academies. Conflict of Interest in Medical Research, Education, and Practice. Washington, DC: National Academies Press; 2009.
JAMA Internal Medicine February 2014 Volume 174, Number 2
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a University of Birmingham User on 05/31/2015
jamainternalmedicine.com
