Areas of concern still relevant 3 decades later
After reviewing Table 1 to identify those suggestions not implemented by FDA and Table 2 to identify those issues that were still relevant in 2011, we consolidated the common issues into 9 broad areas of concern. They are:
- Behavioral impacts;
- Endocrine systems;
- Toxicological insignificance;
- Absorption, distribution, metabolism and excretion (ADME);
- Classifying assessment decisions for consistency and clarity;
- Personal bias and conflicts of interest;
- Reassessment and consistency across substances; and
- Weight of evidence.
Because science has substantially advanced since 1982, the workshops’ participants also raised concerns about FDA's considerations of new scientific developments such as nanotechnology, the interagency Tox21 program designed to screen chemicals for potential toxicity, and biomonitoring. However, we did not include these issues in our analysis since they did not exist at the time of SCOGS.
Additionally, there was an overarching issue that concerned workshop participants: the lack of definitions of “harm” or “adverse effects” in FDA rules and public guidance documents. Participants noted that this gap resulted in FDA interpreting adverse effects on a case-by-case basis, an approach considered less than predictable (Maffini and others 2011). In contrast, other agencies dealing with chemical safety, such as the U.S. Environmental Protection Agency (EPA) (EPA 2013) and the Joint World Health Organization/Food and Agriculture Organization Expert Committee on Food Additives (JECFA) have formal definitions of adverse effects (IPCS 2011). We did not include this issue as an area of concern; rather, we briefly mentioned discussions about harm or adverse effects in the context of the areas of concern Behavioral impacts and Endocrine systems.
Below is a detailed discussion of the 9 areas of concern listed above.
At the time SCOGS was reviewing GRAS substances, a pediatrician proposed that some children may have heightened susceptibility for certain additives in the diet that are manifested by hyperactive behavior and some brain dysfunction (Feingold 1975). The proposal prompted scientists and physicians to gather evidence suggesting that artificial colors and flavors, as well as other additives, in the diet influence the behavior of some children (Weiss 2012).
With this scientific debate as a backdrop, SCOGS recommended that FDA develop guidelines for behavioral testing concluding that
“[m]uch effort is needed in the development of animal tests of relative simplicity that may provide quantifiable and reproducible information on behavioral effects in animals at the levels of intake relevant to human exposure.” It stated that to answer whether “foods and food ingredients” may cause or aggravate some behavioral disorders, the development of such tests “should command a far more aggressive attack than it has up to now,” concluding that “a firm foundation can then be achieved within the next decade or two.”
Participants at the Pew workshops (Maffini and others 2011) raised similar issues stating that:
- A definition for what constitutes harm in the context of behavioral impacts is needed;
- Existing screens do not detect more subtle effects on the structural or functional integrity of the nervous system, such as learning, memory, anxiety, or hyperactivity; and
- Animal tests need to be better designed to reflect complex human behaviors.
They also noted that, although there are many endpoints listed in the Redbook, they capture “obviously abnormal behavior” and “will not detect more subtle effects.”
The current Redbook Neurotoxicity Studies guidance (FDA 2000) recommends a flexible, tiered approach, based on a case-by-case assessment of the available toxicity information of a given compound. FDA recommends performing a systematic clinical evaluation of animals used for basic toxicology testing to include endpoints such as seizure, tremor, paralysis, or other signs of neurological disorder; the level of motor activity and alertness; and any other signs of abnormal behavior or nervous system toxicity. It also recommends conducting a pathological examination of the brain, spinal cord, and peripheral nervous system (FDA 2000). Finally, it suggests that “[a]s appropriate, more sensitive and objective indices of neurotoxicity, such as tests of learning and memory, and quantitative measures of sensory function and motor behavior, could be included as part of the screen” (FDA 2000); however, there are no endpoints or tests recommended.
During the Pew workshops (Maffini and others 2011), FDA scientists noted that “the cost and efficiency of some of these studies have precluded the inclusion of testing for some of the more subtle aspects of behavior” into the guidelines. However, others have reached different conclusions.
During the 1980s, EPA promulgated regulations describing how to conduct behavioral and developmental neurotoxicity testing, respectively, and adopted specific behavioral tests for learning and memory. In the late 1990s, EPA updated its toxicology data requirements for pesticides used on food (40 CFR Subpart F 158.500). It established screening tests that rely on a semiquantitative evaluation of a functional observational test. It includes evident behavior endpoints and requires developmental neurotoxicity tests.
Similarly, the Organization for Economic Co-operation and Development (OECD) has published a guidance document for neurotoxicity testing (OECD 2004) as well as guidelines (OECD 1997, 2007) to be used in chemical testing programs. For OECD, behavioral testing and endpoints provide “one of the most sensitive strategies to reveal subtle functional deficits,” adding that “behavioral endpoints can uncover alterations in neural or extraneural substrates for which no compensatory alternate behavioral response is available.” Its guideline (OECD 2007) provides details of study design, frequency of observations, and endpoints, including a section on learning and memory tests.
In summary, FDA has not aggressively pursued the development of test methodologies for behavioral impacts. It has not incorporated into its Redbook methods that EPA and OECD adopted years ago.
Hormones have been known for hundreds of years to play fundamental roles in basic physiological functions. This understanding led to the development of drugs to manipulate the endocrine system either by correcting problems such as low levels of hormones or by blocking natural hormones from acting in target organs. Furthermore, scientists have shown that some man-made chemicals, not specifically designed to affect human health, can also bind to hormone receptors and trigger agonistic or antagonistic biological effects. Similarly, these chemicals can also interfere with the synthesis or the breakdown of hormones. Chemicals with such actions are called endocrine disruptors (Wingspread Conference 1992).
Recognizing the potential for additives to affect the endocrine system, SCOGS said:
“Recent advances of knowledge on specific tissue receptors disclose additional potential targets for chemical effects or competitive interactions of an added substance with endogenous messengers. For example, in the case of estrogenic hormone receptors and an agent with a high-binding affinity for the receptor, modification of hormonal response might occur at very low concentrations of the agent. While reliable tests of such effects are not currently available, it can be expected that a number will be developed in the future. These tests might indicate unusual binding affinity of agents that cause certain teratogenic effects or influence reproductive or growth patterns by interactions with the relevant hormonal receptors regulating these physiological processes.”
As predicted by SCOGS, in the last 2 decades, scientists have produced a large body of research results on endocrine disrupting chemicals (Arbuckle and others 2008; Woodruff and others 2011; Vandenberg and others 2012).
Participants at the Pew workshops (Maffini and others 2011) identified several issues regarding FDA's handling of endocrine disruptors, including:
- Disagreement on what should be considered an adverse effect and its relevance to human health;
- Difficulty in selecting health-related endpoints such as biomarkers that could predict disease outcomes;
- Disagreement over whether current Redbook tests and endpoints are sufficiently sensitive and encompass significant modes of action, including those important during early life or that become apparent long after exposure; and
- Agreement on the need to understand ADME for endocrine disruptors.
We did not find evidence that FDA acted on or attempted to address SCOGS’ suggestion. Its scientists have maintained that the studies recommended in the Redbook (such as multigenerational reproductive and developmental testing) can and do provide valuable insights into potential endocrine activity due to the possible manifestations of adverse effects (Lorentzen and Hattan 2010). Although open to the possibility of using alternative methods, FDA has yet to recommend that stakeholders use available screening tests for endocrine disruption.
By comparison, other offices at FDA have acted on endocrine disruptors. In the mid-1990s, the agency initiated the Endocrine Disruptor Knowledge Base (EDKB) project (FDA 2010b) with the intention “to serve as a resource for research and regulatory scientists to foster the development of computational predictive toxicology models and reduce dependency on slow and expensive animal experiments” (Ding and others 2010). The project resulted in the development of the EDKB database, which is based on quantitative structure-activity relationships coupled with an integrated system of experimentation and modeling that predicts biological activities. These core features underwent a “rigorous validation” (Tong and others 2002) via the interagency agreement with EPA. The free database currently includes more than 1,800 chemicals, of which more than 200 are allowed in foods.
EPA has also developed and validated screening tests for endocrine disruptors. In response to a 1996 Congressional mandate (Food Quality Protection Act of 1996 P.L. 104-170. 21 U.S.C. 346(a)(p); Amendment to the Safe Drinking Water Act of 1974. 42 U.S.C.§ 300j-17, 1996), in 2009, the agency launched its Endocrine Disruptor Screening Program (EPA 2012), making available test guidelines for validated in vitro and in vivo assays. FDA has expressly rejected the use of at least one of these assays despite the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) determining the assay was validated as “a screening test to identify substances with in vitro ER [estrogen receptor] agonist or antagonist activity” (Birnbaum 2012). FDA responded that “ICCVAM test recommendations are not acceptable for satisfactorily fulfilling the test needs for FDA regulated products” and that “FDA does not envision a use for this method in its current regulatory framework” (Goodman 2012). EPA (Sanders 2012) and the Consumer Product Safety Commission (Hinson 2012) have accepted the new test, and OECD added it to its guidelines (OECD 2012).
Lastly, a battery of new tests and predictive tools to identify potential endocrine disruptors is being developed and undergoing validation within the Tox21 program. The program is a collaboration of FDA, EPA, and the National Institutes of Health “to use robotics technology to screen thousands of chemicals for potential toxicity, use screening data to predict the potential toxicity of chemicals, and develop a cost-effective approach to prioritizing the thousands of chemicals that need toxicity testing” (EPA 2012). The Office of Food Additives Safety joined the intergovernmental project when it was underway; it has nominated chemicals to be tested, and provided toxicological data from its files.
In summary, FDA has not taken a leadership role in the development and validation of new technologies to identify and evaluate additives for potential endocrine disrupting activity. Unlike EPA, it has not adopted or made use of validated screening tests and predictive models.
SCOGS made it clear that, during the safety evaluation of additives, regulators must pay particular attention to susceptible populations. The committee identified these groups based on age, gender, and physiologic state (adolescence, pregnancy, lactation), and noted that groups with specific food preferences and individuals with chronic diseases should also be taken into consideration. It said:
“When the benefits are related not to health, but to organoleptic, technologic, or economic considerations, substantial risk even to a relatively small subgroup of the population is not generally acceptable. A major need in future food safety evaluations is the identification of the population subgroups at special risk, and the extent of the risk.”
Participants at a Pew workshop (Alger and others 2013) noted that, while FDA currently considers one subpopulation (young children), it should include more groups on a routine basis. Participants mentioned that EPA regularly assesses exposure for a wide variety of subpopulations.
FDA routinely assesses exposure for all people aged 2 y and older as one group, as well as children between ages 2 and 5 y as another. It calculates exposure by identifying all of the foods in which the substance will be added, the amount in each food, and the quantity of food consumed by individuals in the United States. The estimated daily intake of an additive is then calculated based on the amount consumed by the so-called “high” consumer represented by the 90th percentile of the people who eat the food containing the chemical (FDA 2006a). For infant formula, the agency uses an approach tailored to infants likely to be fed the formula (FDA 2004). It evaluates other subpopulations on a case-by-case basis.
SCOGS was especially concerned about individuals hypersensitive to food and food additives and described nonspecific cutaneous, gastrointestinal, respiratory, immunologic, and neurologic manifestations as adverse reactions to additives. Although the most common allergens are proteins and peptides found in common foods (for example, soy, nuts, milk, and seafood, as well as gluten-containing food products), certain chemicals commonly used as food additives (such as sulfites) also cause adverse reaction in some individuals. SCOGS wanted FDA to take a proactive role saying that “advances [in cell biology and clinical immunology] may aid in the development of simpler and more reliable procedures for the detection of hypersensitivity.”
FDA only dealt with hypersensitivity in the context of genetically engineered plants. The 1992 policy (FDA 1992) encouraged developers of new plants to consult with FDA early in the genetic engineering process.
EPA also lacks guidance to test for hypersensitivity. In 2011, the European Food Safety Authority released draft guidance underscoring the need for hypersensitivity testing (EFSA 2011).
In summary, FDA has not systematically considered the exposures to sensitive populations except for infants. For hypersensitivity, it has not developed any guidelines to screen or test for potential impacts or offered an effective system for consumers to report health impacts.
“[T]he arbitrary establishment of a concentration at or below which no hazard exists is scientifically untenable. Failure to observe an adverse effect when a substance is widely used for a long time in uncontrolled, casual human applications is insufficient reason to pronounce it safe even at very low levels. The concept of toxicological insignificance ignores the possibility of accumulation in tissues of slowly excreted compounds that may be carcinogenic, teratogenic, or mutagenic. The concept also fails to take into account the possibility of a slow irreversible functional alteration in vital organs.”
Pew workshop participants raised similar concerns (Maffini and others 2011).
Contrary to SCOGS’ suggestion, in 1995 FDA created the Threshold of Regulation rule, which exempts substances used in food contact materials from regulation as food additives if the dietary concentration is below 0.5 parts per billion (ppb) (FDA 1995) and if:
- The chemical has not been shown to be a carcinogen;
- There is no reason to suspect that it is a carcinogen; and
- There is no evidence that it presents other health or safety concerns.
This threshold was calculated based on the carcinogenic potency of known carcinogens (Gold and others 1984), and “the assumption that carcinogenicity is ordinarily the most sensitive toxic endpoint” (Cheeseman and others 1999).
FDA makes extensive use of thresholds for food contact substances including a 4-tier scheme based on estimated cumulative exposures to define minimum recommended toxicology studies (FDA 2002). Except for the 1st tier, which is based on the rule discussed above, it is unknown how the other tiers were developed and whether those thresholds have been reviewed to ensure that they are sufficiently protective of public health.
FDA scientists (Cheeseman and others 1999) and supporters of the concept of the threshold of toxicological concern (Kroes and others 2000) (as it is known in the European Union and JECFA) claim that the “safe dose” based on cancer endpoints provides an “adequate margin of safety” for noncancer endpoints such as neurotoxicity, developmental, or reproductive toxicity, and endocrine disruption. Interestingly, FDA scientists recommended that “members of the endocrine disruptors” class that tested positive in the Ames assay be excluded from threshold of regulation exceptions because “the broad class of endocrine disruptors includes many structures most closely identified with carcinogenicity through a mechanism involving hormone modification” (Cheeseman and others 1999).
Although the concept of thresholds is greatly supported by regulators (Cheeseman 2005; EFSA 2012) and the regulated community (Felter and others 2009), the reasoning behind the levels set by FDA does not reflect current scientific understanding (CDC 2012; Vandenberg and others 2012) and relies heavily on expert judgment (Munro and others 1996; Cheeseman and others 1999).
In summary, contrary to SCOGS’ suggestion, FDA has adopted thresholds in rules and guidance below which industry is not expected to develop toxicity data when evaluating the safety of a chemical.
Absorption, distribution, metabolism, and excretion (ADME)
Understanding the fate of a chemical that enters the human body should be the logical 1st step in assessing its safety. SCOGS stated that:
“[I]f a substance is to be used in food for human consumption, controlled evaluation in human subjects is necessary. To assure the safety of such evaluation, a stepwise approach is required: initial testing in animals to establish a safe level for limited testing in humans, determination of the profile of metabolism and pharmacokinetics in man, choice of animal models most appropriate to the human and testing these models, and final controlled observations on human subjects consuming the substance under the proposed conditions of use in the food supply.”
Participants at the Pew workshop noted that ADME data are necessary, especially for nano-sized additives and endocrine disruptors (Maffini and others 2011). Experts have also pointed out that ADME information can improve the characterization of potential health risks (McLanahan and others 2012).
Despite this evidence, FDA does not require ADME data for substances assigned to the lowest concern level (FDA 1993). It expects ADME data for the 2 higher levels. Although the agency's public statements seem to support the importance of ADME (Aungst 2012), it has not updated its ADME guidance since 1993. Since GRAS is the primary mechanism to allow direct additives in food over the last decade (Neltner and others 2011), we checked whether the notices submitted to FDA contained ADME data. We found that 50% of 22 randomly selected GRAS notifications, about which FDA did not raise questions, did not submit any ADME data.
EPA and the WHO's International Programme on Chemical Safety (IPCS) have highlighted the benefits of using physiologically based pharmacokinetic (PBPK) modeling (EPA 2006) to “facilitate more scientifically sound extrapolations across studies, species, routes, and dose levels” (WHO 2010).
In summary, FDA's guidance allows industry to make safety decisions without the detailed ADME data necessary to understand how the human body handles and eliminates chemicals that may be in food.
Classifying assessment decisions for consistency and clarity
SCOGS boiled down almost all of its GRAS safety assessment conclusions into 5 types. Paraphrasing the committee's language, they are:
- Type 1: Safe and unlikely to warrant future review
- Type 2: Safe, but warrants monitoring for significant increases in consumption
- Type 3: Uncertainties exist that require additional studies
- Type 4: Adverse effects reported with insufficient evidence to be found safe
- Type 5: Insufficient evidence to be found safe
The committee acknowledged that assigning conclusions to these 5 types was a challenge for scientists but said it was necessary to avoid “the tendency of cautious scientists to qualify and ‘write around’ rather than make hard choices.”
Workshops participants expressed concerns about the limited amount of data to make informed decisions and generally agreed that methods are needed to identify and fill gaps in toxicology and exposure data (Maffini and others 2011; Alger and others 2013).
In 1981, FDA scientists (Smith and Rulis 1981) acknowledged SCOGS’ approach and paired the 5 types with possible FDA regulatory action. However, we could not find evidence in the rules, publicly available notices, guidance documents, and Web pages that the agency considered using SCOGS’ conclusion types beyond the Smith and Rulis article.
Because FDA lacks a means to efficiently track significant increases in consumption (Neltner and others 2011), it may have rejected Type 2. In contrast, the Flavor and Extract Manufacturers Assn. essentially puts all of its decisions in Type 2 requiring members to report every 5 y their production levels of GRAS flavors; if the level doubles, the association's expert panel reassesses its decision and may remove the chemical from its GRAS list (Hallagan and Hall 2009).
Other science-based agencies such as the National Toxicology Program and EPA also use a classification system to rate scientific evidence used in chemical evaluation and risk assessment.
Types 3 and 4 would require additional testing. In the 1970s, FDA developed regulations that approved chemicals on an “interim basis pending additional study” (21 CFR Part 180) and FDA conditionally approved 4 chemicals under these regulations. No chemicals have been approved on an interim basis since 1982.
In summary, FDA does not assign its safety conclusions to one of the 5 SCOGS conclusions. It maintains that it approves only chemicals that SCOGS would conclude are safe and unlikely to warrant future review and rejects chemicals that SCOGS would assign to one of the 4 other conclusion categories. The agency does not have a system to reassess the safety of existing chemicals.
Personal bias and conflicts of interest
SCOGS’ members understood that personal leanings and scientific perspectives play an important role during the assessment and warned FDA to consider what it called “extra-scientific factors.” Today, we would call it personal bias. SCOGS said that the “principal sources of subjective variability among evaluators are:
- Personal leanings concerning what constitutes ‘safety;’
- Differences in perception of what constitutes adequacy of data by the same individual for different situations;
- The degree to which scientific popularity (the ‘conventional wisdom’) is an influence; [and]
- Personal weighting of the significance of adverse findings based on unconfirmed studies and/or less than rigorous experimentation.”
SCOGS recognized that even when personal bias is carefully managed, there are advantages of using 2 additional methods to minimize it: peer review and transparency.
Pew workshop participants were also concerned about the lack of transparency on how FDA “makes safety determinations, the data it uses and does not use, and how regulatory decisions are made” (Maffini and others 2011). They noted that “greater transparency in FDA processes would improve predictability and access to information” while acknowledging that companies that invest in safety studies may want a period of competitive advantage before data are made publicly available (Alger and others 2013).
FDA scientists in attendance pointed out that greater transparency could bog down the approval process, but perhaps more important is “the need for independent review and to shelter reviewers from influences outside and inside the agency. This works against transparency but is absolutely required for a science-based process” (Maffini and others 2011).
Regarding advisory panels, FDA uses 2:
- Science Board (FDA 2013b): In recent years, committees of the Board have addressed 2 specific issues that were relevant to food safety at FDA: the safety of bisphenol-A (FDA 2008) and the agency's scientific capacity (FDA 2007). The latter led FDA to launch its Advancing Regulatory Science initiative (FDA 2011).
- Food Advisory Committee (FDA 2012): From 2002 to 2004, the committee considered food additives issues such as acrylamide, allergens, and biotechnology. Since 2004, the committee has met only twice (FDA 2013a).
FDA can also make use of peer reviewers. In 2004, the White House's Office of Management and Budget established that “important scientific information shall be peer reviewed by qualified specialists before it is disseminated by the federal government” (Bolten 2004). Safety assessments are scientific information. The policy states that reviewers must comply with conflict of interest requirements, the review process must include public participation, and the agency must prepare a written response to the peer-reviewed report.
Despite these requirements for agency staff, there are no comparable ones for scientists conducting GRAS safety assessments for food manufacturers, especially where the firm does not notify FDA of the decision. This issue was underscored in 2010 by the U.S. Government Accountability Office (GAO) who concluded that “FDA's oversight process does not help ensure the safety of all new GRAS determinations” (GAO 2010). It also recommended that FDA adopt a rule or guidance to prohibit conflicts of interest for the assessors. Later that year, the agency requested comments on whether it should issue guidance on the subject (FDA 2010c).
In summary, FDA has largely implemented SCOGS’ suggestions on personal bias and conflict of interest for its employees and the safety assessments it makes. However, the agency has not addressed the issue for food manufacturers that make their own determination.
Reassessment and consistency across substances
Looking at the future, SCOGS posed 2 related questions that are still relevant:
“How should a regulatory agency treat new information in its review of food ingredients, especially involving a potential reversal of a standing approval? Should there be any differences with respect to the burden of proof of safety in borderline cases from that employed in the original approval for use in foods?”
Pew workshop participants noted that chemicals need to be reassessed in light of new scientific knowledge and changes in exposure over time. They acknowledged that “it is not practical to reassess all substances and uses immediately” but suggested that FDA should “develop a science-based framework to prioritize and reassess prior safety decisions” (Alger and others 2013).
FDA reassesses additive safety on a case-by-case basis when it identifies a potential public health concern. A recent example involved its decision to ban the use of caffeine in alcoholic beverages (FDA 2010a) because “the combined ingestion of caffeine and alcohol may lead to hazardous and life-threatening situations.” In instances where the public health risk is not that obvious, it is unclear how the agency uses new information to review safety decisions. FDA may also initiate reassessment in response to a citizen petition (Dorsey 2012) or a manufacturer's notification to expand uses of an existing chemical.
Regarding consistency of decisions across substances and agencies, SCOGS advocated for “consistency in rationale,” which suggests “comparability in approach in safety evaluation beyond all food ingredients to all substances ingested by human beings, including drugs and environmental pollutants.”
Pew workshop participants generally agreed “on the importance of including all dietary sources in the exposure assessment so that it accurately represents what a person may actually be exposed to” (Alger and others 2013).
FDA's approach to dietary exposure is to consider all dietary sources to which the additives are added. However, it does not consider tap (drinking) water and pesticides, and there is limited coordination between agencies that regulate the same chemical for different uses (Alger and others 2013). Also unclear is whether it considers other sources such as dietary supplements and naturally occurring substances. In 2007, the National Research Council's (NRC) “Science and Decisions: Advancing Risk Assessment” report (NRC 2007) recommended that exposure assessments should include all sources from which a chemical enters the human body. Although the report was addressed to EPA, it broadly applies to substances regulated across agencies and reflects the spirit of SCOGS’ “consistency in rationale.”
In summary, FDA has not developed a system to prioritize its review of previous safety decisions. Instead, it relies on a case-by-case approach. In addition, it does not appear to closely coordinate its hazard or exposure assessment with EPA when a chemical is regulated by both agencies.
Weight of the evidence
SCOGS understood the varying quality among studies, whether published or not, and noted that assessors should be cautious. It said that “[t]he credibility of a given set of data is increased by its reproducibility and by its coherence with other data within the overall pattern of the organismal response.”
Pew workshop participants (Maffini and others 2011) noted that:
- It is important to incorporate multiple endpoints and tests in a weight-of-evidence determination;
- Consistency of evidence across different studies and laboratories should be favorably compared to the reproducibility of individual studies; and
- Assessment of the weight of the evidence should consider the evidence for harm and no harm across all available studies.
When confronted with multiple studies, FDA uses 8 criteria to weigh the evidence (Maffini and others 2011) derived from a compilation of Redbook, OECD, EPA, and WHO guidelines.
How the criteria are applied depends upon professional judgment. FDA does not seem to use a systematic review framework in which the assessor documents and justifies each decision, such as the Cochrane Reviews. This system is designed to facilitate decision making using stringent guidelines to establish whether or not there is conclusive evidence about a particular question (Cochrane Collaboration 2013). As a result, FDA's analysis raises concerns of reproducibility and predictability.
In summary, FDA maintains it closely scrutinizes all available studies. However, its analysis is often based on professional judgment without using the available methods to compare various studies in a more rigorous, transparent, and reproducible manner.