Evaluating emerging issues in epidemiology

Regulatory Toxicology and Pharmacology 48 (2007) 296–307 www.elsevier.com/locate/yrtph

Evaluating emerging issues in epidemiology

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James J. Collins a, John A. Bukowski b, Douglas L. Weed c,1, Robert L. Brent d, Patti Klein e, Mariette Boerstoel-Streefland f,2, J. Michael Sprafka g, Amy Lavin Williams h, Michael P. Holsapple i,* a The Dow Chemical Co., Midland, MI 48674, USA WordsWorld Consulting, Centerville, OH 45459, USA c The Weinberg Group, Washington, DC 20036, USA d Thomas Jefferson University, Wilmington, DE 19899, USA e Dow Corning Corporation, Midland, MI 48686, USA f Forest Laboratories Inc., Jersey City, NJ 07311, USA g Procter & Gamble Pharmaceuticals, Mason, OH 45040, USA h Noblis, Falls Church, VA 22042, USA ILSI Health and Environmental Sciences Institute (HESI), One Thomas Circle, NW, 9th Floor, Washington, DC 20005, USA b

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Received 4 April 2007 Available online 14 April 2007

Abstract Industry and government institutions need a credible approach for evaluating and responding to emerging public health issues. Representatives of industry, government, and academia met under the auspices of the International Life Sciences Institute’s Health and Environmental Sciences Institute (HESI) to develop successful strategies for dealing with emerging issues based on historical case studies. The case studies chosen for evaluation were (1) tampon use and toxic shock syndrome; (2) hazardous waste and childhood cancer risk in Toms River, New Jersey; (3) fenfluramine and phentermine use and valvular heart disease; (4) silicone breast implants and cancer and auto-immune disease; and (5) progestational drugs and birth defects. We identified eight lessons from these case studies. Foremost, we recommend that public and private institutions not defer action until an issue is scientifically resolved and stress that cooperation among issue stakeholders is critical for effective issue resolution. We suggest establishing a research program as an effective way to assure that good science is included in resolution of the issue. We further recommend frequent and timely communication with all stakeholders, and the development of research approaches to fill gaps when the scientific data on an issue are limited.  2007 Elsevier Inc. All rights reserved. Keywords: Causality; Epidemiology; Evidence; Policy; Risk assessment; Risk communication

1. Introduction

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Disclaimer: This paper contains the personal views and observations of the authors who do not purport to speak for, or represent the views of their employers. * Corresponding author. Address: ILSI Health and Environmental Sciences Institute (HESI), One Thomas Circle, NW, 9th Floor, Washington, DC 20005, USA. Fax: +1 202 659 3617. E-mail address: [email protected] (M.P. Holsapple). 1 Work done while at NCI. 2 Work done while with Organon International. 0273-2300/$ - see front matter  2007 Elsevier Inc. All rights reserved. doi:10.1016/j.yrtph.2007.04.002

Preliminary scientific results suggesting an association between an exposure and disease may eventually prove to be valid or not. In the interim, a response is often required of both government and industry. The broad range of responses can include the following: no action, watchful waiting, additional research, or, in some cases, immediate public health action. These decisions may have profound impact on the health of the public, perception of public health risk, choice among competing public health priorities, and costs to industry and the economy.

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Accepted guidelines for responding to such situations, what we refer to as ‘‘emerging epidemiological issues’’ are not available. Existing interpretative methods, such as criteria-based qualitative methods and the more quantitative approach of meta-analysis, are valuable tools (Hill, 1965; Rothman et al., 1998; Weed, 2000), but may not be useful when the body of available scientific evidence is small as in emerging issues. Approaches for dealing with disease ‘‘clusters’’ have been developed (CDC, 1990), but these approaches are preliminary investigations meant to precede formal study, and have demonstrated limited ability to isolate causal associations (Caldwell and Heath, 1976; Rothman, 1987; Schulte et al., 1987). Industry and government institutions alike would benefit from a coherent and defensible approach for evaluating and responding to emerging issues. The available observational evidence may be scant, consisting of a single analytic epidemiological study, a few descriptive studies, and/or a series of case studies. Evidence from toxicology and other laboratory sciences may or may not be available, may be of variable quality or applicability, and may be only available to certain parties (e.g., unpublished studies). In these situations, the pressures on institutions to intervene may nevertheless be quite strong. The purpose of this paper is to examine this problem, and make recommendations that may help organizations improve their responses. Under the auspices of the ILSI Health and Environmental Sciences Institute (HESI), a group of scientists from academia, industry, and government was convened to discuss how best to approach and evaluate emerging issues in epidemiology in order to assure protection of public health. The group looked for successful strategies based on a review of historical case studies to provide insights on how such issues might be handled better in the future. 2. Methods We selected five historical case studies which the authors were familiar with and were of high public and scientific visibility, and where epidemiological data played an important role in their discovery and ultimate resolution. The five case studies are: (1) tampon use and toxic shock syndrome; (2) hazardous waste and childhood cancer risk in Toms River, New Jersey; (3) fenfluramine and phentermine (Fen-Phen) use and valvular heart disease; (4) silicone breast implants and breast cancer or autoimmune disease; and (5) progestational drugs and birth defects. We briefly review these case studies to explore the amount and strength of the evidence available at the decision point, determine how government organizations and industry responded to that evidence, and discuss our ultimate assessment of those responses. For each case study, keywords were searched in Medline, Toxline, LexusNexus, Current Contents, Dissertation Abstracts Online, The U.S. Food and Drug Administration (FDA) website, and various internet search engines. Personal reprint collections related to the case studies, unpublished reports, and references identified in selected review articles were also utilized. For each case study, background information related to the emerging issue is presented and the point is emphasized when the emerging issue called for immediate action by regulatory agencies or affected industries. This point is subsequently referred to as the ‘‘flashpoint.’’ We also discuss the scientific evidence related to potential associ-

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ations of the agent with the health effect of concern, both before and after the flashpoint. Approaches for dealing with emerging issues in these case studies were developed based on a critical analysis of the commonalities and differences, and the subsequent public health and economic impacts.

3. Case studies The five historical case studies are summarized in Table 1 and discussed below. 3.1. Tampon use and toxic shock syndrome 3.1.1. Background Toxic shock syndrome (TSS) was first described in a 1978 report of seven children with fever, rash, vomiting, diarrhea, low blood pressure, and abnormal laboratory tests. Staphylococcus aureus was isolated from these patients, leading to the suggestion that a staphylococcal toxin was the causative agent (Todd et al., 1978). In January 1980, the Wisconsin and Minnesota health departments reported 12 cases of TSS in adult women (Shands et al., 1980). The Centers for Disease Control and Prevention (CDC),3 in cooperation with state health departments, began informal surveillance and published a summary of all 55 cases reported between October 1979 and May 1980 (CDC, 1980a,b,c). All but three cases were in young women; seven women died. 3.1.2. Flashpoint The flashpoint occurred in May and June of 1980, when reports were published on the recent adult cases (CDC, 1980a,b,c), and on tampon use as a risk factor (CDC, 1980a,b,c). Intense nationwide publicity ensued and the CDC promised Congress that it would ‘‘have the answer by the end of the year’’ (Etheridge, 1992). 3.1.3. Evidence at the flashpoint There was a strong association between TSS and both menstruation and tampon use. In the CDC surveillance summary published in May 1980, 38 of 40 patients (95%) for whom a menstrual history was obtained had onset of illness within five days of the onset of menses (CDC, 1980a,b,c). S. aureus was isolated from the vagina in twothirds of women, but it was not known at the time if this rate was unusually high. A retrospective nationwide case– control study published by CDC in June 1980 implicated tampon use as a risk factor (CDC, 1980a,b,c).

3 Abbreviations used: ATSDR, Agency for Toxic Substances and Disease Control; C–C, case–control; CDC, Centers for Disease Control; CHD, congenital heart defects; CI, confidence interval; CTD, connective tissue disease; ECG, electrocardiograph; FDA, U.S. Food and Drug Administration; LRD, limb reduction defects; NJDHSS, New Jersey Department of Health and Senior Services; NTD, neural tube defects; P&G, Procter & Gamble Company; RR, relative risks; SBI, silicone breast implants; TSS, toxic shock syndrome.

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Table 1 Overview of issues including evidence available when the flashpoint occurred, the immediate impact, and the current scientific opinion of the issue Evidence available before flashpoint

Flashpoint (regulatory decision)

Immediate impact

Evidence available after the flashpoint

Current scientific consensus

TSS from tampons

– TSS case reports WI, MN, CDC – CDC C–C study June, September 1980 – Utah C–C study September 1980 – Traces of TCE and TetraCE in ground water – Incr. childhood cancer rates – Case reports – Uncontrolled ECG survey (30% preval.)

– Press releases – Discussions with P&G (Rely) – Label warnings 1981

– $75 Million lost sales – Litigation

– – – –

– Association apparently real, but not specific to Rely – Rules on absorbency promulgated

– 1995—epidem. study planned (NJ/ ATSDR) – 1996—C–C study initiated – July 1997—FDA issues med. alert – September 1997— FDA requests w’drawal – 1992—FDA calls for three week moratorium on SBI sales – Product liability lawsuits

– Additional remediation some wells – Study did not allay fears – Litigation

Internal epi studies (Rely) Microbiology studies (Rely) Joint press releases with FDA September 1980—Rely tampons withdrawn (85% off shelves within one week) – Provided comments on government study – Laboratory studies

– Estimated >$14 billion litigation costs – Stock value drops

– Product withdrawn September 1997 – Communicate via letter to MDs and full-page ads

– Valvular heart disease confirmed, but <<30% prevalence

– $millions in litigation costs – $billions in settlement to women with CTD – Dow Corning, Bioplasty bankruptcies – Worry/stress – Unnecessary surgery – Numerous ‘negligence’ lawsuits against obstetricians and pharmaceutical companies – Marked change in the use of sex steroids by Physicians

– – – –

– No increased risk for breast cancer or autoimmune disorders (independent reviews by IOM, UK IRG, NSP, American College of Rheumatology) – Health Canada and US FDA approve SBI in 2006 – FDA report removing the warning on progestins, and indicating that they cannot be considered to all be the same – Litigation continues, but to a lesser extent

Water contamination and risk of childhood cancer at Tom’s River, NJ FenPhen and heart valve disorders

Silicone breast implants (SBI) and breast cancer and autoimmune/ connective tissue diseases (CTD)

– Case reports – Media allegations

Non-genital (heart, limbs and brain) congenital malformations from exposure to progestional drugs during pregnancy

– Few small case control studies reported an association with malformations in 1960s and 1970s – One cohort study. No syndrome was identified.

– 1977—FDA issued a box warning indicating that there was an association in separate studies of progestins with limb defects and congenital heart disease

of

Laboratory studies Cancer epidemiology studies CTD epidemiology studies Litigation handled case-by-case

– Large cohort and case control studies (not able to verify the original associations) – FDA hearings 1987 – Warning on oral contraceptives removed

– No overall association with cancer – Odds ratio 5.0 for girls exposed to one well

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3.1.4. Evidence after the flashpoint The Utah Health Department reported to CDC that a new super-absorbent tampon, Rely, manufactured by the Procter and Gamble Company (P&G), had been used by a number of TSS patients. However, the methodology of the CDC case–control study limited examination of TSS in association with particular brands (CDC, 1980a,b,c; Harvey et al., 1982; Hulka, 1982; Schlech, 1982; Etheridge, 1992). Accordingly, a second CDC case–control study on 50 new TSS patients was conducted (CDC, 1980a,b,c; Harvey et al., 1982; Hulka, 1982; Schlech, 1982; Etheridge, 1992). All 50 patients used tampons, compared with 124/ 150 matched controls. Among persons using only one tampon brand, Rely tampons were used by 71% of 42 patients and 26% of 114 matched controls. For four other tampon brands, use in controls exceeded use in cases. A smaller Minnesota study also reported more Rely use in cases (35%) compared to controls (18%) (CDC, 1980a,b,c; Harvey et al., 1982; Etheridge, 1992; Hulka, 1982; Schlech, 1982). The CDC study also documented the association with S. aureus, which was isolated from 43/44 (98%) of appropriately cultured TSS patients, vs. 4/55 (7%) of unmatched women.

warnings about TSS and advising women to use tampons with the minimum absorbency required to control menstrual flow (Donawa et al., 1984). CDC national surveillance indicated that TSS cases, which had risen sharply beginning in the fall of 1979, peaked in August 1980 and declined dramatically after September 1980 (CDC, 1981).

3.1.5. Resolution After meeting with P&G representatives, the FDA and CDC issued a joint press release on September 17, 1980, announcing that use of Rely tampons was associated with an increased risk of TSS. This announcement generated extensive media publicity. On September 19, 1980, the Morbidity and Mortality Weekly Report published the conclusions of the second CDC study, and the Utah Department of Health announced the results of their study, which also showed an association of TSS with Rely tampons (CDC, 1980a,b,c). On September 22, 1980, P&G issued a press release announcing that the company would voluntarily suspend the sale of Rely tampons. In reaching this decision, P&G relied on a report from an external scientific advisory group. This group reportedly concluded that there was no ‘‘direct evidence’’ to link Rely tampons more closely to TSS than with any other tampon brand, but that the results of the latest CDC study could not ‘‘safely be ignored ’’ (Rotbart and Prestbo, 1980). At a meeting on September 23, 1980, the FDA requested additional steps, including a national educational campaign and the buying back of unused Rely tampons. Under a consent agreement, the company undertook the above measures, but denied that the Rely tampon was defective or violated any federal laws. The P&G campaign to withdraw 400,000 cases of tampons involved letters to approximately 340,000 retailers and the mobilization of many P&G staff. Within a week, about 85% of the Rely tampons had been removed from stores. The company lost $75 million, not including product liability lawsuits. A new study published in June 1981 suggested that the risk of TSS increased with tampon absorbency. In June 1982, FDA published a regulation requiring tampon label

3.2.2. Flashpoint In 1995, the NJDHSS completed an ecological study, which found high rates of childhood (ages 0–19) brain and central nervous system cancers in the Tom’s River section of Ocean County where most of the groundwater contamination occurred (NJDHSS, 1997). Testing of well water, including the Parkway well, in 1996 found additional contaminants not previously discovered, some of which were potential carcinogens (NJDHSS and ATSDR, 2001a,b). Reacting to community concerns about groundwater contamination and the results of this cancer study, the ATSDR and NJDHSS developed a research plan in cooperation with all stakeholders. The plan included an update of the ecological cancer incidence study, an extensive exposure evaluation of both water and air, and a case–control study. Other actions included the shutting down of additional wells, improvements in public wells, and declaration of the site as a ‘‘public health hazard.’’

3.2. Community cancer concerns in Toms River, New Jersey 3.2.1. Background In 1974, residents of Dover Township in Ocean County, New Jersey, complained of unusual tastes and odors associated with water from private drinking wells near a new industrial waste site (NJDHSS and ATSDR, 2001a,b). This region had a history of groundwater contamination and poor air quality going back to the 1960s (ATSDR, 2001). In 1986, water contamination was discovered at a well field (the Parkway well), and treatment to remove volatile organics was installed by 1988. The public health implications of this contamination and the poor air quality could not be determined at the time because of limited information on the levels and toxicologic properties of the contaminants.

3.2.3. Evidence at the flashpoint The ecological study of community cancer rates and the pollution found in some wells made up the information available before the flashpoint. 3.2.4. Evidence after the flashpoint The updated cancer incidence study was completed in 1997, with results quite similar to those reported in 1995 (NJDHSS and ATSDR, 2001a,b). Total childhood cancer relative risks (RR) were 1.1 (95% CI 0.9–1.2) and 1.7 (95% CI 1.1–2.5) for Ocean County and Toms River, respectively. The RR for childhood brain cancers were 1.2 (95% CI 0.9–1.5) and 10.0 (95% CI 2.0–29.2), respectively. Leukemia rates were also greater than expected in

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Toms River (RR = 8.0, 95% CI 2.1–20.5), but were at expected levels in Ocean County (RR = 1.0, 95% CI 0.8–1.3). The exposure evaluation study, which was used to reconstruct historical exposure estimates for the case–control study, concluded that chemicals in the groundwater had resulted in exposure of residents in Toms River and the rest of Dover Township (ATSDR, 2001; Richardson et al., 1999; NJDHSS and ATSDR, 2001a,b; NJDHSS et al., 2003) The case–control study, completed in 2003, found ‘‘no association . . . in overall leukemia or brain and central nervous system cancer groupings,’’ for drinking water from any of the well systems with suspected contamination (NJDHSS and ATSDR, 2001a,b). However, for one well system, the Parkway well, prenatal exposure for children diagnosed before age five produced a RR of 4.2 (95% CI 1.1–15.0) for leukemia and nervous system cancers in the highest exposure category. However, there was a protective association in the medium exposure category (RR = 0.1, 95% CI 0.0–0.6) for these causes. No association was seen for females or males with postnatal exposure from this well. The study concluded that, ‘‘although no associations were detected in analyses of the overall study population, a statistically significant association and consistency in multiple measures of association were seen between prenatal exposure to time-specific Parkway well field water and leukemia in female children of all ages’’ (NJDHSS and ATSDR, 2001a,b). Associations were also observed for some cancers and ambient air exposure. 3.2.5. Resolution Public health agencies, the local municipal drinking water company, and involved industry reacted to the concerns of community residents and elected officials by reducing the exposure to drinking water contaminants, closing contaminated private wells, and conducting health studies. The NJDHSS is continuing to monitor exposures and cancer rates. The costs of investigations, additional water clean-up of the site, changes to community water supplies, and litigation were considerable. Although, these studies and cleanups have raised health concerns around drinking water in the community, it is still unclear what role, if any, the contaminated water has had in the historically higher cancer rates among children in the area. There also remains community concern about air quality. 3.3. Fen-Phen use and the risk of valvular heart disease 3.3.1. Background Obesity has been related to several chronic health conditions, and drug therapies for treatment of obesity are still extremely limited. The drugs fenfluramine and phentermine were approved in the U.S. in 1973 and 1959, respectively, as individual agents for short-term use in the medical treatment of obesity. Their use in combination for extended treatment periods (known as the ‘‘Fen-Phen’’ regimen) has never been approved in the US, but has been widely

practiced for long-term treatment of obesity. Reported adverse events associated with the combined use of these anorexiants include abnormalities of mitral, aortic, and tricuspid valves resulting in valvular regurgitation (Conolly and Et, 1997). Other purported adverse events, such as primary pulmonary hypertension, will not be discussed in the current review. 3.3.2. Flashpoint The FDA alerted physicians in July 1997 after reviewing a series of 33 reports of valvular heart disease among women using Fen-Phen. A subsequent electrocardiographic survey suggested that as many as 30% of patients were affected, which prompted FDA to request immediate withdrawal of these drugs from the market on September 15, 1997. 3.3.3. Evidence at the flashpoint The FDA concluded that no definite statements about an association of valvular regurgitation with Fen-Phen use could be made, based on the 33 case reports of valve abnormalities in women who took the drug combination for an average of 12 months. The FDA recognized that the information from the electrocardiographic survey came from pooled data rather than a formal clinical investigation, making interpretation difficult given the absence of controls. 3.3.4. Evidence after the flashpoint Subsequent studies and publications confirmed the association with valvulopathy, but at a lower prevalence than initially reported. A systematic review of the available literature described 57 randomized controlled trials, seven observational studies, and seven controlled electrocardiographic surveys (Loke et al., 2002). The prevalence estimates averaged approximately 20% in the observational surveys, but only 6% in the controlled trials. No cardiac complaints were identified in the randomized controlled trials involving over 5100 patients, suggesting that overt signs or symptoms of cardiomyopathy were not apparent. 3.3.5. Resolution The actions taken in this case were rapid and protective of public health although the initial studies overestimated the risk. The aftermath for both patients and manufacturers is ongoing. Most cases of valvular disease were mild or moderate and generally did not require valve repair or replacement. Follow-up studies have suggested no further worsening, and in some cases, improvement of valvulopathy after drug discontinuation. However, it is unknown if some patients will suffer serious clinical sequela (Hensrud et al., 1999; Seghatol and Rigolin, 2002). For the pharmaceutical defendants, the litigation aftermath has been enormous. In 1999, American Home Products announced a $3.75 billion settlement of lawsuits immediately following drug withdrawal, and set aside $14 billion for future costs.

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3.4. Silicone breast implants and cancer or auto-immune disease 3.4.1. Background Silicone-gel breast implants (SBI) came on the market during the early 1960s for reconstructive and cosmetic purposes. No systemic health effects were reported over the next 10–20 years, although it became generally known that silicone could leak from these products and cause granulomas and lymphadenopathy (Travis et al., 1985; Warner et al., 1991). The adverse outcomes subsequently alleged to have been caused by SBI include a variety of systemic health problems including diverse cancers, assorted connective tissue diseases (CTD), health effects in children of mothers using the devices, and non-specific signs and symptoms. Breast cancer and CTD (in particular, scleroderma or systemic sclerosis) represent the focus of the current discussion since both were prominent in the controversy. 3.4.2. Flashpoint When an FDA Panel convened in 1991 to review more than 300 studies provided by SBI manufacturers regarding disease risk and material safety, there was already considerable public, media, and political pressure to act. The Panel concluded that the submitted data provided insufficient evidence on the risks and benefits of SBI. In early 1992, the FDA Commissioner called for a voluntary moratorium on the use of SBI, emphasizing that this action was taken because of insufficient scientific data to support their continued use. The FDA Panel later reconvened and concluded that no causal link had been established between SBI and auto-immune disease, but that epidemiological studies should be instituted to assess the risk of autoimmune disease and that further use of SBI should be limited to reconstructive surgery (Connell, 1998). 3.4.3. Evidence at the flashpoint Implant manufacturers helped fund the first formal epidemiology study of breast cancer in 1982. Results were initially presented in a doctoral dissertation, then published in 1986, and updated in 1992 (Deapen et al., 1986; Deapen and Brody, 1992). Subsequent studies were also completed (Glasser and Lee, 1989; Berkel et al., 1992; Birdsell et al., 1993). Relative risks in all of these studies were near one, suggesting no association between SBI and cancer. Beginning in the 1960s, a few case reports were published that postulated a relationship between cosmetic injections of a variety of vaguely described materials and auto-immune disease. These reports suggested possible associations with systemic symptoms, so-called ‘‘human adjuvant disease,’’ and a variety of CTD. Additional case reports were published in the late 1970s through 1990, including reports suggesting an association of these conditions with SBI (Uretsky et al., 1979; Van Nunen et al., 1982; Baldwin and Kaplan, 1983; Kaiser et al., 1990). Human adjuvant disease, a relatively non-specific, poorly defined condition predicated on the presence of foreign material in the breast, was not useful

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as a diagnosis in etiologic research. Early epidemiological studies published in the late 1980s, therefore, addressed various other CTD, finding no elevated risk among women with breast implants (Weisman et al., 1988). There was little early mechanistic laboratory data (Kossovsky et al., 1993; Press et al., 1992; Teuber et al., 1993). 3.4.4. Evidence after the flashpoint In addition to an increase in laboratory research, the issue generated several larger epidemiological studies by government, academic, industry, and private research organizations (Teuber et al., 1993; Friis et al., 1997a; 1997b; Brinton et al., 2000; Holmich et al., 2003). Most of the research results were summarized in reports by the UK Independent Review Group (Silicone Gel Breast Implants Independent Review, 1998), the National Science Panel (Diamond et al., 1998), and the Institute of Medicine (Bondurant et al., 1999). In general, these reviews supported concerns about local complications and calls for more research, but discounted both the claims of systemic disease and the theories supporting them. Similar conclusions were reached by professional groups (Ferguson, 1997; American Medical Women’s, 1998; American Society of Plastic and Reconstructive Surgeons and American Society for Aesthetic Plastic Surgery, 1998; European Committee on Quality Assurance and Medical Devices in Plastic, 1998) and by regulatory agencies (Australian Commonwealth Department of Health and Family Services, 1998; Health Canada, 1998). 3.4.5. Resolution The issue of breast cancer was resolved relatively quickly based largely on the epidemiology studies, with relatively little litigation or media coverage. A possible explanation for the quick resolution of this issue is that cancer represents a well-defined disease, which could be studied rigorously. CTD were more contentious, probably because disease hypotheses were poorly articulated and the studies took a great deal of time and resources. The accumulating scientific evidence ultimately showed no association between SBI and CTD, but not before theories of harm had been accepted in some courts and media reports. Against this backdrop, a jury in 1991 awarded a woman with implants $7.3 million for CTD. The number of legal cases increased to the thousands and ultimately spawned two multi-billion dollar settlements. In addition to the financial costs to manufacturers from litigation and reduced product use, this issue has undoubtedly produced emotional distress among women with SBI, as well as unnecessary surgeries to remove intact implants. Use of other silicone implants such as testicular, chin, small joint orthopedics, etc., was also impacted. In October 2003, the General and Plastic Surgery Advisory Panel voted in favor of INAMED Corporation’s Premarket Approval Application (PMAA) that would allow silicone gel-filled breast implants to be marketed without restriction while research on the devices continued. In January 2004, however, FDA rejected the advice of its expert

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panel (Young, 2004), and simultaneously published a new guidance document for manufacturers seeking a PMAA for these devices (Food and Drug, 2004). INAMED (now Allergan, Inc.) and Mentor Corporation sought regulatory review and approval from Health Canada as well as US FDA in 2005. After review by these regulatory authorities, silicone gel-filled breast implants were approved in 2006, thus making them available worldwide (Walker, 2006; Foss, 2006). 3.5. Progestational drugs and non-genital congenital malformations 3.5.1. Background Beginning in the late 1960s, there were a number of studies suggesting an association of exposure to various sex steroids in pregnant women with non-genital, congenital malformations in their offspring (Gal et al., 1967; Levy et al., 1973; Nora and Nora, 1973, 1975; Janerich et al., 1974; Heinonen et al., 1977). These malformations included congenital heart defects (CHD), neural tube defects (NTD), limb reduction defects (LRD), and vacteral association (Nora and Nora, 1975). During this period, drugs with estrogenic and progestational activity were being utilized clinically for multiple purposes such as bleeding during pregnancy, pregnancy diagnosis, threatened abortion, and contraception. A significant proportion of the pregnant population during the 1960s and 1970s had exposures to sex steroids (Oakley et al., 1973). 3.5.2. Flashpoint Based on the results of these epidemiology studies, the FDA in 1977 required package-insert warnings for progestational drugs, and contraceptives containing progestational drugs, stating that LRD and CHD occurred more frequently in the offspring of exposed mothers. These warnings referred to an association of sex-steroid exposure with the occurrence of birth defects, but indicated that a definitive conclusion on causality had not been reached. 3.5.3. Evidence at the flashpoint By 1977, there were several published studies reporting an association between exposure to sex steroids during pregnancy and the occurrence of CHD, NTD, and LRD (Gal et al., 1967; Levy et al., 1973; Nora and Nora, 1973,1975; Janerich et al., 1974; Heinonen et al., 1977). However, these findings were not consistent for any specific exposure-malformation association. There were also much larger studies indicating no association, as well as criticism of some of the studies on which the FDA based their 1977 warning (Laurence, 1972; Lancet, 1974; Wilson and Brent, 1981; Michaelis et al., 1983; Katz et al., 1985; Resseguie et al., 1985). 3.5.4. Evidence after the flashpoint During the late 1970s and 1980s, a large number of epidemiological studies on this topic were published. Most

did not demonstrate an association of progestin exposure with CHD, NTD, or LRD, and none described a ‘‘progestational non-genital organ teratogenic syndrome’’ (Check et al., 1958, 1986; Peterson, 1969; Spira et al., 1972; Oakley et al., 1973, 1998; Mulvihill et al., 1974; Greenberg et al., 1975; Yasuda and Miller, 1975; Goujard and Rumeau-Rouquette, 1977; Janerich et al., 1977, 1980; Smith et al., 1977; Bracken et al., 1978; Rosenfield, 1978; Rothman and Louik, 1978; Vessey, 1978; Janerich, 1979; Matsunaga and Shiota, 1979; Oakley, 1979; Rothman et al., 1979; Ferencz et al., 1980; Czeizel et al., 1981; Darling and Hawkins, 1981; Savolainen et al., 1981; Torfs et al., 1981; Michaelis et al., 1983; Rosenfield et al., 1983; Wiseman and Dodds-Smith, 1984; Katz et al., 1985; Resseguie et al., 1985; Rock et al., 1985; Yovich et al., 1985; Lammer et al., 1986; Pardthaisong et al., 1988, 1992; Gray and Pardthaisong, 1991; Pardthaisong and Gray, 1991; Czeizel and Kodaj, 1995). A number of published reviews and meta-analyses of this literature also did not support an association and concluded that progestational drugs did not produce non-genital malformations (Chez, 1970; Ambani et al., 1977; Keith and Berger, 1977; Nocke, 1978; Briggs et al., 1979; Schardein, 1980; Benagiano and Fraser, 1981; Smithells, 1981; Wilson and Brent, 1981; World Health Organization Scientific, 1981; Aro et al., 1984; Kallen et al., 1984; Stakeman et al., 1984; Scialli, 1988; Brent, 1989, 2005; Bracken, 1990; Raman Wilms et al., 1995; Conolly and Et, 1997). 3.5.5. Resolution An FDA Committee addressed the issue of progestin teratogenicity at a 1987 meeting. The meeting consensus was that the evidence did not support an association between progestational drugs and non-genital malformations (Corfman, 1988). The major arguments were inconsistent epidemiology findings, no time trend of effects with increased steroid use, no findings of non-genital malformations in animal teratology studies (Carbone et al., 1990b,1990a; Carbone and Brent, 1993), the fact that primordia and early limb and heart structures do not contain receptors for progestational drugs (Hochner-Celnikier et al., 1986), and evidence that cases in the positive reports with CHD did not have LRDs and vice versa. Following this meeting, the FDA removed the warning from oral contraceptives. Eleven years later, the warning on non-genital malformations was removed from all progestational drugs utilized in conventional therapeutic doses (FDA, 1999). 4. Discussion The case studies we have selected for discussion represent a broad range of issues with varying amounts of information available at the flashpoint. Each of these cases relied heavily on epidemiology studies for their initiation and eventual resolution. We have provided encapsulated overviews of these issues, but each of these issues is far

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more complex than we are able to show in this paper. The cases are somewhat unique in that they were highly publicized, had potential major health and cost implications, and had a well-defined flashpoint where the science was brought to the public attention and action was required. The actions at the flashpoint in these cases all included initiating more scientific research. They also all called for health interventions (for example, label warnings about TSS and tampons, closed wells in Tom’s River, the institution of a voluntary moratorium on the use of SBI, an FDA withdrawal of Fen-Phen from the market, and placement of a warning on progestins). Based on a review of the case studies, we summarize some useful lessons for dealing with emerging epidemiological issues. Each lesson does not apply universally. However, the lessons represent a toolbox that can be useful in addressing future emerging epidemiological issues. 4.1. Lesson 1: public and private institutions should not defer action until an issue is scientifically resolved Emerging epidemiological issues will generate public and private responses based on incomplete scientific information. The preferred approach for emerging issues should be to use the synthesis of available scientific evidence to make decisions that protect public health, balance societal costs and benefits, and initiate a reasonable path forward toward final issue resolution. Decisions need to be flexible enough to incorporate new information given that the initial response is based on limited evidence and may change as more data and epidemiological studies are planned and completed. While this approach is consistent with an aspect of the precautionary principle, the decision is viewed as temporary until more definitive information becomes available (Foster et al., 2000; Weed, 2004). Further, the principle of ‘‘sufficient certainty’’ as described by Neutra, requires that protective actions not be fixed, but should depend on the severity or the irreversibility of the health or environmental impact (Neutra and Delpizzo, 2002). 4.2. Lesson 2: inconsistent or complex science findings influence the public’s perception of risk While a definitive science answer does not assure that the public will use science to determine the level of risk, simple consistent scientific findings often resolve the issue. Because of the inconsistency or complexity of the science, the time needed to scientifically resolve an issue varies on a case-by-case basis. Some issues are resolved relatively quickly; for example, the case of toxic shock syndrome associated with tampon use was resolved in two years because industry and regulators could agree on the major science findings. However, other issues, such as progestational drugs and non-genital congenital malformations, can take much longer to resolve because of the large number of studies and the lack of consistent findings. The

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length of time to scientific resolution can vary depending on a number of factors, including: (1) the amount and quality of the initially available scientific evidence; (2) how well-defined the endpoint is; (3) whether this endpoint is an acute or chronic effect; (4) the rarity of the endpoint; and (5) the resources available to do the research necessary to determine causation. 4.3. Lesson 3: epidemiological evidence should not be considered in isolation Public and private responses to emerging issues should be based on a synthesis of all available epidemiological, clinical, and laboratory evidence, in order to achieve maximal societal benefit. For example, the laboratory evidence that argued persuasively against progestational drugs as a cause of non-genital birth defects could have helped place preliminary epidemiological results in perspective. The availability of this evidence may have averted the stress and negative health and economic impacts caused by years of unnecessary label warnings. Nevertheless, the public is more comfortable with epidemiology studies rather than laboratory evidence. Thus, any resolution will have to have a strong epidemiology component to convince the public. 4.4. Lesson 4: societal values and public perception may influence the appropriate course of action Societal values and public perception have pivotal roles in the decision-making process and may, at times, overwhelm the scientific data. Even though the scientific evidence argued persuasively against progestational drugs as a cause of non-genital birth defects, these drugs were so widely used that the public’s perception of risk was based solely on preliminary epidemiology studies, which urged action. Failing to issue the label warning may also have caused public stress and loss of public confidence in the product. 4.5. Lesson 5: effective risk communication can decrease public anxiety, protect public health, and limit economic losses The joint press conference held by CDC and FDA on the TSS issue, combined with the massive educational campaign immediately undertaken by P&G, resulted in a rapid decrease in reported cases, as well as rapid product removal from store shelves. These actions, undoubtedly, went a long way in restoring public trust and limiting subsequent negative publicity and litigation. 4.6. Lesson 6: cooperation among industry, regulators, research institutions, public health officials and the public is critical for effective issue resolution Regulatory agencies usually have the means to eliminate or reduce potential exposures while awaiting

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confirmatory evidence. In the case of Toms River, health officials were able to close suspect wells until additional information became available. On the otherhand, industry usually has product or process information that is vital to the health assessment process. In fact, industry is in the unusual position of being viewed by many as the most knowledgeable, but least trusted, source of health information regarding its products and processes (Covello, 1993). Academic research institutions can provide additional scientific evidence, which is perceived by many to possess fewer conflicts of interest than other sources. Involvement of those who believe they are adversely impacted is also important to provide perspective on what information should be developed to best address concerns. In the case of Toms River, the public health response plan included six rules of engagement: (1) find willing participants, (2) set an equal partnership, (3) consider all perspectives, (4) define goals and roles for each stakeholder, (5) consider innovative solutions, and (6) assure scientific credibility (Maslia et al., 2005). Cooperation among these groups will help assure the public that the best science is being brought to bear on an issue, while public health and public interests are being protected. It is realized, however, that cooperation among these groups is sometimes difficult to achieve. 4.7. Lesson 7: the amount spent on research to resolve an issue is often very small compared to the impact on public health and the costs associated with loss of public trust The issues associated with the case studies generated substantial concern among members of the public and huge costs to industry and government. These costs to the public, industry, and government were far greater than any monies spent on research to resolve these issues. A more proactive approach to scientifically resolve these issues before they reached the flashpoint could have resulted in significant benefits to all parties. 4.8. Lesson 8: emerging public health issues provide an opportunity to increase public safety The case studies examined in this paper all dictated specific actions to assure public safety. These visible actions may also have provided an opportunity to increase public safety in other areas; for example, by convincing industry and regulators to promote more epidemiology studies around product safety or take more preventive actions in the marketplace, such as requiring child-resistant packaging for pharmaceuticals. 5. Conclusions and recommendations The above lessons suggest some general recommendations that should maximize the outcome for all stakeholders.

(1) A research program must be perceived by the public as helping rather than delaying resolution of the issue. A research program to address the issue should be the first scientific priority, but thought must be given to how the public perceives this program. Convincing the public of the need for quality data should be the first goal of any research program. This approach may lead, not only to quickly reducing threats to public health, but also to a reduction in the costs and public anxiety associated with extended issue resolution. (2) It is vital to bring all stakeholders together to address issues collaboratively and to collect information needed to resolve the issue. Attempts should be made to bring as many stakeholders together as possible to help resolve the issue, although it should be recognized that this may not be practical in situations in which there is a perceived imminent public health danger. Questions that a group of stakeholders should address include: • How is the issue defined and what are the significant outcomes of concern? • What can be concluded based on the initially available data? • What are the significant data gaps and what research is needed to address them? • What are the necessary steps to bring the issue to resolution? (3) Effective and timely communication is essential. Communications should be delivered by trusted spokespeople, should be in a language that the lay public can understand, should communicate the spectrum of available scientific evidence, and should address both potential risk and societal values as they relate to the perception of that risk. Expert panels may play an important role in obtaining the public’s trust and communicating the science as it relates to the public risk. (4) Limited, inconsistent data associated with emerging epidemiological issues require additional evaluation and follow-up research. Existing causal criteria are open to conflicting interpretation by stakeholders when there are only a few data, or when the data are of limited quality. In these situations, the additional information needed to draw causal conclusions should be established by all stakeholders early in the process and formalized into a research plan that is agreed upon by all stakeholders and widely communicated. This approach has the best chance of providing the data needed to evaluate whether a causal association truly exists. The case studies reviewed in this paper triggered the genesis of an epidemiological toolbox consisting of eight and four general recommendations. Taken together, we believe these points provide the basis for successful strategies on how important public health issues can be more effectively addressed in the future.

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Acknowledgments This paper was authored by participants of the Emerging Issues in Epidemiology Project Committee of the International Life Sciences Institute’s (ILSI) Health and Environmental Sciences Institute (HESI). The authors of this paper acknowledge the contributions of its past participants in the overall analysis of the case studies used in this paper. In particular, the authors thank David M. Bell (U.S. CDC) for contribution of the toxic shock syndrome case study and review of the paper throughout its many revisions, and Steven A. Anderson (U.S. FDA) and Patricia A. Murphy (U.S. EPA) for their input during the writing process. The authors also acknowledge Jerald Fagliano (N.J. Department of Health and Senior Services), Elizabeth Delzell (University of Alabama at Birmingham), and John Acquavella (Amgen) for their critical reviews of the draft manuscript. HESI is a global branch of ILSI, a public, non-profit scientific foundation that brings together scientists from academia, government, industry, and the public sector to solve problems with broad implications for the well-being of the general public. HESI provides an international forum to advance the understanding and application of scientific issues related to human health, toxicology, risk assessment and the environment. HESI is widely recognized among scientists from government, industry and academia as an objective, science-based organization within which important issues of mutual concern can be discussed and resolved in the interest of improving public health. As part of its public benefit mandate, HESI’s activities are carried out in the public domain, generating data and other information for broad scientific use and application. HESI’s programs are supported primarily by its industry membership. HESI also receives support from a variety of government agencies in the US and internationally. Further information about HESI can be accessed at . References Ambani, L.M., Joshi, N.J., et al., 1977. Are hormonal contraceptives teratogenic? Fertil Steril 28, 791–797. American Medical Women’s, Association, 1998. Silicone gel breast implants. J. Am. Med. Assoc. 53, 33–34, 47. American Society of Plastic and Reconstructive Surgeons and American Society for Aesthetic Plastic Surgery, 1998. Joint postion statement: silicone breast implants: Scientific update www.plasticsurgery.org. Aro, T., Haapakoski, H., et al., 1984. Multivariate analysis of the risk indicators of limb reduction defects. Int. J. Epidemiol. 13, 459–464. ATSDR, 2001. Summary of Findings: Historical Reconstruction of the Water-distribution Serving the Dover Township Area, New Jersey: January 1962–December 1996, ATSDR, Atlanta, GA. Australian Commonwealth Department of Health and Family Services, T.G.A., 1998. Breast Implant Information Booklet (second ed.). Baldwin, C.M., Kaplan, E.N., 1983. Silicone-induced human adjuvant disease? Ann. Plast. Surg. 10, 270–273. Benagiano, G., Fraser, I., 1981. The depo-provera debate commentary on the article Depo-Provera, a critical analysis. Contraception 24, 493–528.

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