On average, children consumed foods from three of the seven food groups and nearly Women owned an average of 3 of 10 assets that were considered. Mothers had heard an average of 5 of the 8 IYCF messages. Descriptive statistics of child, maternal and household characteristics for children under 24 months and their mothers in Suaahara study in Nepal. Access to IYCF information was associated with 1. Bivariate associations of child, maternal and household characteristics with infant and young child feeding practices in children 0—24 months in Suaahara study in Nepal.
Child sickness in the past 15 days due to diarrhoea or fever was included as a covariate for exclusive breastfeeding, minimum meal frequency and dietary diversity models. Ownership and control of assets did not have a significant direct or indirect relationship with exposure to IYCF information or any of the IYCF outcomes.
Specific domains of women's bargaining power were associated with different IYCF practices. Social participation was associated with higher exposure to IYCF information, which subsequently was associated with early initiation and dietary diversity. No other domains were significantly related to early initiation and dietary diversity, and no significant direct or indirect relationships were observed with minimum meal frequency.
The positive association between social participation and exposure to IYCF information is consistent previous findings. Group membership through targeted nutrition programming and relevant behaviour change messages may improve IYCF outcomes Kumar et al.
Although exposure to IYCF messages may indicate gain in knowledge on child nutrition practices, it was only associated with early initiation and dietary diversity, but not exclusive breastfeeding and minimum meal frequency. Contextual factors such as use of traditional foods for infants may get precedence over knowledge of practicing exclusively breastfeeding or norms surrounding breastfeeding maybe stronger than the effect of nutrition knowledge. IYCF messages were also specifically about diet quality rather than quantity, which could have resulted in the lack of association with minimum meal frequency despite an overall increase in exposure and possible increase in knowledge.
The lack of a significant relationship between minimum meal frequency and information may also be due to a high prevalence of minimum meal frequency in our sample. For example, women's financial autonomy was positively associated with exclusive breastfeeding in infants 3—5 months in rural India Shroff et al.
Our results may be because most mothers made the household decisions regarding child health and child feeding. The coefficient for exposure to IYCF messages and exclusive breastfeeding was 0. Ownership and control of assets did not have a direct association with any of the IYCF outcomes. Although economic independence may relate to child nutrition, the results with IYCF practices have been mixed.
For example, in India, maternal wealth as determined by her employment and household wealth had no significant positive association with IYCF practices N. Malhotra, Workload was not significantly associated with IYCF practices, also contrary to our expectation. Child care could be compromised when mothers have a higher workload if more time is allocated to other activities or if children are left unattended Samman et al.
Working mothers may not get enough opportunity to exclusively breastfeed their child A. Time allocation may be contextual and may affect IYCF practices differently. Therefore, women spending more time working for wages or in subsistence agriculture may be able to provide diverse foods, irrespective of access to information. We also did not find any significant indirect effect through exposure to IYCF information for workload except for a small effect with early initiation.
Future research can help our understanding of specific aspects of women's time allocation for care practices that may relate most to IYCF practices. Specific bargaining domains may be important for improving certain IYCF practices. Although women may be better able to access health resources if they have more economic control, this control and access to economic resources likely has a small effect on breastfeeding behaviours in this population.
No significant direct relationship between other domains may suggest the need for measures that capture specific aspects of IYCF practices. For example, information on economic control of food resources or food expenditure may more precisely capture the relationship between economic control of resources and dietary diversity. This is the first study to have simultaneously examined several domains of household bargaining and several IYCF practices in South Asia, providing a comprehensive view of the social, economic and cultural aspects of household bargaining power and IYCF practices.
Additionally, we focused on testing a possible mechanism linking maternal bargaining power and IYCF outcomes; such testing is essential for elucidating the nature of relationships between bargaining power and IYCF practices. Our study has certain limitations. Fourth, although the measures for bargaining domains are widely used, there is limited research on the validity of all these measures Yount et al.
We also acknowledge that bargaining power domains can operate through different paths, not tested in this analysis, to relate differently to ICYF outcomes. Future research could focus on specific aspects of the individual domains of bargaining. Mechanisms linking bargaining power to knowledge or intention of IYCF practices could be assessed to provide evidence of relationship between bargaining and cognitive processes such as knowledge and intention, which are shown to be associated with practices Nguyen et al.
Overall, our study highlights that addressing poor feeding practices will require strengthening women's bargaining power and exposure to IYCF information. SK designed and conducted the analysis and wrote the paper. EAF and KC guided the analysis and interpretation of the results. Women's bargaining power and child feeding in Nepal: Linkages through nutrition information. Matern Child Nutr. National Center for Biotechnology Information , U.
Journal List Matern Child Nutr v. Published online Sep 3. Shibani Kulkarni , 1 Edward A. Blake 1. Edward A. Christine E. Author information Article notes Copyright and License information Disclaimer. Shibani Kulkarni, Email: ude. Corresponding author. Email: ude. Keywords: bargaining power, IYCF practices, nutrition information. Key messages. Statistical analysis Analyses were conducted in Stata SE version Open in a separate window.
Figure 1. Table 1 Descriptive statistics of child, maternal and household characteristics for children under 24 months and their mothers in Suaahara study in Nepal. Table 2 Bivariate associations of child, maternal and household characteristics with infant and young child feeding practices in children 0—24 months in Suaahara study in Nepal. Table presents unadjusted bivariate estimates. Women's autonomy and men's involvement in child care and feeding as predictors of infant and young child anthropometric indices in coffee farming households of Jimma Zone, South West of Ethiopia.
Maternal height and child growth patterns. The Journal of Pediatrics , 2 , — Feminist Economics , 3 1 , 1— Economic status, education and empowerment: Implications for maternal health service utilization in developing countries. Dietary diversity is associated with child nutritional status: Evidence from 11 demographic and health surveys. The Journal of Nutrition , 10 , — Retrieved from. What dimensions of women's empowerment matter most for child nutrition?
What works? Interventions for maternal and child undernutrition and survival. The Lancet , , — Maternal and child nutrition: Building momentum for impact. The Lancet. Campbell Systematic Reviews , 11 9 , 1— Associations between women's autonomy and child nutritional status: A review of the literature. Global Food Security , 13 , 30— Women's empowerment in agriculture and child nutritional status in rural Nepal. Public Health Nutrition , 18 17 , — Women's empowerment and child nutritional status in South Asia: A synthesis of the literature.
Factors associated with mothers' knowledge on infant and young child feeding recommendation in slum areas of Bahir Dar City, Ethiopia: Cross sectional study. BMC Research Notes , 10 1 , Intrahousehold bargaining and resource allocation in developing countries. The World Bank Research Observer , 28 1 , 52— Utilization of delivery services at the primary health care level in rural Vietnam. Journal of Paediatrics and Child Health , 41 7 , — Care and nutrition: Concepts and measurement.
World Development , 27 8 , — Indian Journal of Community Medicine , 32 3 , A qualitative study exploring perceived barriers to infant feeding and caregiving among adolescent girls and young women in rural Bangladesh. BMC Public Health , 15 1 , Intrahousehold resource allocation: An overview No. Harpham, T. Maternal social capital and child wellbeing in comparative perspective.
Effect of a nutrition intervention during early childhood on economic productivity in Guatemalan adults. Heavy agricultural workloads and low crop diversity are strong barriers to improving child feeding practices in the Bolivian Andes. World Health Organization infant and young child feeding indicators and their associations with child anthropometry: A synthesis of recent findings.
Resources, agency, achievements: Reflections on the measurement of women's empowerment. Development and Change , 30 3 , — Gender equality and women' empowerment: A critical analysis of the third millennium development goal 1. Gender and Development , 13 1 , 13— Factors influencing feeding practices of extreme poor infants and young children in families of working mothers in Dhaka slums: A qualitative study.
How does women's time in reproductive work and agriculture affect maternal and child nutrition? Global Food Security , 17 , — Building a network theory of social capital. We believe results from these and other performance-based studies will encourage surgeons to use Tc 99m tilmanocept as they look to optimize outcome for their patients and improve patient experience.
These data indicated the strong correlation of macrophage presence in sentinel nodes relative to non-sentinel nodes suggesting that SLNs have a preferred biological nexus to the primary tumor site. Correlations were supported by macrophage counts, Tc 99m counts, and receptor analyses. These data further support the targeting of the CD receptor. Manocept Platform - Diagnostics and Therapeutics Background. Activated macrophages play important roles in many disease states and are an emerging target in many diseases where diagnostic uncertainty exists.
This flexible and versatile platform serves as an engine for purpose-built molecules that may significantly impact patient care by providing enhanced diagnostic accuracy, clinical decision-making, and target-specific treatment. Impairment of the macrophage-driven disease mechanisms is an area of increasing focus in medicine. The number of people affected by all the inflammatory diseases combined is estimated at more than 40 million in the United States and perhaps million worldwide, making macrophage-mediated diseases an area of remarkable clinical importance.
In July , the Company completed a license agreement with UCSD for the exclusive world-wide rights in all diagnostic and therapeutic uses of tilmanocept, except for the use of Tc 99m tilmanocept in Canada, Mexico and the United States, which rights have been licensed directly to Cardinal Health by UCSD in connection with the Asset Sale.
The license agreement is effective until the third anniversary of the expiration date of the longest-lived underlying patent. Under the terms of the license agreement, UCSD has granted Navidea the exclusive rights to make, use, sell, offer for sale and import licensed products for all diagnostic and therapeutic uses as defined in the agreement and to practice the defined licensed methods during the term of the agreement.
Navidea may also sublicense the patent rights, subject to certain sublicense terms as defined in the agreement. Navidea also agreed to reimburse UCSD for all patent-related costs and to meet certain diligence targets. In April , we announced that based on a meeting with the FDA, we would begin the clinical trial development process for our IV injection protocols for use of tilmanocept in RA and other disease states.
The addition of this new route of administration would enable further development of tilmanocept in broader immunodiagnostic disease applications including RA, KS and CV. Rheumatoid Arthritis. Our efforts to exploit the involvement of macrophages in the natural history of many diseases has led us through our strategy of expanding the use of tilmanocept and open new market opportunities.
Importantly, one of the largest defined market opportunities resides in early diagnosis and disease monitoring for RA. RA can be difficult to detect because it may begin with subtle symptoms such as achy joints or joint stiffness especially in the morning.
Further, many diseases behave like RA early on; for example, gout and lupus. There is no single test that confirms an RA diagnosis and even combinations of tests provide little specificity for RA. Current diagnostic tools such as x-rays, ultrasound and MRI fall short of being able to quantitatively measure inflammation and the underlying macrophage inflammatory component, which is a key driver of RA progression.
Misdiagnosis results in billions of dollars being spent each year unnecessarily on therapies, which may also result in significant side effects. Early diagnosis and treatment improves outcomes. In patients with RA, joint damage occurs early, often within the first two years of the disease, and is irreversible. Additionally, once treatment is started, it becomes necessary to objectively monitor progression and measure how well a treatment is working or not.
Approximately 10 million patients in economically advantaged countries alone are diagnosed with RA, of which approximately half are misdiagnosed due in large part to a lack of an accurate and cost-effective means for early detection and differential diagnosis.
More succinctly, our primary market research suggests that early detection alone in the U. Our goals for the use of tilmanocept in RA are:. Reliable diagnosis of RA by imaging;. Early differential diagnosis of RA;. Use in monitoring patient response to RA treatments; and. Quantitative assessment of the disease process via imaging and application to therapeutic response. Based on our work to date, we believe we can achieve all of the diagnostic disease-managing elements with tilmanocept.
The study has enrolled four cohorts of subjects: participants with active RA and arthritis-free individuals evaluating two different tilmanocept doses in each group. Study results will provide information regarding trial design for follow-on studies. This study is complete and we are comprehensively analyzing the study data sets. The first subject was dosed and imaged in February This study will enroll up to 30 subjects with dose escalation ClinicalTrials.
Cardiovascular Disease. This study is complete and examined the ability of Tc 99m tilmanocept to localize in high-risk atherosclerotic plaques. These specific plaques are rich in CDexpressing macrophages and are at high risk for near term rupture resulting in myocardial infarctions, sudden cardiac death and strokes.
Recently, it has been observed that CD expressing macrophages densely populate vulnerable plaques or thin cap fibroatheromas but not other kinds i. Contrast with NaF18 was a parallel evaluation. In May , we reported that the first subjects were dosed subcutaneously at Massachusetts General Hospital, and we have now completed enrollment in this study. Other Immuno-Diagnostic Applications. We recognize this repurposing represents a major refocusing of the original NAV initiative, but we are confident that this change represents the best course of action at this time towards benefiting patients afflicted with colorectal cancer and is one which is consistent with the excitement we are seeing on many fronts related to our work on the Manocept platform.
To this end, we have completed two preclinical evaluations, clinical trial protocol development, and site review; we are awaiting IRB confirmation for the clinical portion of this initiative. However, there can be no assurance that if further clinical trials for this product proceed, that they will be successful, that the product will achieve regulatory approval, or if approved, that it will achieve market acceptance.
See Risk Factors. Macrophage Therapeutics Background. In December , the Company formed a new business unit, Macrophage Therapeutics, to further explore therapeutic applications for the Manocept platform. Goldberg, and the balance by Platinum. Navidea retains ownership of the remainder of MT Common Stock. Navidea also granted MT an exclusive license for certain therapeutic applications of the Manocept technology. A payload of a select therapeutic molecule is conjugated to each immunoconstruct through a linkage that will release the molecule within the targeted tissue: MT contains doxorubicin moieties an anthracycline antitumor antibiotic , conjugated to the Manocept backbone while MT contains a potent anti-inflammatory agent.
MT has contracted with independent facilities to produce sufficient quantities of the MT and MT class agents along with the concomitant analytical standards, to provide material for planned preclinical animal studies and future clinical trial.
During investor update conference calls held during , MT reported the following from its ongoing pre-clinical animal studies:. An 8-week, preclinical mouse study in an arthritis mouse model with a Manocept anti-inflammatory targeted therapeutic product, MT, was completed with initial results reporting clear anti-inflammatory activity with no apparent significant side-effects;. An animal study in an asthma model that measured the ability of MT to decrease all three markers of pro-inflammatory markers secreted by disease-causing macrophages was completed and successfully demonstrated an anti-inflammatory effect;.
A study in a rodent neuro-inflammation model confirmed the ability to cross the blood-brain barrier while maintaining the desired activity of the therapeutic linked to our delivery agent;. We have looked at a number of different dosing regimens and compared performance of both families of our therapeutic products. We have also looked at initiating dosing later in the course of the disease to determine if we can have an impact on preventing fibrosis.
According to the group that ran these studies Stelic, Japan , our agents performed the best of all agents they have ever tested in their STAM TM animal model. Finally, the livers of these animals were analyzed and showed no evidence of off-target or histo-pathological damage.
We completed dosing in a neuro-inflammation model which confirmed that the anti-inflammatory construct very effectively crosses the blood-brain barrier. This study also confirmed that the addition of the drug conjugate to the Manocept backbone did not affect blood-brain barrier activity.
We completed four independent cancer-modeling studies evaluating the TAM-depleting performance of compounds from the MT class of conjugates. In three of these models employing the MT conjugate alone, we observed an immediate reduction on the rate of tumor growth. In a fourth cancer model where the MT agent was tested in combination with a tumor targeted antibody we also observed a significant co-effect on tumor reduction.
This latter study was repeated and further highlighted the potentiation of the targeted antibody to the tumor driven by the MT agent targeting to the TAMs, a key component of the tumor microenvironment. The novel Manocept construct is designed to specifically deliver doxorubicin, a chemotoxin, which can kill KS tumor cells and their TAMs potentially altering the course of cancer. KS is a serious and potentially life threatening illness in persons infected with HIV and the third leading cause of death in this population worldwide.
The prognosis for patients with KS is poor with high probabilities for mortality and greatly diminished quality of life. If successful, the information from these studies will be combined with other information in an IND application that will be submitted to the FDA requesting permission to begin testing the compound selected in human KS patients. Navidea and MT continue to evaluate emerging data in other disease states to define areas of focus, development pathways and partnering options to capitalize on the Manocept platform, including ongoing studies in KS and RA.
The immuno-inflammatory process is remarkably complex and tightly regulated with indicators that initiate, maintain and shut down the process. Macrophages are immune cells that play a critical role in the initiation, maintenance, and resolution of inflammation. They are activated and deactivated in the inflammatory process. Because macrophages may promote dysregulation that accelerates or enhances disease progression, diagnostic and therapeutic interventions that target macrophages may open new avenues for controlling inflammatory diseases.
There can be no assurance that further evaluation or development will be successful, that any Manocept platform product candidate will ultimately achieve regulatory approval, or if approved, the extent to which it will achieve market acceptance.
NAV Candidate for Divestiture. Amyloid plaque pathology is a required feature of AD and the presence of amyloid pathology is a supportive feature for diagnosis of probable AD. Patients who are negative for amyloid pathology do not have AD. NAV has been studied in rigorous pre-clinical studies and clinical trials in humans. Results suggest that NAV has the potential ability to image patients quickly and safely with high sensitivity and specificity.
In May , the Board of Directors made the decision to refocus the Company's resources to better align the funding of our pipeline programs with the expected growth in Tc 99m tilmanocept revenue. This realignment primarily involved reducing our near-term support for our neurological product candidates, including NAV, as we sought a development partner or partners for these programs.
We continue to have active interest from potential partners or acquirers; however, our negotiations have experienced delays due in large part to litigation brought by one of the potential partners see Part II, Item 1 — Legal Proceedings. The Company believed the suit was without merit and filed a motion to dismiss the action. Navidea is currently preparing for a trial which is expected to take place within the next twelve months. At this time it is not possible to determine with any degree of certainty the ultimate outcome of this legal proceeding, including making a determination of liability.
The term sheet outlined the terms of a potential agreement between the parties to sublicense NAV to Cerveau in return for license fees, milestone payments and royalties. With the exception of certain provisions, the term sheet was non-binding and was subject to the agreement of AstraZeneca, from whom the Company has licensed the NAV technology.
The Company had 60 days to execute a definitive agreement, however no definitive agreement was reached. Discussions related to the potential partnering or divestiture of NAV are ongoing. Loss of these neurons is a hallmark of PD. In addition to its potential use as an aid in the differential diagnosis of PD and movement disorders, NAV may also be useful in the diagnosis of Dementia with Lewy Bodies, one of the most common forms of dementia after AD.
This realignment primarily involved reducing our near-term support for our neurological product candidates, including NAV In April , the Company entered into an agreement with Alseres to terminate the sub-license agreement dated July 31, for research, development and commercialization of NAV Under the terms of this agreement, Navidea transferred all regulatory, clinical and manufacturing-related data related to NAV to Alseres.
Alseres agreed to reimburse Navidea for any incurred maintenance costs of the contract manufacturer retroactive to March 1, In addition, Navidea has supplied clinical support services for NAV on a cost-plus reimbursement basis. However, to this point, Alseres has been unsuccessful in raising the funds necessary to restart the program and reimburse Navidea.
As a result, we have taken steps to end our obligations under the agreement and notified Alseres that we consider them in breach of the agreement. We are in the process of trying to recover the funds we expended complying with our obligations under the termination agreement.
As of the filing of this document, we remain in discussions and Alseres has expressed its commitment to pay the related payables. Market Overviews. Tc 99m Tilmanocept — Cancer Market Overview. Cancer is the second leading cause of death in the U. The Agency for Healthcare Research and Quality has estimated that the direct medical costs for cancer in the U. Additionally, the ACS estimates that approximately 1. For the types of cancer to which our oncology agents may be applicable breast, melanoma, head and neck, prostate, lung, colorectal, gastrointestinal and gynecologic , the ACS has estimated that over 1.
Breast cancer is the second leading cause of death from cancer among all women in the U. The probability of developing breast cancer generally increases with age, rising from about 1. According to the ACS, over , new cases of breast cancer are expected to be diagnosed during in the U.
The use of ILM is also common in melanoma. The ACS estimates that approximately 87, new cases of melanoma will be diagnosed in the U. In addition to breast cancer and melanoma, we believe that our oncology products may have utility in other cancer types with another , new cases expected during in the U. If the potential of Tc 99m tilmanocept as a radioactive tracing agent is ultimately realized, it may address not only the breast and melanoma markets on a procedural basis, but also assist in the clinical evaluation and staging of solid tumor cancers and expanding lymph node mapping to other solid tumor cancers such as prostate, gastric, colon, head and neck, gynecologic, and non-small cell lung.
Tc 99m tilmanocept is approved by the U. FDA for use in solid tumor cancers where lymphatic mapping is a component of surgical management and for guiding sentinel lymph node biopsy in patients with clinically node negative breast cancer, melanoma or squamous cell carcinoma of the oral cavity. Tc 99m tilmanocept has also received European approval in imaging and intraoperative detection of sentinel lymph nodes in patients with melanoma, breast cancer or localized squamous cell carcinoma of the oral cavity.
Impairment of the macrophage-driven disease mechanism is an area of increasing focus in medicine. The number of people affected by all the inflammatory diseases combined is estimated at more than 40 million in the United States and perhaps million worldwide, making these macrophage-mediated diseases an area of remarkable clinical importance.
AA also estimates that there are over 15 million AD and dementia caregivers providing AD is the sixth-leading cause of death in the country and the only cause of death among the top 10 in the U. Based on U. In February , the American Academy of Neurology reported in the online issue of Neurology that the number of people with AD may triple by Marketing and Distribution. Upon closing of the Asset Sale, the Supply and Distribution Agreement between Cardinal Health and the Company was terminated and Cardinal Health has assumed responsibility for marketing Lymphoseek in the Territory.
Unlike the U. With respect to Tc 99m tilmanocept commercialization in Europe, we have chosen a specialty pharmaceutical strategy that should be supportive of premium product positioning and reinforce Tc 99m tilmanocept's clinical value proposition, as opposed to a commodity or a generics positioning approach. In March , we entered into an exclusive sublicense agreement for the commercialization and distribution of a 50 microgram kit for radiopharmaceutical preparation tilmanocept in the European Union with SpePharm AG an affiliate of Norgine BV , a European specialist pharmaceutical company with an extensive pan-European presence.
Under the terms of the exclusive license agreement, Navidea transferred responsibility for regulatory maintenance of the Tc 99m tilmanocept Marketing Authorization to SpePharm in January SpePharm will also be responsible for production, distribution, pricing, reimbursement, sales, marketing, medical affairs, and regulatory activities. The initial territory covered by the agreement includes all 28 member states of the European Economic Community with the option to expand into additional geographical areas.
SpePharm is currently performing the customary pre-launch market access activities to support commercial launch in the EU during the first half of In August , Navidea entered into an exclusive agreement with Sinotau, a pharmaceutical organization with a broad China focus in oncology and other therapeutic areas, who will develop and commercialize Tc 99m tilmanocept in China.
As part of the agreement, Sinotau is responsible for costs and conduct of clinical studies and regulatory applications to obtain Tc 99m tilmanocept approval by the China Food and Drug Administration CFDA. Upon approval, Sinotau will be responsible for all Tc 99m tilmanocept sales, marketing, market access and medical affairs activities in China and excluding Hong Kong, Macau and Taiwan.
Navidea and Sinotau will jointly support certain pre-market planning activities with a joint commitment on clinical and market development programs pending CFDA approval. See Item 3 — Legal Proceedings. Tc 99m tilmanocept is in various stages of approval in other global markets and sales to this point in these markets, if any, have not been material. However, we believe that with international partnerships to complement our position in the EU, we will help establish Tc 99m tilmanocept as a global leader in lymphatic mapping, as we are aware of no other company which has a global geographic range.
We cannot assure you that Tc 99m tilmanocept will achieve regulatory approval in any market outside the U. We also cannot assure you that we will be successful in securing collaborative partners for other global markets or radiopharmaceutical products, or that we will be able to negotiate acceptable terms for such arrangements.
We currently use and expect to continue to be dependent upon contract manufacturers to manufacture each of our product candidates. We may need to invest in additional manufacturing and supply chain resources, and may seek to enter into additional collaborative arrangements with other parties that have established manufacturing capabilities.
It is likely that we will continue to rely on third-party manufacturers for our development and commercial products on a contract basis. Tc 99m Tilmanocept Manufacturing. Similarly, following the transfer of the Tc 99m tilmanocept Marketing Authorization to SpePharm, our contract with Gipharma will be transferred to SpePharm.
We cannot assure you that we will be successful in completing future agreements for the supply of Tc 99m tilmanocept on terms acceptable to the Company, or at all. NAV Manufacturing. Supplies of NAV used in clinical development through Phase 2b were manufactured by AstraZeneca through various arrangements. Navidea has continued to incur costs related to maintaining our NAV manufacturing sites while seeking to partner or out-license the product.
If and when established, we also cannot assure you that we will be able to maintain agreements or other purchasing arrangements with our subcontractors on terms acceptable to us, or that our subcontractors will be able to meet our production requirements on a timely basis, at the required levels of performance and quality, including compliance with FDA cGMP requirements. In the event that any of our subcontractors are unable or unwilling to meet our production requirements, we cannot assure you that an alternate source of supply could be established without significant interruption in product supply or without significant adverse impact to product availability or cost.
Any significant supply interruption or yield problems that we or our subcontractors experience would have a material adverse effect on our ability to manufacture our products and, therefore, a material adverse effect on our business, financial condition, and results of operations until a new source of supply is qualified. Competition in the pharmaceutical and biotechnology industries is intense. We face competition from a variety of companies focused on developing oncology and neurology diagnostic drugs.
We compete with large pharmaceutical and other specialized biotechnology companies. We also face competition from universities and other non-profit research organizations. Many emerging medical product companies have corporate partnership arrangements with large, established companies to support the research, development, and commercialization of products that may be competitive with our products. In addition, a number of large established companies are developing proprietary technologies or have enhanced their capabilities by entering into arrangements with or acquiring companies with technologies applicable to the detection or treatment of cancer and other diseases targeted by our product candidates.
Smaller companies may also prove to be significant competitors, particularly through collaborative arrangements with large pharmaceutical and established biotechnology companies. Many of these competitors have products that have been approved or are in development and operate large, well-funded research and development programs. Many of our existing or potential competitors have substantially greater financial, research and development, regulatory, marketing, and production resources than we have.
Other companies may develop and introduce products and processes competitive with or superior to ours. We expect to encounter significant competition for our pharmaceutical products. Companies that complete clinical trials, obtain required regulatory approvals and commence commercial sales of their products before us may achieve a significant competitive advantage if their products work through a similar mechanism as our products and if the approved indications are similar.
A number of biotechnology and pharmaceutical companies are developing new products for the treatment of the same diseases being targeted by us. In some instances, such products have already entered late-stage clinical trials or received FDA approval and may be marketed for some period prior to the approval of our products.
We expect that competition among products cleared for marketing will be based on, among other things, product efficacy, safety, reliability, availability, price, and patent position. Tc 99m Tilmanocept Competition. Surgeons who practice the lymphatic mapping procedure for which Tc 99m tilmanocept is intended currently use other radiopharmaceuticals such as a sulfur colloid or other colloidal compounds.
In addition, some surgeons still use vital blue dyes to assist in the visual identification of the draining lymphatic tissue around a primary tumor. NAV Competition. Several potential competitive [ 18 F] products have been approved for use as biomarkers to aid in detection of AD.
Florbetapir also received marketing authorization in the EU in January In addition to fluorbetapir, there are two other beta-amyloid imaging agents available: florbetaben from Piramal Enterprises, Imaging Division, and flutemetamol from GE Healthcare. Patents and Proprietary Rights. The patent position of biotechnology, including our company, generally is highly uncertain and may involve complex legal and factual questions.
Potential competitors may have filed applications, or may have been issued patents, or may obtain additional patents and proprietary rights relating to products or processes in the same area of technology as that used by the Company. The scope and validity of these patents and applications, the extent to which we may be required to obtain licenses thereunder or under other proprietary rights, and the cost and availability of licenses are uncertain.
We cannot assure you that our patent applications or those licensed to us will result in additional patents being issued or that any of our patents or those licensed to us will afford protection against competitors with similar technology; nor can we assure you that any of these patents will not be designed around by others or that others will not obtain patents that we would need to license or design around.
We also rely upon unpatented trade secrets. We cannot assure you that others will not independently develop substantially equivalent proprietary information and techniques, or otherwise gain access to our trade secrets, or disclose such technology, or that we can meaningfully protect our rights to our unpatented trade secrets. We require our employees, consultants, advisers, and suppliers to execute a confidentiality agreement upon the commencement of an employment, consulting or manufacturing relationship with us.
The agreement provides that all confidential information developed by or made known to the individual during the course of the relationship will be kept confidential and not disclosed to third parties except in specified circumstances. In the case of employees, the agreements provide that all inventions conceived by the individual will be the exclusive property of our company.
We cannot assure you, however, that these agreements will provide meaningful protection for our trade secrets in the event of an unauthorized use or disclosure of such information. We also employ a variety of security measures to preserve the confidentiality of our trade secrets and to limit access by unauthorized persons. We cannot assure you, however, that these measures will be adequate to protect our trade secrets from unauthorized access or disclosure.
Tilmanocept Intellectual Property. Tilmanocept is under license from UCSD for the exclusive world-wide rights in all diagnostic and therapeutic uses of tilmanocept, except for the use of Tc 99m tilmanocept in Canada, Mexico and the United States, which rights have been licensed directly to Cardinal Health by UCSD in connection with the Asset Sale.
Navidea maintains license rights to Tc 99m tilmanocept in the rest of the world, as well as a license to the intellectual property underlying the Manocept platform. The first composition of matter patent covering tilmanocept was issued in the United States in June This patent will expire in May , but a request for patent term extension has been filed to further extend the life of this patent. The claims of the composition of matter patent covering tilmanocept have been allowed in the EU and issued in the majority of major-market EU countries in These patents will expire in , but a request for supplemental protection certificates are in process to further extend the life of these patents.
The composition of matter patent has also been issued in Japan, which will expire in We have filed additional patent applications in the U. We have filed further patent applications jointly with The Ohio State Innovation Foundation related to CD expressing cell-related disorders.
We have filed further patent applications related to 2-heteroaryl substituted benzofurans. NAV Intellectual Property. NAV is being developed under an exclusive worldwide license from AstraZeneca. The NAV license grants Navidea commercialization rights to the fluorine labeled biomarker for use as an aid in the diagnosis of AD. NAV is the subject of 3 issued patents in the U. Government Regulation. The research, development, testing, manufacture, labeling, promotion, advertising, distribution and marketing, among other things, of our products are extensively regulated by governmental authorities in the United States and other countries.
Failure to comply with applicable U. We also may be subject to regulation under the Occupational Safety and Health Act, the Atomic Energy Act, the Toxic Substances Control Act, the Export Control Act and other present and future laws of general application as well as those specifically related to radiopharmaceuticals.
Most aspects of our business are subject to some degree of government regulation in the countries in which we conduct our operations. As a developer, manufacturer and marketer of medical products, we are subject to extensive regulation by, among other governmental entities, the FDA and the corresponding state, local and foreign regulatory bodies in jurisdictions in which our products are intended to be sold.
These regulations govern the introduction of new products, the observance of certain standards with respect to the manufacture, quality, safety, efficacy and labeling of such products, the maintenance of certain records, the tracking of such products, performance surveillance and other matters. Failure to comply with applicable federal, state, local or foreign laws or regulations could subject us to enforcement action, including product seizures, recalls, withdrawal of marketing clearances, and civil and criminal penalties, any one or more of which could have a material adverse effect on our business.
We believe that we are in substantial compliance with such governmental regulations. However, federal, state, local and foreign laws and regulations regarding the manufacture and sale of radiopharmaceuticals are subject to future changes. We cannot assure you that such changes will not have a material adverse effect on our company. For some products, and in some countries, government regulation is significant and, in general, there is a trend toward more stringent regulation.
In recent years, the FDA and certain foreign regulatory bodies have pursued a more rigorous enforcement program to ensure that regulated businesses like ours comply with applicable laws and regulations. We devote significant time, effort and expense addressing the extensive governmental regulatory requirements applicable to our business.
To date, we have not received a noncompliance notification or warning letter from the FDA or any other regulatory bodies of alleged deficiencies in our compliance with the relevant requirements, nor have we recalled or issued safety alerts on any of our products. However, we cannot assure you that a warning letter, recall or safety alert, if it occurred, would not have a material adverse effect on our company.
In the early- to mids, the review time by the FDA to clear medical products for commercial release lengthened and the number of marketing clearances decreased. In response to public and congressional concern, the FDA Modernization Act of the Act was adopted with the intent of bringing better definition to the clearance process for new medical products.
While the FDA review times have improved since passage of the Act, we cannot assure you that the FDA review processes will not delay our Company's introduction of new products in the U. In addition, many foreign countries have adopted more stringent regulatory requirements that also have added to the delays and uncertainties associated with the development and release of new products, as well as the clinical and regulatory costs of supporting such releases.
It is possible that delays in receipt of, or failure to receive, any necessary clearance for our new product offerings could have a material adverse effect on our business, financial condition or results of operations. The U. Drug Approval Process. None of our drugs may be marketed in the U. The steps required before a drug may be marketed in the U.
Preclinical tests include laboratory evaluation of product chemistry, toxicity and formulation, as well as animal studies. The conduct of the preclinical tests and formulation of the compounds for testing must comply with federal regulations and requirements.
The results of the preclinical tests, together with manufacturing information and analytical data, are submitted to the FDA as part of an IND, which must become effective before human clinical trials may begin. Clinical trials involve the administration of the investigational product to human subjects under the supervision of qualified investigators.
Clinical trials are conducted under protocols detailing the objectives of the study, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated. Clinical trials typically are conducted in three sequential phases, but the phases may overlap or be combined. The study protocol and informed consent information for study subjects in clinical trials must also be approved by an institutional review board at each institution where the trials will be conducted.
Study subjects must sign an informed consent form before participating in a clinical trial. Phase 1 usually involves the initial introduction of the investigational product into people to evaluate its short-term safety, dosage tolerance, metabolism, pharmacokinetics and pharmacologic actions, and, if possible, to gain an early indication of its effectiveness.
Phase 3 trials usually further evaluate clinical efficacy and further test its safety by using the product candidate in its final form in an expanded subject population. There can be no assurance that Phase 1, Phase 2 or Phase 3 testing will be completed successfully within any specified period of time, if at all. Furthermore, we or the FDA may suspend clinical trials at any time on various grounds, including a finding that the subjects or patients are being exposed to an unacceptable health risk.
The FDA and the IND sponsor may agree in writing on the design and size of clinical studies intended to form the primary basis of an effectiveness claim in an NDA application. These agreements may not be changed after the clinical studies begin, except in limited circumstances. The existence of a SPA, however, does not assure approval of a product candidate.
Assuming successful completion of the required clinical testing, the results of the preclinical studies and of the clinical studies, together with other detailed information, including information on the manufacturing quality and composition of the investigational product, are submitted to the FDA in the form of an NDA requesting approval to market the product for one or more indications. The testing and approval process requires substantial time, effort and financial resources.
Before approving a NDA, the FDA usually will inspect the facility or the facilities where the product is manufactured, tested and distributed and will not approve the product unless cGMP compliance is satisfactory.
A complete response letter outlines conditions that must be met in order to secure final approval of the NDA. The approval letter authorizes commercial marketing of the drug for specific indications. Generally, drugs that may be eligible for one or more of these programs are those for serious or life threatening conditions, those with the potential to address unmet medical needs and those that provide meaningful benefit over existing treatments.
We cannot assure you that any of our drug candidates will qualify for any of these programs, or that, if a drug candidate does qualify, the review time will be reduced or the product will be approved. After approval, certain changes to the approved product, such as adding new indications, making certain manufacturing changes or making certain additional labeling claims, are subject to further FDA review and approval.
Obtaining approval for a new indication generally requires that additional clinical studies be conducted. Post-Approval Requirements. Accordingly, manufacturers must continue to expend time, money and effort in the area of production, quality control and distribution to maintain cGMP compliance.
We use and will continue to use third-party manufacturers to produce our products in clinical and commercial quantities, and future FDA inspections may identify compliance issues at our facilities or at the facilities of our contract manufacturers that may disrupt production or distribution, or require substantial resources to correct.
Marketing of prescription drugs is also subject to significant regulation through federal and state agencies tasked with consumer protection and prevention of medical fraud, waste and abuse. We must comply with restrictions on off-label use promotion, anti-kickback, ongoing clinical trial registration, and limitations on gifts and payments to physicians. Before our products can be marketed outside of the United States, they are subject to regulatory approval similar to that required in the U.
No action can be taken to market any product in a country until an appropriate application has been approved by the regulatory authorities in that country. The current approval process varies from country to country, and the time spent in gaining approval varies from that required for FDA approval. In certain countries, the sales price of a product must also be approved.
The pricing review period often begins after market approval is granted. Even if a product is approved by a regulatory authority, satisfactory prices may not be approved for such product. In Europe, marketing authorizations may be submitted at a centralized, a decentralized or national level.
The centralized procedure is mandatory for the approval of biotechnology products and provides for the grant of a single marketing authorization that is valid in all EU member states. A mutual recognition procedure is available at the request of the applicant for all medicinal products that are not subject to the centralized procedure. The EC granted marketing authorization for Tc 99m tilmanocept in the EU in November , and a reduced-mass vial developed for the EU market was approved in September While we are unable to predict the extent to which our business may be affected by future regulatory developments, we believe that our substantial experience dealing with governmental regulatory requirements and restrictions on our operations throughout the world, and our development of new and improved products, should enable us to compete effectively within this environment.
Regulation Specific to Radiopharmaceuticals. Our radiolabeled targeting agents and biologic products, if developed, would require a regulatory license to market from the FDA and from comparable agencies in foreign countries. The process of obtaining regulatory licenses and approvals is costly and time consuming, and we have encountered significant impediments and delays related to our previously proposed biologic products. The process of completing pre-clinical and clinical testing, manufacturing validation and submission of a marketing application to the appropriate regulatory bodies usually takes a number of years and requires the expenditure of substantial resources, and we cannot assure you that any approval will be granted on a timely basis, if at all.
Additionally, the length of time it takes for the various regulatory bodies to evaluate an application for marketing approval varies considerably, as does the amount of preclinical and clinical data required to demonstrate the safety and efficacy of a specific product. The regulatory bodies may require additional clinical studies that may take several years to perform. The length of the review period may vary widely depending upon the nature and indications of the proposed product and whether the regulatory body has any further questions or requests any additional data.
Also, the regulatory bodies require post-marketing reporting and surveillance programs pharmacovigilance to monitor the side effects of the products. We cannot assure you that any of our potential drug or biologic products will be approved by the regulatory bodies or approved on a timely or accelerated basis, or that any approvals received will not subsequently be revoked or modified. The NRC issues medical use licenses to medical facilities and authorized physician users, develops guidance and regulations for use by licensees, and maintains a committee of medical experts to obtain advice about the use of byproduct materials in medicine.
The NRC or the responsible Agreement State also regulates the manufacture and distribution of these products. The FDA oversees the good practices in the manufacturing of radiopharmaceuticals, medical devices, and radiation-producing x-ray machines and accelerators.
The states regulate the practices of medicine and pharmacy and administer programs associated with radiation-producing x-ray machines and accelerators. We cannot assure you that we will be able to obtain all necessary licenses and permits and be able to comply with all applicable laws. The failure to obtain such licenses and permits or to comply with applicable laws would have a materially adverse effect on our business, financial condition, and results of operations.
Corporate Information. Our telephone number is Other trademarks or service marks appearing in this report may be trademarks or service marks of other owners. We make available free of charge on our website our Annual Reports on Form K, Quarterly Reports on Form Q, Current Reports on Form 8-K and other filings pursuant to Section 13 a or 15 d of the Exchange Act, and amendments to such filings, as soon as reasonably practicable after each is electronically filed with, or furnished to, the SEC.
Financial Statements. Our consolidated financial statements and the related notes, including revenues, income loss , total assets and other financial measures are set forth at pages F-1 through F of this Form K. Research and Development. As of March 10, , we had 22 full-time and 6 part-time employees. Item 1A. Risk Factors. An investment in our common stock is highly speculative, involves a high degree of risk, and should be made only by investors who can afford a complete loss.
You should carefully consider the following risk factors, together with the other information in this Form K, including our financial statements and the related notes, before you decide to buy our common stock. Our most significant risks and uncertainties are described below; however, they are not the only risks we face.
If any of the following risks actually occur, our business, financial condition, or results of operations could be materially adversely affected, the trading of our common stock could decline, and you may lose all or part of your investment therein. If Cardinal Health or SpePharm AG do not achieve commercial success with Tc 99m tilmanocept, we may be unable to generate significant revenue or become profitable.
Navidea is entitled to receive royalty and milestone payments from SpePharm based on net sales derived from Tc 99m tilmanocept. We cannot assure you that Cardinal Health or SpePharm will achieve commercial success in North America or in the EU, or any other global market, that Cardinal Health or SpePharm will realize sales at levels necessary for us to achieve sales-based earnout, royalty or milestone payments, or that such payments will lead to us becoming profitable.
If we do not successfully develop any additional product candidates into marketable products, we may be unable to generate significant revenue or become profitable. Additional diagnostic and therapeutic applications of the Manocept platform, including diagnosis of other solid tumor cancers, rheumatoid arthritis and cardiovascular disease, are in various stages of pre-clinical and clinical development. Regulatory approval of additional Manocept-based product candidates may not be successful, or if successful, may not result in increased sales.
Additional clinical testing for products based on our Manocept platform or other product candidates may not be successful and, even if they are, we may not be successful in developing any of them into a commercial product which will provide sufficient revenue to make us profitable. We are continuing to seek to partner or sub-license our NAV candidate, which is designed to enable PET imaging of beta-amyloid deposits in the brain, believed to correlate with the presence of AD.
While discussions with a potential licensee have progressed, our pending litigation with Sinotau has prevented completion of a licensing transaction. Pending resolution of the Sinotau litigation, we continue to incur costs to maintain our ability to support future clinical evaluation of this product candidate to preserve it for eventual sub-licensing.
Many companies in the pharmaceutical industry suffer significant setbacks in advanced clinical trials even after reporting promising results in earlier trials. Even if our Manocept trials are viewed as successful, we may not get regulatory approval for marketing of any Manocept product candidate. Our Manocept product candidates will be successful only if:.
We are dependent on the achievement of a number of these goals in order to generate future revenues. The failure to generate such revenues may preclude us from continuing our research and development of these and other product candidates.
We cannot guarantee that we will obtain regulatory approval to manufacture or market our unapproved drug candidates and our approval to market our products or anticipated commercial launch may be delayed as a result of the regulatory review process. Obtaining regulatory approval to market drugs to diagnose or treat diseases is expensive, difficult and risky.
Preclinical and clinical data as well as information related to the CMC processes of drug production can be interpreted in different ways which could delay, limit or preclude regulatory approval. Negative or inconclusive results, adverse medical events during a clinical trial, or issues related to CMC processes could also delay, limit or prevent regulatory approval. Even if we receive regulatory clearance to market a particular product candidate, the approval could be conditioned on us conducting additional costly post-approval studies or could limit the indicated uses included in our labeling.
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|Automated spread betting platform shoes||Exclusive breastfeeding age: 0—6 mo. Corporate Information. In certain countries, the sales price of a product must also be approved. In addition, class action litigation has often been instituted against companies whose securities have experienced substantial decline in market price. We cannot be certain that such prosecution efforts have been or will be conducted in compliance with applicable laws and regulations or will result in valid and enforceable patents.|
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|Matched betting calculator snra||If any of the following risks actually occur, our business, financial condition, or results of operations could be materially adversely affected, the trading of our common stock could decline, and you may lose all or part of your investment therein. We expect to encounter significant competition for our pharmaceutical products. We continually assess our clinical trial plans and may, from time to time, initiate additional clinical trials to support our overall strategic development objectives. World Development27 8— Other trademarks or service marks appearing in this report may be trademarks or service marks of other owners.|
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