Evidence on determinants of prices for orphan medicines is scarce and not available for Italy. The aim of this paper is to provide an evidence on variables affecting the annual treatment cost of orphan drugs in Italy, testing the hypothesis of a negative correlation with the dimension of the target population and a positive correlation with the added therapeutic value of the drug and the quality of the evidence of pivotal studies.Drugs with a European orphan designation reimbursed in Italy in the last 6 years (2014–2019) were considered. Univariate, cluster analysis and multiple regression models were used to investigate the correlation between the annual treatment cost and, as explanatory variables, the dimension of the target population, the existence of Randomized Clinical Trials as a proxy of the quality of the pivotal studies, the added therapeutic value.In the univariate analysis prevalence and added therapeutic value, as expected, have a negative and positive correlation with cost respectively. The correlation with RCT is not significant. In the multivariate model, coefficients for prevalence and added value are confirmed but for the latter are not significant anymore. We also found, through an interaction analysis, that the existence of an RCT has a positive impact on annual treatment cost when the target population is very small.Our results suggest that value arguments and sustainability (dimension of the target population and its impact on budget impact) issues are considered for orphan drugs pricing: the role played by sustainability is systematically supported by our results. A more transparent and reproducible price negotiation process for orphan drugs is needed in Italy. This paper has contributed to highlight the implicit drivers of this process. Market access for pharmaceuticals in Italy is regulated by the Italian Medicines Agency (AIFA) and the Regions.Price and reimbursement (P&R) for new medicines and indications are negotiated by AIFA and the relevant company on the grounds of a dossier. This dossier is sent by the company after the publication of the European Commission Deliberation . The dossier includes information on the target disease (target population and disease severity), the level of unmet need, the added therapeutic value, the impact on pharmaceutical budget , and prices in other countries , 2.Pharmaceutical companies may also apply for the innovativeness status for their product/indication, in parallel with P&R. AIFA provides for full or conditional innovativeness (or may reject the request). Full innovativeness status provides the relevant medicine/indication with some advantages from an access perspective. These advantages consist of two dedicated funds  and immediate patient access at the regional level. For other medicines clinicians should wait for the inclusion into the regional formulary, if any, to prescribe the drug for the target population. The latter advantage is provided also in the case of conditional innovativeness. The criteria to get innovativeness status are the unmet therapeutic need, the added therapeutic value, and the quality of the evidence . To apprManaged Entry Agreements (MEAs), including discounts, financial-based agreements (e.g. price–volume agreements), and outcome-based agreements (e.g. performance-linked reimbursement) are extensively used in P&R negotiation –8. MEAs Patients may also benefit from two early access programs covered by the Italian National Health Service, i.e. medicines reimbursed before approval. The first one concerns medicines for which there is evidence at least from phase II studies, showing favourable clinical efficacy and safety data in settings where there are no valid therapeutic alternatives or the existing alternatives are more expensive. The second one regards orphan medicines and other medicines for rare diseases and severe diseases .Once the P&R process is concluded, the actual access of the drug depends on Regions, which are accountable for the health care budget. The Regional Governments have implemented different pharmaceutical policies. These policies include binding regional formularies, cost-sharing, guidelines on drug procurement, direct distribution of drugs by hospitals, clinical governance and prescription targets, regulation of information and advice provided by pharmaceutical companies’ sales representatives .In 2019, orphan medicines accounted for 5.6% of public pharmaceutical expenditure in Italy . Their mOrphan drugs share also the same rules of other medicines to get innovativeness status; however, it has been stated that medicines for rare diseases may be recognized innovative also with a low quality of evidence  since thFinally, regional policies are applied to orphan drugs as well as other medicines: e.g. there is no accelerated pathway for the inclusion of orphan medicines into the regional formularies.The empirical evidence on variables influencing orphan drug prices is quite scarce. There is some evidence showing a price–volume trade-off, with higher prices for orphan versus non-orphan drugs  and ultrThe aim of this paper is to investigate the determinants of orphan drugs annual treatment cost in Italy, where the empirical evidence is limited to the role played by the disease prevalence , 16. OurMedicines covered by the analysis are the ones that obtained European orphan designation  and have positively concluded their reimbursement procedure in Italy over the last 6 years (2014–2019). The information system in AIFA did not allow us collecting data for previous years. If the drug had more than one indication, the first one in order of approval time was considered; if two or more indications were approved simultaneously, two or more observations were used for the analysis if the annual treatment costs were different (due to different dosages per indication). If the annual treatment costs were the same, we considered the indication with the highest prevalence.The dependent variable is the orphan medicine annual treatment cost. The annual treatment cost was calculated on the grounds of the net price (i.e. including hidden discounts and the expected impact of outcome-based managed entry agreements), dosage and treatment schedule reported in the Summary of Product Characteristics - SmPC (including loading dose), one year of treatment duration unless a shorter time is envisaged by the SmPC (e.g. for one-shot therapies). If there are different prices for reimbursed presentations , the highest one was chosen. To estimate the impact of financial-based and outcome-based MEAs, the Java program “Plot Digitizer” was used .Three main independent variables were analysed in their impact on the cost: (1) the prevalence of the disease, as it was reported by the pharmaceutical companies in the P&R Dossier; (2) a variable detecting the quality of the pivotal studies, as they were reported on the EPAR document (European Public Assessment Report), i.e. whether they are designed as Randomised Clinical Trials (RCT); (3) the added therapeutic value  as it was graded by the French Transparency Commission  and pubWe could not rely on the Italian evaluation of the added therapeutic value, since it is appraised, graded and reported only for medicines whose marketing authorization holder applies for innovativeness status . The FreOur hypothesis was of negative correlation for the prevalence-cost relation, because of the expected trade-off between the unit price and volumes, while we expected a higher added value to bring higher prices in the negotiation process. Due to its relevance in terms of quality of the scientific evidence produced, we also expected RCT pivotal studies would correspond to higher costs; however, since these characteristics are not officially included in the cost decisional process, we were dubious about its statistical significance. Other data were retrieved from pivotal clinical studies, including the phase in the clinical development process, the primary endpoint , and other elements of the study design . Given the inevitably small sample size of the database, a parsimonious model was preferred, and we decided to focus on the RCT, considering it the best proxy of the quality of the studies.We also collected other data on orphan drugs reimbursement status as control variables, i.e. the year when the price and reimbursement decision was published, the ATC  of the indication (L—Antineoplastic and immunomodulating agents vs others), and the class of reimbursement .Other possible explanatory variables are the availability of alternative treatments (level on unmet need), their prices (that could represent a benchmark for pricing the new comers) and disease severity . We haveFactors influencing the cost were analysed through multiple approaches. The association between each explanatory variable and the cost was firstly observed with graphs of descriptive statistics, together with t-tests and correlation tests. Subsequently, a cluster analysis was run, whose rationale was to identify groups of drugs having specific characteristics  and significantly different levels of annual treatment costs. Given that we treated ASMR as a continuous variable while the same does not hold for prevalence and RCT, we faced a clustering data of mixed types calling for the use of a proper distance metric, such as the Gower distance. Once obtained the dissimilarity matrix, we did clustering from it, using the Partition Around Medoids algorithm. To select the optimal number of clusters we relied on silhouette width approach, an internal validation metric which is an aggregated measure of how similar observation is to its own cluster compared to its closest neighbouring cluster. In a further step, we performed a series of regression analyses: first, we focused on (three) univariate regressions, where only one variable was used; then, we performed one multivariate regression with all the three variables included and another where we added also interaction terms. Eventually, we repeated the analysis with the set of the above-mentioned control variables .The number of orphan drugs that concluded the P&R process in Italy during the period under review is 69, with a maximum of 19 in 2017 and a minimum of 5 in 2014 , with only three drugs having values lower than 3 , and 8 drugs not having that information available.Figure From the cluster analysis, we selected four clusters. Table Table Interesting insights can be gained from regression 5, where an interaction term between the prevalence and RCT was added.2.Results show that when the prevalence is below the median value, costs are higher for RCT-driven orphan drugs Fig. . The oppEventually, we inserted some control variables in regression 6 to control for potential confounding factors, such as the class of reimbursement, ATC level, and reimbursement year. It emerges that some reimbursement years have significant coefficients, while others do not. Even if they do not change the direction of the other coefficients, they do affect their significance and magnitude, as could be expected given the small sample size of the study.The present paper investigated the role played by the dimension of the target population, the existence of an RCT, and the added therapeutic value on the price of orphan drugs in Italy.Most of our findings seem to support the expected results. In general, the higher is the prevalence, the lower is the annual treatment cost, thus confirming a trade-off between prices and the target population, in alignment with previous contributions. It has to be stressed that the analysis relies on estimates of the target population included in the P&R dossier submitted by the relevant company. These estimates are based on the indication for which the company requires the reimbursement, but they do not necessarily coincide with the actual indication covered by the Italian National Health Service. Numbers for the latter, if eventually different from the former, may influence the P&R negotiation, but they are not necessarily available.The added therapeutic value score, as measured by the French ASMR  is, as expected, negatively associated with the annual treatment cost, but its statistical significance disappears, moving from univariate and cluster analyses to multiple regression. It seems that the dimension of the target population (i.e. budget impact considerations) prevails on the added therapeutic value  as a price driver when both are investigated simultaneously.The existence of an RCT, which was used as a proxy of the quality of the evidence, is never significant before introducing interaction with prevalence. The availability of an RCT pivotal study is positively correlated with the costs for medicines targeted to lower prevalence, but this correlation becomes non-significant when the prevalence is higher. This result is quite controversial. On the one hand, RCTs are more complex with low numbers. The choice of carrying out an RCT when the prevalence is low could be considered an important effort towards a higher quality of the evidence, that could be presumed to be correlated with the cost. On the other side, when the prevalence is too low (e.g. ultra-rare diseases) the presence of an RCT could be methodologically implausible and we may expect a negative impact on the perceived value and prices if prices are value-based.variables other than volumes and added therapeutic value played a more important role: e.g. the ATC classification and some others not considered in our study, including the availability of other treatments and the delay between Health Technology Assessment (HTA) and commercialization, are correlated with orphan drugs prices;the French study did not investigate the interaction between explanatory variables, like the one we reported, i.e. RCT and prevalence. This highlighted the interesting, but controversial, finding that the presence of an RCT is associated with higher annual treatment costs when the target population is smaller.Our results seem consistent with other findings. As it was mentioned before our analysis supports the trade-off between annual treatment cost and volumes and the correlation between annual treatment costs and added therapeutic value. Other variables  do not appear to have an impact on prices. It emerges that some reimbursement years have significant coefficients, while others do not. The correlation with reimbursement years could be associated with a tougher approach to cost-containment when this (negative) correlation was found. Findings of the above-mentioned French study  are quitOur study has three main limitations.The first and most important one is the limited number of observations which drove our choice to consider a limited set of explanatory variables. For example, we used RCT as a proxy of quality. We also collected data on other variables that may detect the quality, but we decided to exclude them, either not to lose a degree of freedom (e.g. blinding) or because they are much more discretional . Moreover, as it was mentioned before, other variables included in the above-mentioned French study, like disease severity , were noThe second limitation is that we relied on annual cost estimates, which may underestimate the cost of chronic treatments. The main problem of chronic treatments is that, in most circumstances, their mean duration is not available and we preferred to use annual treatment cost estimates, like other studies .Finally, we relied on the added therapeutic value on the French grades for ASMR whose evaluation is done in comparison with products of the same pharmaco-therapeutic class that are already reimbursed in France. The rationale of this choice was discussed in the ‘Methods’ paragraph: we could not rely on the Italian appraisals on the added therapeutic value, since it is ranked and published only for medicines for which pharmaceutical companies have applied for innovativeness. Innovativeness was appraised for 38% of the medicines/indications included in our analysis, while 67% of appraised medicines got a full or conditional innovativeness status. The added therapeutic value was systematically ranked one grade better in Italy than in France, with most of the minor and moderate added value in France appraised as moderate and important in Italy respectively. As a consequence, the relative position among the candidate products was the same across France and Italy, with the Italian Medicines Agency providing better ranking than the French Transparency Committee regarding the evaluation of the grade of innovativeness.Despite its limitations, this paper provides some important insights into orphan drugs pricing and reimbursement in Italy.Our results suggest that both value-based pricing and sustainability (dimension of the target population and budget impact) issues are considered: the former is supported by a positive association between the added therapeutic value and the annual treatment cost, the latter by a negative association of annual treatment costs with the dimension of the target population. However, the trade-off between prices and expected volumes appears to be supported by the statistical analyses, whereas the positive correlation between added value and annual treatment costs disappears when it is assessed within a multiple regression model. The role played by the quality of the evidence is much more controversial. It seems that those who assess, appraise and negotiate P&R, are aware of the difficulty of providing robust evidence for orphan drugs and less influenced by the quality of the evidence, although we could not rely on a counter-analysis for non-orphan medicines.The literature found that in most European countries orphan medicines undergo the same HTA process of non-orphan drugs : the cur


Love and strong social bonds are known buffers in the experience of adversity. Humans often form strong bonds with non-human animals. The human-animal bond refers to a mutually beneficial and dynamic relationship between humans and non-human animals. Previous research suggests that strong bonds with pets may promote resilience in the experience of adversity, but a strong bond with a pet can also complicate this very experience of adversity, particularly among low-resourced and disadvantaged populations. What is the role of the human-animal bond in adversity, and what is the role of adversity in the bond between a human and a non-human animal? In this article we outline the state of research on the role of various types and sources of adversities in multispecies households  to consider this overarching question. We focus specifically on intimate partner violence, housing discrimination, LGBTQ+ identity-based discrimination, racism, neighborhood disadvantage, and economic inequality. We then outline an agenda for future research about love, adversity, and multispecies relationships, and discuss implications for public policy and community-based interventions. •The human-animal bond may attenuate the deleterious effects of stress on wellbeing.•Adversities can exacerbate stress and thereby challenge multispecies relationships.•Complex questions arise in the interplay between adversity and the human-animal bond. HoweverThe purpose of this essay is threefold: (1) first, we review current theoretical orientations toward explaining relationships between humans and non-human animals. We follow with a working definition, and explanation of our orientation toward the construct of adversity. (2) Next, we review select literature concerning human-pet relationships and adversities in many forms. (3) We set an agenda for future research with the goal of further understanding the myriad ways in which adverse experiences and scenarios may impact people, pets, and their shared bonds within multispecies relationships. We conclude with recommendations for public policy and community partnerships aimed at alleviating some of the adversities faced by multispecies families.2A driving factor of the prevalence of multispecies families is the human-animal bond (HAB), a term defined as the, “mutually beneficial and dynamic relationship between people and other animals that is influenced by behaviors that are essential to the health and wellbeing of both” . It is hOne of the unique characteristics of human-animal relationships is that pets are often perceived by humans as being a reliable, nonjudgmental source of companionship and support, especially in the context of stressful situations or adversity . As a reAt a biological level, bonds between humans and pets are hypothesized to rely on neuroendocrine pathways involving oxytocin and vasopressin, molecules that play critical roles in mammalian emotions and social behavior. In the brain, these neuropeptides act as neurotransmitters and neuromodulators, with important actions in limbic regions and the autonomic nervous system . Both pePendry and Vandagriff provide an important framework from which to understand the biobehavioral mechanisms through which HAI attenuates the stress response system . Buildin2.1The evolutionary and theoretical perspectives outlined above offer insights into the importance of humans' social bonds with non-human animals in the context of adversity. In this article, we use the term adversity to refer to adverse life experiences  that have the potential to influence human development in a way that disrupts typical development, compromises an individual's adjustment, and/or has the potential to lead to undesirable outcomes ,48. AdveAdversity increases an individual's risk for a variety of negative health and social outcomes, such as poor psychological and physical health outcomes and housing and economic insecurity . BroadlyIn addition, adversity may influence the characteristics of the HAB. For example, selective social behavior and strong bonds with pets may form in response to adversity and the perception that one's welfare is dependent on the presence of the other . PositivDespite rapid growth in research and theory regarding the HAB, and benefits of HAI, few studies have considered how HABs contribute to negative emotions, such as fear and stress responses, and how this may impact the stress response system, particularly among populations disproportionately impacted by adversity. Many people live in social environments  that increase their risk of exposure to maladaptive and atypical forms of HAI. In these situations, individuals may experience fear as a result of being exposed to potentially traumatic experiences  or adverse situations  that threaten an individual's ability to maintain a relationship with a beloved pet and/or threaten the welfare of an animal to which an individual is bonded. Given that HAI involves complex, dynamic emotions and behaviors, it is critical that research consider the interplay between positive and negative experiences associated with the HAB, and the ways that multispecies relationships impact, and are affected by, adversity. From a biological perspective, adversity is known to have long-lasting effects on many of the same pathways implicated in the HAB ,63. Howe3In this section we review literature on the interactions between adversity and multispecies bonds, and the resulting impact on people and pets within these relationships. We pay specific attention to the ways that love and fear interact within these multispecies households  to result in greatly varied health and wellbeing outcomes for all household members, including both human and non-human animals. We recognize there are myriad sources and contributors to adversity, as well as responses to them. These adversities range from interpersonal trauma to systemic inequalities, which can interact and accumulate to result in extremely varied and individualized experiences. Additionally, we recognize that individuals and groups are often represented by various social categorizations, which can combine for varied experiences of disadvantage or privilege . Althou3.1Few areas of research demonstrate the intersection of love, fear, and the HAB as effectively as studies on the link between intimate partner violence (IPV) and animal cruelty. IPV is a form of family violence characterized by a variety of behaviors within an intimate relationship that are intended to assert control and power over another individual. These behaviors include psychological, physical, and/or sexual harm by a current or former intimate partner . IPV occAcross studies, it is estimated that 25%–71% of IPV survivors with pets report having experienced violence toward an animal by their abusive partner ,76. FaveNumerous qualitative studies suggest that adult and child survivors of IPV live within a duality of finding support in their bond with a pet while also experiencing chronic fear and guilt about having that bond exploited by their partner ,78. Vict3.2Access to affordable housing in the U.S. is a widespread problem. It is estimated that, as of 2020, over 50% of renters in the U.S. were considered “rent burdened,” which is defined as spending more than 30% of monthly income on rent . HousingThe above issues are reflected in recent studies: pet ownership is a common barrier to finding and maintaining affordable rental housing both within the U.S. and elsewhere. The experience of renting with pets can itself cause perceived feelings of insecurity and instability, sometimes even prompting renters to hide pets from landlords, thereby putting themselves at an increased risk of eviction if the pet is discovered . The effThe problem of renting with pets is especially salient for families and individuals who are already facing other forms of disadvantage, such as discrimination and/or resource constraint. Rental units that restrict pets, or certain types of pets, are more common in disadvantaged communities and communities of color . Additio3.3+“) to demonstrate additional ways in which love for pets and multispecies relationships are shaped by adversity. We also highlight ways in which HAI may operate as a risk and protective factor in the context of sexual and gender minority stress.The dynamic interplay of love, fear, and HABs is also demonstrated in literature on HAI in marginalized populations, such as historically (and currently) underrepresented groups . However, few studies have examined how the experiences of risk and resilience associated with living with pets may be impacted by the unique stressors and sociocultural context faced by individuals who hold marginalized identities . In thisEmerging evidence suggests that the risks and benefits of living with pets may be particularly salient for LGBTQ+ individuals. LGBTQ+ communities experience disproportionate risk for adversity  and a broad range of health disparities which stem from oppressive sociocultural structures and attitudes toward LGBTQ+ people; the experience of navigating cis-heteronormative social contexts and associated stressors is often called minority stress . MinoritSocial support  and belongingness are important factors that promote healthy identity development and resilience in this population  as well Despite these benefits of HAI, the subtle and overt forms of minority stress that are disproportionately prevalent in the daily lives of LGBTQ+ people may make this population more vulnerable to potential hardships associated with pet ownership. The aforementioned qualitative study of 117 LGBTQ+ young adults also found that 90% of the sample reported stress associated with living with or caring for pets  and that these stressors were salient and influential experiences that compromised, or had the potential to compromise, wellbeing via emotional and financial burdens . In thatAlthough pets may be an important source of social support and companionship that can promote resilience in the context of adversity, multispecies families experience unique challenges that have the potential to exacerbate vulnerabilities that result from systemic inequalities. The degree to which bonds with pets may exacerbate vulnerability, particularly in the absence of essential resources is discussed further below. Next, we discuss the degree to which comfort and coping through HAI may be compromised by another form of adversity---racism.3.4We begin this section with a statement regarding our own positionality: the authors of this essay identify as White, therefore, we acknowledge that we cannot fully appreciate nor understand the experience of pet ownership for people of color.Race is a known predictor of pet ownership in the U.S.: according to recent population estimates, approximately 29% of Black individuals in the U.S. own pets, compared to over 70% of White individuals . Some maThe continued oppression and discrimination against people of color is evident in current practices and assumptions within animal welfare, subsequently limiting access to pet ownership for these populations . While pBeyond breed-specific discrimination, communities of color experience disproportionate social control and punishment via institutionalized practices of animal control agencies, in addition to policing . For exa3.5A widely-cited study by Wood and colleagues outlines a potential mechanism for the ways in which pets may be beneficial to health: social capital . Social Spatial context, dubbed “neighborhood effects” in social science, refers to the geographic contextual and ecological factors that influence the social lives of the individuals located within the geospatial bounds . This co3.6Economic inequality shapes the health and wellbeing of all members of multispecies households. Among marginalized and disadvantaged people, the responsibility of pet ownership, and the experience of a bond with a pet, may compete with other priorities for limited resources. This phenomenon creates an extra vulnerability in the face of adversities. Previous studies suggest that economically disadvantaged pet owners will be more likely than other pet owners to risk their own health and safety in order to prioritize their pet(s), particularly when the individual has a strong bond to their pet .Stoltz and colleagues show that dogs have become actors within the “budgetary unit” of American families, therefore the family decision-makers are responsible for considering the dog's wants and needs alongside that of human family members . They asGuenther outlines the concept of “the irresponsible owner,” which Guenther dubs a myth, in The Lives and Deaths of Shelter Animals . Guenthe4Researchers interested in adversity and multispecies bonds face a multidisciplinary field with somewhat disjointed methodological and theoretical traditions. Here we detail three topics we feel warrant additional research, and make recommendations for future directions. We build upon the current state of research outlined in previous sections to investigate the interplay between adversity and the HAB.4.1for whom, under what conditions, and also, why for some and not others? We posit that, in order to get at these questions, researchers must better understand the role of adversity in multispecies relationships. Here we recommend a few avenues of potential exploration. First, we urge HAI researchers to direct efforts toward better understanding HABs in marginalized populations with the goal of exploring the interaction of stressors and supports associated with HAI. It is our belief that a false assumption has been made in considering the effects of HAI to be comparable for all people. This assumption fails to recognize the unique effects of how identity and HAI play out in everyday life. Notably, we are unaware of any research concerning the potential moderating role of comfort from pets on the relationship between experiences of racial or ethnic discrimination and wellbeing among people of color. This topic warrants investigation. Second, there are myriad validated measures concerning constructs like attachment to pets and comfort from pets  howeverets (see ) is usefets (see ) would bets  and the American Society for the Prevention of Cruelty to Animals (ASPCA) have made great strides in the provision of veterinary care to vulnerable communities with the goal of empowering pet owners to maintain the health and welfare of their pets, and also prevent pet relinquishment to shelters. However, questions remain about the lasting impact of these programs, which are often provided on a temporary basis and, due to funding limitations, are not permanent fixtures in their communities. Veterinary care is often expensive; low-income, and even “middle class” pet owners often cannot afford to provide their pets with regular healthcare that is recommended by the veterinary industry. Thinking beyond questions of access and affordability, as veterinary medicine (and the pet product industry) is a business, researchers may find themselves wondering if the concept of idealized pet health maintenance and welfare  is serving pets and their owners. We might ask: does the conceptualization of optimal pet health and welfare unintentionally reproduce racial and socioeconomic inequalities in access to pet ownership? If so, how might we better support marginalized and disadvantaged individuals in ways that serve both pet and owner?4.3The availability of data is integral to research efforts for understanding the role of adversity in human-pet relationships, and more broadly, interactions between pets and people in society. We argue for the inclusion of extensive HAI measures in large, probability-based data collection efforts that allow for generalization to entire populations. Because HAI research has long relied on less rigorous sampling methodology (and quite often nonprobability sampling), entire populations, particularly those who are non-White and/or low-SES, are not represented in the current HAI knowledge base. Along these lines, although rigor in HAI has improved in recent years, there is a crucial need for further longitudinal HAI research, as well as better understanding of pet relationships beyond the simple dichotomy of pet owner versus non-pet owner. Short HAI measures have been included in a handful of large population surveys, such as the General Social Survey in 2018, the Health and Retirement Study in 2012, and the Panel Study of Income Dynamics's Child Development Supplement in 2014 and 2019. However, these HAI measures were overly simplistic and failed to capture the complexity of HABs and HAIs. While they did allow for the investigation of some outstanding HAI questions, they were not administered to full samples, often had a limited availability of correlates due to data structure and survey scope, and had not undergone rigorous psychometric evaluations in diverse populations )5.2Opportunities exist for public policy aimed at alleviating adversities placed on multispecies relationships. First, we recommend the inclusion of pet ownership as a protected status against housing discrimination. As we detail above, many of the barriers faced by multispecies families that in turn force the separation of pets from their people originate in the inability to find affordable rental housing and temporary shelter services that allow pets. We predict that sweeping pet-friendly housing policy will make enormous strides in preserving multispecies bonds, particularly among marginalized communities and those who experience disproportionate adversity. Additionally, communities should encourage the partnering of human social welfare services with those of animal services in order to provide support to the holistic family unit in times of hardship and adversity. For example, the provision of temporary boarding or foster services for pets of individuals who are temporarily unavailable to care for them due to hospitalization or other issues would prevent both the permanent separation of pets from their families, as well as alleviate barriers to entering in-patient healthcare or accessing other services , grant numbers 5R21HD097769-02, 5R01-HD-66503-4, and 1L60HD103238-01. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.Research reported in this publication was supported by the


Food safety is imperative, especially for infants and young children because of their underdeveloped immune systems. This requires adequate nutritious food with appropriate amounts of macro- and micronutrients. Currently, a well-established system for infant food is enforced by the regulatory bodies, but no clear system exists for complementary food, which is consumed by children from the age of 6 month to 24 months. As the child grows beyond 6 months, the need for nutrients increases, and if the nutritional needs are not fulfilled, it can lead to health problems, such as stunted growth, weak immune system, and cardiovascular diseases. Hence, it is important to have regulatory bodies monitoring complementary food in a similar capacity as is required for infant formula. The objective of this review is to provide an overview of the existing regulatory bodies, such as the Codex Alimentarius, International Standard Organization (ISO), Food and Drug Administration (FDA), etc., and their regulations specifically for infant formula that can be adopted for complementary foods. This study focuses on the development of a hazard analysis and risk-based preventive controls (HARPC)-based food safety plan to ensure safe food processing and prevent any possible outbreaks. Nutrition at an early stage of life lays a foundation for the optimal growth and development of the human body. Breast milk is the primary food source for children under the age of six months, but as the child grows older, nutrient needs increase. Hence, a complementary food is required to fulfill all nutritional requirements, including energy, proteins, carbohydrates, fats, minerals, and vitamins . If propIn the recent years, issues concerning contamination, fraud and adulteration of infant formula and complementary food have been reported to have increased . ConsideContamination can occur at numerous points of the food processing stage, i.e., before, during, and after processing. For example, at the point of raw material collection, transportation, cleaning, packaging, etc. Rigorous quality assurance (QA) and quality control (QC) processes can mitigate food safety incidents by having a good understanding of potential sources and routes of contamination . QualityRegulatory bodies are responsible for building laws and regulations to prevent the occurrence of food safety issues . CountriThe objective of this paper is to provide an overview of the current food safety and quality standards required for complementary food. Regulations that exist for infant formula that could be adopted for complementary food. This study focuses on the need for more strict standards and aims to build a food safety plan based on HACCP and FSMA regulations for a nutritious ancient seed/grain-based complementary food product.In the first few months after birth, the child is protected by maternal antibodies, but as the child grows older, the ability of the child to cope with pathogenic microorganisms is still in an emerging stage . Food poCommercially prepared infant formulas and complementary foods are mostly brought in powdered form because it is convenient to use, has a longer shelf life and is easy to store. Hence, these powders are considered to be in the low moisture food category and are more susceptible to the growth of various pathogenic bacteria that can survive in dry and low-moisture environments . FoodborCronobacter spp. and Cronobacter sakazakii are of great public health concern. C. sakazaki is a member of the Enterobacteriaceae family and is a Gram negative, facultatively anaerobic, non-sporulating, motile rod-shaped bacterium. It is responsible for causing outbreaks linked with reconstituted powdered infant formula. It is particularly fatal for infants and creates health complications such as urinary tract infection, neonatal meningitis, sepsis, and seizures [Infections caused by pathogenic seizures ,18.Salmonella, which can lead to death of infants and is the reason behind several outbreaks. This bacterium can cause diarrhea, which can further progress into meningitis or bacteremia. The source of transmission can range from poor hygiene, contamination of raw materials, processing failures or even environmental contamination. There are several recorded outbreaks that are related to Salmonella enterica in countries like Spain, China, France, and Greece. One of the major outbreaks occurred in 2018, wherein 12 million cans of baby milk manufactured by a French company were recalled from over 83 countries [Microorganisms such as bacteria, viruses, and yeast are the major cause of biological hazards. Another major concern for infant food is the growth of ountries ,20.Clostridium botulinum is a reason of concern for infant food, as this microorganism can cause a neuromuscular disorder called botulism. C. botulinum is capable of synthesizing seven neurotoxins, namely A to G, and can cause an imbalance in the intestinal microbiota leading to inflammatory bowel disease. The toxinfection is facilitated by the high pH and a microbiota development process that enables the spores to germinate and produce neurotoxins [rotoxins .Klebsiella pneumonia can be grown in powdered infant formula and is classified as hazard category B. It has the potential to cause nosocomial infections like pneumonia, septicemia and urinary tract infections in individuals who have weak immune systems. The bacterium is strong enough to survive in the stomach environment and protect itself from natural defense cells; it can also resist antibiotics [ibiotics .Staphylococcus aureus. Some of the species of Staphylococcus are capable of producing exotoxins which can suppress the immune response and cause symptoms such as diarrhea, abdominal colic and vomiting. The source of contamination can be failures during processing or reconstitution of the product [Another microorganism harmful for infants that can contaminate infant formula is  product . B. cere product .Presence of any chemical residue, such as pesticides, antibiotics, herbicides, insecticides, sanitizers etc., in food can lead to chemical hazards. These chemical residues should either be in a permissible amount that is set by the regulatory authorities or should not be found in the food product entirely. The sources of chemical hazards include environmental contamination, processing steps, additives, etc. In the case of baby food, heavy metals such as cadmium, lead, arsenic, and mercury are the major cause of concern. Exposure to these heavy metals can lead to severe health issues, such as brain damage, and lung and skin cancer In 2008, 300,000 people reported illness; 860 children were hospitalized, out of which 154 were classified as severe cases due to consumption of substandard milk and infant formula leading to kidney stone formation and kidney failures. The reason for the outbreak was melamine, which was added to formula make it appear that the product was higher in protein content because of its high nitrogen content. Melamine is not approved by food standard commissions. The outbreak prompted authorities to improve the safety standards, such that even low concentration of chemicals should be considered harmful .Physical hazards include the discovery of foreign objects such as broken glass, plastic, stones, wood, or metal in the food product. The sources for physical hazards primarily include glass storage containers, packaging material, equipment, etc. Children are more prone to choking hazards. Physical hazards can lead to cuts in the throat and can also affect intestines . The recThe Codex Alimentarius defines the standards for follow-up formula as food made from either milk of cows or other animals, or from constituents of plant origin. Preparation should be carried out in a way that prevents any possible spoilage and contamination. The regulation describes that the product should be nutritionally sufficient to promote normal growth of the child with the help of essential nutrient contents of protein, fat, carbohydrates, vitamins, and minerals. All ingredients should be of good quality and appropriate for ingestion. The energy content of 100 mL of product should not be less than 60 kcal and should not be greater than 85 kcal. The essential nutrients required for complementary food are listed in The International Organization for Standardization (ISO) is a worldwide organization of national standard bodies. The aim of this organization is to develop standards in cooperation with international industry bodies which are relevant to the market and provide solutions to challenges at the global level. The ISO has strict standards for infant formula, considering its usage for a potentially vulnerable population. The different sections of the regulation mention the range of the essential macro- and micronutrients that should be present in the formula, as well as the appropriate method of quantification, as overviewed in The FDA has no specific requirement for complementary food and includes it in general food products. However, it has robust infrastructure and regulations for infant formula, pertaining to its consumption during the critical period of growth of a child. These regulations, if applied to complementary food, can help prevent all types of hazards which have severe consequences for the health of children.Within FDA, the Center for Food Safety and Applied Nutrition (CFSAN) is accountable for the regulation of infant formula along with the Office of Nutritional Product, Labelling and Dietary Supplements (ONPLDS) and Office of Food Additive Safety (OFAS). The Federal Food Drug Cosmetic Act (FFDCA) is a law that falls under United States Code and gives control to the FDA to manage food, drugs, cosmetics, and medical devices. FFDCA describes infant formula as a food consumed by children less than 12 months old that purports special dietary use for simulation of human milk. Under Section 412 of the FFDCA, prior to the marketing of a new formula, the formula should be registered. Subsequently, the FDA has to be notified if there are any changes in the formula. This section of the FFDCA also describes the responsibility of the FDA to monitor the implementation of all provisions. Every person responsible for either manufacture or distribution of the formula is required to adhere to the requirements stated in the regulation . The codHACCP and FSMA are the food safety systems that enable the development of efficient controls for the production of food products so that there is a minimal occurrence food-related hazard . These fHACCP is a management system that addresses food safety from various aspects. It involves addressing food safety issues by analysis of biological, chemical and physical hazards in all sections of food manufacturing, including growing, harvesting, processing, and distributing . The HACThe preliminary tasks in development of the HACCP plan involves assembling the team, contemplation about the kind of food and its ingredients, and planning for processing and distribution with respect to its targeted consumer and intended use. Assembling the team involves collecting individuals who have the knowledge and experience with the target food product. These individuals have the responsibility to conduct the hazard analysis, identify potential hazards, suggest the controls and critical limits, frame procedures for monitoring and verification, recommend corrective actions and validate the food safety plan. The identified hazards are further categorized into their likeliness of occurrence, i.e., if they are reasonably likely to occur or non-reasonably likely to occur, so as to have relevant corrective steps associated with each hazard.The HACCP plan is formulated as a flow diagram to provide a clear outline of the steps in the production process, which includes steps that occur before and after processing. This plan is approved only after on-site review of the operations for verification of accuracy . Under tThe FSMA was signed on 4 January 2011 with the objective of safeguarding public health by strengthening food safety systems. It gives the FDA new incentives to have the same standards for both imported and domestic food products to build a unified food safety system. It also authorizes preventive controls across the food supply, safety standards for the product, and surveillance of intentional contamination. The law directs the FDA to inspect facilities at regular intervals and to have access to records documenting execution of the food safety plan. It also requires that testing of food products should be done by accredited laboratories to maintain high quality standards. The FSMA also specifies response tools for when problems arise, despite preventive controls, in the form of mandatory recalls and detention of products. The FDA can also suspend the registration of the facility ,43. The On 17 September 2015, the FDA declared Hazard Analysis and Risk-based Preventive Controls (HARPC) as a new food safety regulation. HARPC comes under FSMA in the FFDCA. It is also called the FSMA food safety plan. The HARPC regulation enforces preventive controls to identify potential risks or threats to the food supply so that proper corrective steps could be taken instead of fixing critical limits, as was the focus in HACCP. The regulation covers aspects such as manufacturing, processing, storage and corresponds to preventive control management components, monitoring procedures, corrective actions and corrections, verification, validation, and preparation of recall plans. The manufacturing facility is required to have a written record of a monitoring program for regular evaluation, which should be approved by the FDA to make sure there are no inadequacies. Corrective actions should be implemented if the preventive controls are not properly executed if there are doubts regarding the effectiveness of the food safety plan and if there are discrepancies in the implementation of a food safety plan. HARPC also requires food facilities to propose steps to confirm that everything is operating correctly, and a record of everything should be documented if ever a reanalysis is required. HARPC makes the manufacturing process more transparent, with improved control over suppliers, partners and buyers . The sevThe HARPC plan covers food safety concerns beyond CCPs. HARPC relies on aspects such as FDA regulations, standards and guidance documents for preventive control instead of only process controls. All the regulations in FSMA are grounded in HACCP ,48. The A food safety plan provides a methodical approach for the minimization of food hazards. It directs the activities required for the safety of the food, including manufacturing, processing and storage of the food product. It describes the preventive controls and the actions required for maintaining food safety. A food safety plan includes process controls, food allergen controls, sanitation controls, supply chain controls and recall plans with corresponding documents for monitoring, corrective action and verification steps .For the safe production of complementary food, the first most important task is developing the product description and understanding its essentials, such as packaging type and material, storage conditions, distribution and intended consumers. Development of a flow diagram gives a detailed understanding of the handling of ingredients and processing steps. It shows the in-process control system spread throughout the different stages of production, from acceptance of raw materials to distribution of the finished product. For example, the growing awareness about the health benefits of ancient seed grains like millets, amaranth arebecoming a popular ingredient in baby food products. Millets have high amounts of protein content, B-group vitamins, minerals such as calcium, iron, phosphorous, manganese and magnesium . The proSalmonella and Cronobacter, as both are known to thrive in dry places [The ingredients and packaging material for the food are received from a supplier verified by the FDA and are stored according to the manufacturer’s requirements. The safety of the ingredients and packaging material is evaluated by Office of Nutritional Product, Labelling and Dietary Supplements (ONLPDS) in consultation with Office of Food Additive Safety (OFAS). The FFDCA act mentions that all manufacturers should use safe food ingredients that are generally recognized as safe (GRAS) or are approved as food additives for use in infant formula. The current laws state that a manufacturer is required to provide the FDA assurance of the nutritional quality of the formulation before marketing . The regy places . The ingy places ,55. For Commercial processing has many stages, with consideration for the type of ingredients, quality and application to ensure the highest quality and safety of the food. The process flow diagram in Cleaning is a preliminary operation in production and involves the removal of contaminants from the desired raw material. Processing techniques, such as sorting, grading, screening, dehulling, etc., help in obtaining the uniformity of the raw material. The raw materials are sorted into different categories based on their properties, such as size, shape, weight, and color. For size sorting, various kinds of screens and sieves can be utilized .The period of soaking of ingredients in water varies depending on the kind of grains used. Traditionally, soaking takes about 8–16 h at temperatures ranging from 10 to 25 °C in a steep tank. In this step, there is an increase in moisture content from 15% to 50% .The fermentation process increases digestibility, palatability and the shelf life of the food product. This process increases the protein digestibility and overall nutritional value of the product. It is performed at 30–50% moisture for 24–72 h at 30 °C using an acid-forming bacteria. Changing the temperature, moisture and type of the inoculum alters the pH of the end product .Milling helps in reducing the size of the raw material, which lowers the fiber content and bulk of the material. It also lowers the phytates and tannins.. Milling results in a fine particle product but requires equipment that should be used with extensive technical skills for operation. In wet milling, the particles are added in a liquid, where they undergo processes, such as shearing, crushing and attrition. A mill consists of small beads or spheres which are activated by high-speed agitation, which transmits kinetic energy. When the material is pumped inside, the solids suspended in the liquid are torn apart for size reduction .This procedure is used to evaluate the size distribution or gradation of the material. It is done to remove fine materials that are difficult to sieve prior to drying. Wet sieving applies to solids that are insoluble in water and remain unchanged, even if heated at 110 °C .This step involves evaporation of the milk mixture. This process is important, as it enhances the spray drying operation and increases the shelf life of the final product. Based on the sensitivity of the ingredients, one-stage or two-stage evaporators are used. Excessive processing can also lead to denaturation of proteins .The mixture is dried in a spray-dry system. The spray dryer consists of basic elements, such as an air filter, intake fan, heat source, feed source, feed pump, atomizer, drying chamber, cyclone separator, etc. One of the main advantages of a spray drying operation is the short residence time, which makes it suitable for both heat-sensitive and heat-resistant foods. The temperature of the system has to be kept sufficiently high to achieve maximum efficiency .The primary ingredients are required to be blended together. The ingredients are added to the base liquid, which can either be water or skimmed milk, and are stored in a large vessel for complete hydration. The vessels are mostly large stainless-steel tanks in which the base liquid is first added at a temperature of 60 °C, followed by fats, oils and emulsifiers. Vitamin, minerals and stabilizing gums are added later in the process because of their sensitivity to heat. The pasteurization process helps in protecting against spoilage from bacteria, yeast and mold. It involves heating (85–94 °C for 30 s) and cooling of the product under a controlled condition so that microorganisms cannot survive. Several methods can be utilized for pasteurization, of which the most common would be passing the material through a tube adjacent to a plate heat exchanger, so that the mixture is heated indirectly .Standardization steps make sure that the key parameters, such as the pH, fat concentration and vitamin and mineral content are in proper amounts. If the materials in the formula are insufficient, then the batch has to be reworked so as to reach the optimum level.Clostridium botulinum. A stable and compatible packaging material avoids any kind of physical and chemical damage and extends the shelf life of the product. Depending on the state of the product, packaging is done with materials approved by the FDA. For example, a liquid infant formula is required to be thermally processed in a low-acid package and in a hermetically sealed container. The packaging should be manufactured following the FDA guidance for the preparation of a food contact notification (FCN) for food contact substances (FCS) in contact with infant formula in both liquid and powdered formula. The guidance considers the migration of chemical substances from packaging and other food contact articles.Packaging holds a great deal of importance for complementary food, as it separates the food from the external environment and factors like oxygen, light, humidity, temperature and pathogens. Types of packaging and packaging materials can also cause hazards; for example reduced-oxygen packaging can create an environment that is susceptible to growth of For migration testing, the data should reflect severe temperature/time conditions using different food simulants and should adhere to prescribed toxicology recommendations ,65.CommoAccording to 21 CFR107.10, labelling should be carried out as per Section 201 (z) of the FFDCA. The labelling should include a statement about the number of fluid ounces which provide 100 Kcal and detailed information of the amount of nutrients with prescribed names and units. In addition, a use-by date and directions for use are also required to be added, including aspects such as dilution, storage, etc. .Clostridium botulinum. Sources such as scientific papers, epidemiological studies and data should also be considered in the identification of hazards. The severity of illnesses should be assessed in terms of the probability of the occurrence of a hazard in the absence of preventive controls [Hazard analysis involves the recognition of hazards associated with the food product or the process. Information from product testing results, consumer complaints, function and design of the facility can be used as an incentive for the analysis. Hazards associated with the raw material can occur because of food allergen cross-contamination or because of pathogens associated with that food product. Many manufacturing processes have a tendency to introduce hazards, such as metal fragments, broken glass, etc. If the parameters of a particular process are not set properly, they can also contaminate the food; for example, improper cooling can lead to growth of microbial pathogens. Different cleaning protocols are required depending on the equipment and how prone the equipment is to damage. Sanitary conditions within the processing facility and employee hygiene are also contributing factors when conducting the hazard analysis. Types of packaging and packaging material can also cause hazards; for example, reduced-oxygen packaging can create an environment that is beneficial for the growth of controls ,70.The critical control points are required to be monitored. For infant formula, one of the key control procedures requires analyzing the variance in nutrient levels at all production steps and addresses the situation as appropriate. For analysis, at least one of the indicator nutrients has to be tested during production, after the addition of the nutrient premix and at the final manufacturing step. The analysis must be done in every physical form of the formulation, whether it is powder, ready-to-eat or concentrate. Similar evaluations in complementary food could help children meet adequate nutrition demands.If monitoring of controls shows any deviation from the critical limits, it is important to take corrective actions. The food safety plan directs the facility regarding whether the corrective action must be enforced immediately, such as through recleaning and sanitizing. It is the responsibility of ONLPDS to evaluate if an infant formula has met the set guidelines .The critical control points associated with complementary food includes supply-chain control, food allergen control, sanitation control and process control. The supply chain control includes verification of controls used by the suppliers to control hazards of raw material before the manufacture receives it. Food allergen controls involve labelling and controls that can prevent cross-contamination, such as product sequencing and sanitation control. Sanitation controls also help to prevent microbial contamination. Process controls include critical parameters, such as time and temperature . The preVerification includes crosschecking control strategies, such as the calibration of instruments and review of previous records  .ValidatiA recall plan is required to be included in the food safety plan in case a batch of formula or complementary food raises food safety concerns specifically for hazards requiring a preventive control. Information from previous recalls gives the understanding of the likelihood of occurrence. According to 21 CFR 7.3, a recall is classified into 3 categories, I, II and III, wherein class I describes a situation where there is reasonable probability of occurrence of hazard that can cause serious adverse health consequences, class II describes exposure to a violative product which can cause temporary or medically reversible adverse health consequences and class III describes a violative product which is not likely to cause any illness or injury . The wriThe applicability provision states that if the infant formula manufacturer does not adhere to processing guidelines, quality factors, good manufacturing practices, quality control procedures and quality factor records as stated, the formula is considered to be adulterated. The regulation also covers the registration, submission and notification aspect of the manufactured formula. The audit procedure includes methods that should be used to review if the facility is working in accordance with current good manufacturing practices with quality control procedures which are necessary for infant formula. The audit plan includes an evaluation of production and in-process control systems in comparison with the written procedures, review of the records and deviation at every stage necessary to avoid adulteration.The U.S Federal Food Law emphasizes that any adulterated or misbranded food cannot be sold. Adulterated food consists of food with any substance, additive, pesticide, or putrid and chemical residue that is injurious to human health. It also includes food which is prepared under unsanitary conditions, or food products made from a diseased animal. Misbranded food consists of food whose labelling or advertising is false and misleading. It also restricts the selling of food under another name and including the word “imitation” when required. The information of the label should be accurate in terms of weight, measure or numerical count .Although globalization has improved food systems in terms of accessibility, availability, and affordability, it has also made the food supply chain vulnerable to outbreaks. The COVID-19 pandemic, instigated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected almost 188 countries, leading to the death of more than 1 million people thus far . The virAdequate and appropriate macro- and micronutrients are one of the most important factors which sets the bifacial relationship between infection and immunity. Around the world, food regulations are being enforced to mandate industries to adopt best food handling practices to avoid any risk of foodborne illness. Even with the presence of a well-crafted system, there are no strict regulations for complementary food specifically in terms of nutritional requirements. These regulations can help children ranging in age from 6 months to 24 months meet nutritional goals for their optimal growth and development. Currently, undernutrition is responsible for the death of 45% of children under the age of five, and, hence, it is crucial to take steps to prevent it. National food laws and regulations constitute the food safety model, which deals with food hazards through response actions and effective plans for mitigation of risk. Food safety regulations are based on comprehensive risk analyses performed by the regulatory bodies. These regulatory bodies have a unified mission to evaluate and inspect implementation and are ideally organized in a way wherein the state and local government work as an integrated enterprise with well-defined responsibilities and adequate funding. The Baby Food Safety Act of 2021, which was introduced on March 25th, 2021, is one such example of how safety requirements can be imposed, as the bill establishes the permissible levels of cadmium (5 ppb), lead (5 ppb), mercury (2 ppb) and inorganic arsenic (10 ppb) in infant and complementary food products. The act is an amendment to the Federal Food, Drug and Cosmetic Act (21 U.S.C 321) and states that preventive control measures should be employed.A strong food safety system should always be kept modernized and updated with the ongoing settings. Earlier, the food safety culture was limited to addressing how the people involved in production should work to make a product safe, but now it is considered that the safety of both the product and people deserve equal attention. The unprecedented situation of the COVID-19 pandemic unveiled the requirement of a digital and transparent food system, where issues such as control parameters and contamination are also needed to be taken care of. It can be further improved by incorporating technological changes, such as blockchain technology, which helps enable the distribution of a database across a network of computers, helping in traceability across the processing chain. The data generated from improved AI/ machine learning technologies for food safety and process controls can help in performing predictive analytics to prevent contamination at any step along the supply chain.