Research Original Investigation Conflicts of Interest in Approvals of Additives to Food Determined to Be Generally Recognized as Safe Out of Balance Thomas G. Neltner, JD; Heather M. Alger, PhD; James T. O’Reilly, JD; Sheldon Krimsky, PhD; Lisa A. Bero, PhD; Maricel V. Maffini, PhD Invited Commentary IMPORTANCE Food and Drug Administration (FDA) guidance allows food manufacturers to page 2036 determine whether additives to food are “generally recognized as safe” (GRAS). Manufacturers are not required to notify the FDA of a GRAS determination, although in some instances they notify the agency. The individuals that companies select to make these determinations may have financial conflicts of interest. OBJECTIVE To determine the extent to which individuals selected by manufacturers to make GRAS determinations have conflicts of interest between their obligations to ensure that the use of the additive is safe and their financial relationships to the company. DESIGN Using conflict of interest criteria developed by a committee of the Institute of Medicine, we analyzed 451 GRAS notifications that were voluntarily submitted to the FDA between 1997 and 2012. MAIN OUTCOMES AND MEASURES Number of GRAS notices submitted to the FDA; frequency of various types of relationships between decision maker and additive manufacturer; frequency of participation on GRAS panels by individuals; and number of GRAS safety determinations identified by the FDA that were not submitted to the agency. RESULTS For the 451 GRAS notifications, 22.4% of the safety assessments were made by an employee of an additive manufacturer, 13.3% by an employee of a consulting firm selected by the manufacturer, and 64.3% by an expert panel selected by either a consulting firm or the manufacturer. A standing expert panel selected by a third party made none of these safety assessments. The 290 panels that made GRAS determinations had an average of 3.5 members, with a maximum of 7. Ten individuals served on 27 or more panels; 1 individual served on 128 panels (44.1%). At least 1 of the 10 individuals with the most frequent service was a member of 225 panels (77.6%). CONCLUSIONS AND RELEVANCE Between 1997 and 2012, financial conflicts of interest were ubiquitous in determinations that an additive to food was GRAS. The lack of independent review in GRAS determinations raises concerns about the integrity of the process and whether it ensures the safety of the food supply, particularly in instances where the manufacturer does not notify the FDA of the determination. The FDA should address these Author Affiliations: The Pew concerns. Charitable Trusts, Washington, DC (Neltner, Alger, Maffini); College of Law, University of Cincinnati, Cincinnati, Ohio (O’Reilly); Department of Urban and Environmental Policy & Planning, Tufts University, Medford, Massachusetts (Krimsky); Department of Clinical Pharmacy and Institute for Health Policy Studies, University of California, San Francisco (Bero). Corresponding Author: Thomas G. Neltner, JD, The Pew Charitable JAMA Intern Med. 2013;173(22):2032-2036. doi:10.1001/jamainternmed.2013.10559 Trusts, 901 E St NW, Washington, DC Published online August 7, 2013. 20004 (tneltner@gmail.com). 2032 jamainternalmedicine.com Copyright 2013 American Medical Association. All rights reserved. Downloaded From: http://archinte.jamanetwork.com/ by a University Of Connecticut Health Center User on 06/02/2015 Conflicts of Interests in Food Additive Approvals Original Investigation Research A dditives to food are a fundamental part of the food sup- is defined to mean “a reasonable certainty in the minds of com- ply, providing flavor; enhancing taste, appearance, and petent scientists that the substance is not harmful under the nutrient value; and preventing spoilage, as well as serv- intended conditions of use.”8 The safety of the GRAS additive ing as components of food packaging.1 The term food additive must be generally recognized, which “requires common knowl- has a specific legal meaning, that is a substance whose use “re- edge about the substance throughout the scientific commu- sults or may reasonably be expected to result, directly or in- nity knowledgeable about the safety of substances directly or directly, in its becoming” part of food or affecting the charac- indirectly added to food.”9 Congress recognized that the po- teristics of food.2 Congress excluded from the legal definition tential health effects of additives are often difficult to iden- those additives whose use is designated as “generally recog- tify and may take years to recognize.10,11 nized as safe” (GRAS). In common parlance, however, the term In 2010, the US Government Accountability Office (GAO) is used to refer to food additives in general. scrutinized the GRAS program, concluding that the FDA According to the US Food and Drug Administration (FDA), should strengthen its oversight.4 Among other recommen- the Food Additives Amendment of 19583 allows manufactur- dations, the GAO said the FDA should “minimize the poten- ers to determine when an additive is GRAS.4 Such a review is tial for conflicts of interest in companies’ GRAS determina- known as a GRAS determination. Common GRAS additives in- tions” and “require any company that conducts a GRAS clude trans fat, caffeine, salt, and sweeteners derived from the determination to provide FDA with basic information—as stevia plant (Stevia rebaudiana), such as the sweetener known defined by the agency to allow for adequate oversight— as Truvía (The Truvía Company, LLC). In past decades, the FDA about this determination.”4(p34) made many formal GRAS determinations, but the agency has Given this background, we used criteria developed by an made very few such determinations recently. Institute of Medicine (IOM) committee for medical research, After a GRAS determination is made, manufacturers are not education, and practice to evaluate the conflicts of interest of required to notify the FDA, although in some instances the the individuals who make GRAS determinations.11 agency is notified. When the agency has agreed with the deter- mination, it has responded by formally approving the manu- facturer’s decision in its regulations or by informing the com- pany in writing that it has “no questions” about the chemical’s Methods safety (referred to as a GRAS “no questions” letter).5 After 1997, Assessment of Severity of Conflicts of Interest the agency phased out the first option, replacing it with the sec- The IOM committee11(p46) defined conflict of interest as follows: ond option. When the agency has disagreed, it has sent a letter a set of circumstances that creates a risk that the profes- to the manufacturer stating that there is an insufficient basis for sional judgment or actions regarding a primary interest will be the GRAS determination. The company then decides how to pro- unduly influenced by a secondary interest. ceed. Notices to the FDA either involve new GRAS additives (not previously reviewed or approved by the FDA) or additives that We assessed the severity of a conflict based on the likelihood have already been reviewed or approved, with expanded uses, that a decision could be unduly influenced by a financial in- differing purities, or increased concentrations.6 terest, and the seriousness of possible harm if the decision was A standing expert panel sponsored by the Flavor and Ex- influenced.11 tract Manufacturers Association (FEMA) also makes GRAS de- For purposes of our study, we considered the primary in- terminations about additives that are flavors and informs the terest as ensuring that a use of an additive was GRAS, consis- FDA in writing of its decisions. However, these written com- tent with federal law. The secondary interest was the poten- munications are not considered formal notifications to the tial for financial gain from a determination that enabled a agency and are not publicly available. Also, these communi- manufacturer to sell a new additive, to expand the use of an cations are unrelated to the GRAS notifications to the agency existing additive to new foods, or to increase the amount of from companies.6 Decisions by the FEMA panel, but not their an additive in food. We did not evaluate the nonfinancial pro- rationale or the safety assessment data, are periodically pub- fessional interests of the individuals; this could not be done lished in Food Technology, a trade magazine. Food manufac- with the available information. turers generally accept the decisions of the FEMA panel as con- We identified the possible categories of individuals firmation that a flavor additive is GRAS. Since 1963, the FDA making GRAS determinations based on their relation to has monitored the panel’s decisions on more than 2700 addi- manufacturers of additives. Table 1 gives these categories tives that are flavors; the agency, however, does not review the and the criteria we used to assess the likelihood that a deter- decisions. mination by an individual would be unduly influenced by In 2011, Neltner et al6 estimated that more than 10 000 ad- the financial interests of a manufacturer. Table 2 gives the ditives are allowed in food, 43% of which are GRAS additives. criteria we used to assess the seriousness of possible harm if Manufacturers have made GRAS determinations that allow the a GRAS determination was unduly influenced by the finan- use of an estimated 1000 of these additives, without notify- cial interests of a manufacturer of an additive, based on ing the FDA.6 The manufacturers or FEMA notified the agency whether there was an FDA review and whether the notifica- of the remaining GRAS additives. tion to the agency was made public. Federal ethics laws and To qualify for a GRAS determination, manufacturers of ad- regulations prohibit FDA employees from having financial ditives must conclude that the use of the additive is safe.7 Safe conflicts of interest.12 jamainternalmedicine.com JAMA Internal Medicine December 9/23, 2013 Volume 173, Number 22 2033 Copyright 2013 American Medical Association. All rights reserved. Downloaded From: http://archinte.jamanetwork.com/ by a University Of Connecticut Health Center User on 06/02/2015 Research Original Investigation Conflicts of Interests in Food Additive Approvals Table 1. Likelihood That a Decision by an Individual Making a “Generally Recognized as Safe” Determination Would Be Unduly Influenced by the Financial Interests of a Manufacturer of an Additive Category of Decision Makers Value of the Secondary Interesta Scope of the Relationshipb Extent of the Discretionc Employee of manufacturer of additive Job security/stock ownership Long-term and deep Significant especially if safety data are limited Employee of consulting firm selected Secure more work from maker Duration and depth varies significantly Significant especially if safety data are limited by manufacturer of additive and others Expert panel selected by consulting firm Being selected for more panels Typically short and shallow, unless Varies with panel or manufacturer of additive regular panelist Standing expert panel selected Continuing to serve Short and shallow, unless third party Limited depth and duration by third party on panel is close to additive manufacturer Employee of the FDA None Financial interests prohibited Limited especially with external peer reviews 11(p54) Abbreviation: FDA, US Food and Drug Administration. therefore the risk.” a c Secondary interest is the potential financial gain from a decision that enables a Discretion is a factor in search of published literature, evaluation of manufacturer of an additive to sell the new chemical or more of a previously toxicological data, assessment of cumulative exposure from all dietary sources allowed chemical. including pharmacologically similar chemicals, and extent to which there is a b Scope refers to the duration and depth of the relationship. According to the genuine dispute whether there is reasonable certainty that the substance is Institute of Medicine, “Longer and closer associations increase the scope and not harmful under the intended conditions of use. Table 2. Seriousness of Possible Harm If a “Generally Recognized as Safe” (GRAS) Determination Is Unduly Influenced by the Financial Interests of Manufacturer of an Additive Scope of the Type of FDA Review Value of the Primary Interesta Consequences Extent of Accountability Abbreviation: FDA, US Food and Drug No FDA review Significant value in consumer Significant since addi- Limited especially if additive is Administration. health and confidence in safety tive may be used in a not on ingredient list a Primary interest is ensuring a of food supply wide range of foods chemical’s use is generally FDA review but does Same as above Same as above Moderate if FDA has resources to recognized as safe consistent with not make notice review information publicly availableb federal law. b FDA review and makes Same as above Same as above Significant if information posted Such as the biotechnology review or notice publicly and additive on ingredient list food contact substance notification. availablec c Such as through GRAS notifications. Assessment of GRAS Notices Voluntarily Submitted actual undue influence or harm because the available docu- to the FDA mentation was insufficient. Finally, we reviewed instances With a small number of GRAS notices, we conducted a pilot analy- since 1997 when the FDA sought to obtain a GRAS safety de- sis. The author who performed the evaluation (H.M.A.) shared termination that it had not received a notification for. the results with coauthors and a third-party contractor special- izing in checking facts. The authors discussed disagreements and, with feedback from the contractor, reached consensus on the cat- egorization of the notices. After further refinement of the meth- Results odology, one author (H.M.A.) then reviewed the 451 GRAS no- Assessment of GRAS Notices Submitted to the FDA tices posted on FDA’s website13 that were submitted to the agency Of the 451 GRAS notices voluntarily submitted to the FDA be- between 1997 and 2012; the contractor randomly selected and tween 1997 and 2012, 22.4% were made by an employee of an evaluated 15% of the notices for quality control. additive manufacturer, 13.3% were made by an employee of a The criteria to classify who made the GRAS determina- consulting firm selected by a manufacturer, and 64.3% were tions included the following: (1) standing expert panel if the no- made by an expert panel selected by the manufacturer or a firm tice referred to an ongoing panel similar to FEMA’s that con- that was a consultant to the manufacturer (Table 3). A deter- sidered additives from many manufacturers; (2) expert panel mination by a panel reflected the view of the entire panel, not if such a panel was named in the notice and selected by the an individual member or a subset of members. manufacturer or a consulting firm hired by the manufacturer; We found no instances where a manufacturer who sub- (3) manufacturer’s employee if a panel was not identified and mitted a GRAS notice to the FDA used a standing expert panel an individual signed the notice on behalf of the firm; or (4) em- selected by a third party—the method least likely to involve a ployee of consulting firm if an employee of the firm signed the conflict of interest (Table 2)—to establish whether an additive notice and there was no expert panel. We excluded FDA em- met the GRAS criteria. ployees because the agency only reviews the notices; it does not make the determinations. We also calculated the fre- Assessment of Frequency of Participation on GRAS Panels quency of the service of individuals on expert panels and noted by Individuals the affiliations of those most commonly selected. The 290 panels that made GRAS determinations averaged 3.5 We considered only the likelihood of undue influence of members, with a maximum of 7. In total, 216 individuals served GRAS determinations and the seriousness of possible harm. on at least 1 panel. Most were consultants, and almost all of them We did not evaluate specific decisions to determine if there was had doctor of philosophy degrees; some were physicians or held 2034 JAMA Internal Medicine December 9/23, 2013 Volume 173, Number 22 jamainternalmedicine.com Copyright 2013 American Medical Association. All rights reserved. Downloaded From: http://archinte.jamanetwork.com/ by a University Of Connecticut Health Center User on 06/02/2015 Conflicts of Interests in Food Additive Approvals Original Investigation Research Table 3. Type of Individuals Making “Generally Recognized as Safe” Table 4. Profession and Frequency of Service of 10 Individuals Determinations Submitted to the US Food and Drug Administration Who Served on 27 or More of the 290 Panels That Made “Generally Recognized as Safe” Determinations Notices, No. (%) Decision Maker (n = 451) Panels Served on, Employee of manufacturer of additive 101 (22.4) Individual Profession No. (%) Employee of consulting firm selected 60 (13.3) 1 Consultant and emeritus professor 128 (44.1) by manufacturer of additive 2 Consultant 41 (14.1) Expert panel selected by consulting firm 290 (64.3) 3 Consultant and professor 40 (13.8) or manufacturer of additive Standing expert panel selected by third party 0 4 Consultant and emeritus professor 38 (13.1) 5 Consultant 35 (12.1) 6 Consultant 34 (11.7) other advanced degrees. However, 10 individuals served on 27 7 Consultant and emeritus professor 34 (11.7) or more panels; 1 person served on 128 panels (Table 4). Over 8 Consultant 28 (9.7) the 15-year period, at least 1 of these 10 individuals partici- 9 Consultant and emeritus professora 28 (9.7) pated in 225 panels (77.6%), accounting for 43.1% (433 of 1004) 10 Consultant 27 (9.3) of the total number of seats on all 290 panels. Thus, only 65 pan- a Deceased. els (22.4%) did not include 1 of these 10 individuals. All 10 iden- tified themselves as consultants; 5 cited academic positions. Assessment of GRAS Safety Determinations served on panels because the FDA does not request informa- Not Submitted to the FDA tion on other financial and nonfinancial conflicts of interest. From 1997 to 2012, we found only 1 instance when the agency Fourth, our results do not prove that the conflicts of interest sought to obtain a GRAS safety determination that it had not that we identified actually compromise the GRAS decision pro- received a notification for. In 2010, the FDA sent letters to 4 cess, although they raise such concerns. As the IOM commit- companies inquiring whether they had determined that the use tee noted, the existence of a conflict of interest does not mean of caffeine in alcoholic beverages was GRAS.14 The FDA has af- that a decision itself will be biased.11 The individuals making firmed caffeine as GRAS in cola-type drinks. The agency was these safety decisions may (1) act with great integrity and com- reacting to reports of serious injuries or deaths among young pletely ignore their employer’s business interests; (2) work in people consuming the beverages. In fact, none of the 4 com- organizations that take strong measures to protect employ- panies had made GRAS determinations. A year later, in 2011, 1 ees from conflicts of interest; or (3) see no conflicts because company submitted a GRAS notice that the agency found in- they believe a company takes seriously its legal obligation to sufficient. Subsequently, the FDA issued warning letters to all produce safe products and would not jeopardize its reputa- 4 firms directing them to stop the use of caffeine in alcoholic tion for short-term gain. beverages until the agency formally approved it. All compa- Despite the limited number of GRAS determinations that nies appear to have removed caffeine from such products.14 we evaluated, it is concerning that at least one of 10 individu- als served on more than three-quarters of the 290 panels. First, is there a limited pool of experts? This is unlikely. There are multiple schools offering food science, toxicology and risk as- Discussion sessment degrees, and the Institute of Food Technologists has Between 1997 and 2012, we found that financial conflicts of in- certified 1200 food scientists.15 Second, is it beneficial to draw terest were ubiquitous in determinations that an additive to from a limited number of experts? Possibly. Certain experts may food was GRAS. The lack of independent review in GRAS de- know the GRAS review criteria and procedures well, and be- terminations raises concerns about the integrity of the pro- cause of the experience gained over many years their deci- cess and whether it ensures the safety of the food supply, par- sions may be less likely to be questioned by the FDA. How- ticularly in instances when the manufacturer does not notify ever, repeated use of the same experts would limit the range the FDA of the determination. When manufacturers or their of knowledge and experience on the panels. Third, does the consultants convene an expert panel to make GRAS determi- concentration of expertise compromise the quality of deci- nations, they often pick one of a small number of individuals sions? Our study cannot answer this question. to serve on the panel. Congress gave the FDA the responsibility to ensure that the Our study has limitations. First, although we analyzed the manufacturers of additives to food properly make GRAS de- 451 publicly available GRAS notices submitted to the FDA, we terminations. As recommended by the GAO, minimizing con- lacked comparable data on the many GRAS determinations, flicts of interest in these determinations should be an essen- without notifications to the FDA.6 Second, we did not evalu- tial part of that effort. The FDA’s actions should be informed ate GRAS determinations by the FEMA panel. These determi- by its own drug development regulations16 and policies on con- nations are limited to additives that are flavors and are not for- flict of interest for its advisory committee members,17 the poli- mally submitted to the agency; the publicly available cies of FEMA’s expert panel,18 and guidance from the Euro- information is incomplete. Third, our analysis of conflicts of pean Food Safety Authority’s advisory panels.19,20 To minimize interest was limited to the employment of individuals who and manage conflicts of interest, an essential first step is for jamainternalmedicine.com JAMA Internal Medicine December 9/23, 2013 Volume 173, Number 22 2035 Copyright 2013 American Medical Association. All rights reserved. Downloaded From: http://archinte.jamanetwork.com/ by a University Of Connecticut Health Center User on 06/02/2015 Research Original Investigation Conflicts of Interests in Food Additive Approvals the FDA to require that it be notified of all GRAS determina- lic all notifications of GRAS determinations, including those tions and the financial conflicts of interest of those who make made by the FEMA panel, and all the information that it re- these determinations. The agency should routinely make pub- ceives about conflicts of interest in these determinations. ARTICLE INFORMATION 3. Food Additives Amendment of 1958. Pub L No. 14. US Food and Drug Administration. Serious Accepted for Publication: July 18, 2013. 85-829, 72 Stat 1784. concerns over alcoholic beverages with added 4. Government Accountability Office. Food Safety: caffeine. November 2010. www.fda.gov Published Online: August 7, 2013. /ForConsumers/ConsumerUpdates doi:10.1001/jamainternmed.2013.10559. FDA Should Strengthen Its Oversight of Food Ingredients Determined to Be Generally Recognized /ucm233987.htm. Accessed March 25, 2013. Author Contributions: Mr Neltner had full access as Safe (GRAS). February 2010. Publication No. 15. Institute of Food Technologists. The Certified to all the data in the study and takes responsibility GAO-10-246. www.gao.gov/products/GAO-10-246. Food Scientist (CFS) credential. www.ift.org for the integrity of the data and the accuracy of the Accessed March 25, 2013. /certification.aspx. Accessed June 6, 2013. data analysis. Study concept and design: Neltner, Krimsky, Bero. 5. O’Reilly JT. GRAS Roots: How to Advocate for 16. US Food and Drug Administration; Financial Acquisition of data: Neltner, Alger. and Defend “General Recognition” of Safety for Disclosure by Clinical Investigators. Financial Analysis and interpretation of data: Neltner, Alger, Food Ingredients and Drugs. Washington, DC: Food disclosure by clinical investigators—FDA: final rule. O’Reilly, Krimsky, Bero, Maffini. and Drug Law Institute; 2009. Food and Drug Law Fed Regist. 1998;63(21):5233-5254. Drafting of the manuscript: Neltner, Krimsky, Institute Monograph Series: Vol. 1, No. 2. 17. US Food and Drug Administration. Guidance for Maffini. 6. Neltner TG, Kulkarni NR, Alger HM, et al. the public, FDA advisory committee members, and Critical revision of the manuscript for important Navigating the US Food Additive Regulatory FDA staff on procedures for determining conflict of intellectual content: Neltner, Alger, O’Reilly, Krimsky, Program. Compr Rev Food Sci Food Safety. interest and eligibility for participation in FDA Bero, Maffini. 2011;10(6):342-368. advisory committees. 2008. www.fda.gov Administrative, technical, or material support: 7. 21 USC §321 and §348. /downloads/RegulatoryInformation/Guidances Neltner, Alger, O’Reilly, Krimsky, Maffini. /UCM125646.pdf. Accessed July 10, 2013. Study supervision: Neltner. 8. 21 CFR §170.3(i). 18. Flavors and Extracts Manufacturers Conflict of Interest Disclosures: Mr Neltner and 9. 21 CFR §170.30(a). Association. FEMA Expert Panel Conflict of Interest Mss Alger and Maffini are employees of The Pew 10. HR Report No. 2284, 85th Congress Second Protections and Procedures. http://www Charitable Trusts. No other disclosures were Session. Washington, DC: Congressional Record; .femaflavor.org/gras#conflict. Accessed July 10, reported. 1958:4-5. 2013. Funding/Support: This work was supported by The 11. Lo B, Field MJ, eds; Committee on Conflict of 19. European Food Safety Authority. Policy on Pew Charitable Trusts. Interest in Medical Research, Education, and Independence and Scientific Decision-Making Additional Contributions: Erik D. Olson, JD, Practice, Board on Health Sciences Policy, Institute Processes of the European Food Safety Authority: provided general guidance and reviewed the of Medicine of the National Academies. Conflict of executive summary. 2011. www.efsa.europa.eu/en manuscript. Neesha R. Kulkarni, JD, provided Interest in Medical Research, Education, and /keydocs/docs/independencepolicy.pdf. Accessed analysis and writing assistance. Erin D. Bongard, Practice. Washington, DC: National Academies March 25, 2013. MS, provided editing assistance. Liz Fuller-Wright Press; 2009. 20. European Food Safety Authority. 2012. was the consultant for checking facts. 12. US Food and Drug Administration. About Decision of the Executive Director implementing FDA—ethics. www.fda.gov/AboutFDA EFSA’s Policy on Independence and Scientific REFERENCES /WorkingatFDA/Ethics/default.htm. Accessed Decision-Making Processes regarding Declarations 1. Institute of Food Technologists. Explore our March 25, 2013. of Interests. www.efsa.europa.eu/en/keydocs/docs areas of focus... food additives. 2013. 13. US Food and Drug Administration. GRAS notice /independencerules.pdf. Accessed March 25, 2013. www.ift.org/knowledge-center/focus-areas inventory. www.accessdata.fda.gov/scripts/fcn /product-development-and-ingredient-innovations /fcnNavigation.cfm?rpt=grasListing. Accessed /food-additives.aspx. Accessed March 25, 2013. March 15, 2013. 2. 21 USC §321. Invited Commentary Conflicts of Interest in the Regulation of Food Safety A Threat to Scientific Integrity Marion Nestle, PhD, MPH Conflicts of interest in medical research, education, and prac- guidelines produced by the IOM focus on financial connec- tice are well known to increase the risk of undue influence by tions with industry, largely because such connections are easier corporate sponsors. Because conflicts of interest are so preva- to monitor than other conflicting interests, such as career ad- lent and troublesome, the Institute of Medicine (IOM) was vancement or personal favors.1 asked to develop guidelines Although conflicts created by financial relationships with for dealing with them. An drug and device companies have been a source of concern for Related article page 2032 IOM committee reviewed the decades, concerns about the effects of food company spon- substantial body of evidence demonstrating that financial ties sorship on nutrition research, practice, and policy are more re- with pharmaceutical and medical device companies influ- cent. Nevertheless, financial ties with food and beverage com- ence prescribing practices; the opinions of experts; and the de- panies are now recognized as influences on federal dietary sign, conduct, and interpretation of research studies. The guidelines, opinions of nutrition professionals, and the inter- 2036 JAMA Internal Medicine December 9/23, 2013 Volume 173, Number 22 jamainternalmedicine.com Copyright 2013 American Medical Association. All rights reserved. Downloaded From: http://archinte.jamanetwork.com/ by a University Of Connecticut Health Center User on 06/02/2015