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Newsletter – Summer 2018
By Thomas Seoh
President and Chief Executive officer
Dear Friends of Kinexum,
Welcome to the Summer 2018 Kinexum Newsletter!
We have three expert guest authors: (i) Professor Lutz Heinemann discusses the status of biosimilar insulins; (ii) Rob Claar describes fast-track opportunities for development of stem cells and other advanced therapies in Japan; and (iii) Dr. Bart Van der Schueren, Belgian representative to the EMA, reflects on key differentiators between the EMA and the FDA. In addition, our Lana Pauls contrasts her experiences at the FDA, at IQVIA, the world's largest CRO, and at Kinexum.
ByLutz Heinemann, PhD, Science Consulting in Diabetes GmbH, Neuss Germany
In view of the high number of patients with diabetes who regularly need subcutaneous insulin injections, it is obvious that the market for the different insulin formulations is huge, well above $5 billion on a worldwide basis. Until recently, three pharmaceutical companies (Eli Lilly, Novo Nordisk, and Sanofi) dominated this market. Because patent protection for human insulin and some insulin analogues that have been developed by these companies in the past has expired, "copies" of such insulins can be brought to the market.
ByLana Pauls, MPH
Regulatory, Clinical Operations and Project Management, Kinexum
I joined Kinexum earlier this year, filling two roles:
Director, Client Engagement, and
Consultant, focusing on regulatory affairs, regulatory strategy, CTD submission development, and project management
The purpose of this article is to compare and contrast my regulatory perspective and experiences over the three VERY DIFFERENT roles I have played over the past three decades.
FROM KINEXUM FOUNDER: A tale of two different scientific worlds
By Alexander Fleming, Executive Chairman
A number of Kinexers, myself included, are about to make the annual pilgrimage to the American Diabetes Association meeting where we will be immersed in the cacophony of basic science and clinical data, technologies spanning nutrition, drugs, biologics, devices, and digital products, and commercialism.
It is quite remarkable to behold the impact of a hormonal deficiency state on so many people and the responses of our professional, industrial, and commercial infrastructures to this disorder. Diabetes is big business, big science and medicine, and once a year in the US, a big meeting. (Read more)
Fast track OPPORTUNITIES in Japan for Regenerative Medical Products
By Robert E. Claar, CEO of Hekabio KK
Kyoto University professor Shinya Yamanaka co-won the 2012 Nobel Prize in physiology or medicine for his 2006 discovery that mature cells in mice could be reprogrammed and induced to become immature and pluripotent stem cells (iPS cells). This dramatically accelerated what was already a nascent revolution in Japan for regenerative medicine. New legislation was created, government and private funds became available, new companies and industry associations sprung up and old companies entered this new field.
The European Regulatory Framework: personal perspectives.
By Dr. Bart Van der Schueren
IG Endocrinologie UZ Leuven
European regulators rightly understood that harmonization was needed between its 28 (soon to be 27 because of Brexit) member states in terms of the requirements to obtain marketing authorization.
Note from Kinexum CEO (cont.) …
We welcome David Brill, a US/European regulatory affairs expert who spent some decades at Boehringer Ingelheim, and Kinexum Associate Jennifer Zhao, a magna cum laude graduate of the Dartmouth College Class of 2018, who begins an initial one year stint with us in July.
Rob Claar presented on his topic in a Kinexum webcast earlier this month, and Bart Van der Schueren will present on July 13, and we will have a future webcast on US and EU regulation of advanced therapies. Recordings and slides of our webcasts are available on our website. Also, our Fall Newsletter will contain a follow up piece on CMC aspects of advanced therapies. Please - we would love any feedback on your interest level and value to you of these articles and webcasts.
From Kinexum Founder: A Tale of Two Different (cont.) …
I will go on from Orlando to a very different scene, the annual meeting of the American Aging Association (AGE) and American Federation of Aging Research in Philadelphia, where I will address the assembly on "Blazing clinical development and regulatory pathways for healthspan interventions." See https://www.americanagingassociation.org/Meeting
The AGE meeting consists mainly of basic scientists who utilize in vitro and animal models to discover and characterize candidate agents for extending lifespan. It is a much smaller scientific community with little corporate support. It's a much smaller meeting than ADA's. The diabetes and healthy lifespan worlds could not be more different even though virtually every older adult has keen interest in the subject of anti-aging treatments, and many products with a healthy aging message are on the market. Some high-powered companies, like Google's Calico, have signed up for a moonshot-like commitment to finding lifespan interventions. But, compared to diabetes, the anti-aging world has very limited R&D going on.
The most important reason for this tale of two different scientific worlds is simply economic—lack of incentives for investing in an enterprise that will lead to valuable products. Development and regulatory pathways for drug-like, healthy lifespan products remain to be established. Until they are, our society will continue to pay for a lot of products with a good story but little data for to support safety and effectiveness. It is not an easy challenge to solve because lifespan therapies will require more time and money to show safety and effectiveness than treatments for diabetes or other chronic illnesses.
There are ways forward. One good example is the TAME trial (Targeting Aging with Metformin), led by Nir Barzilai and supported by Kinexum. TAME serves as a model for combining multiple, age-related conditions together, including cancer, cardiovascular disease and Alzheimer's disease, in a single composite efficacy endpoint that, if positive, could support a healthy lifespan indication. Metformin has been around a long time. No one is going to make a lot of money on metformin, even if it is approved for this indication. But, since we have abundant evidence of metformin's safety and epidemiologic evidence of efficacy against each of those conditions, it represents the low hanging fruit among all the potential interventions for healthy aging. A related example with great promise is NuSirt and its combination of approved agents with accumulating clinical evidence of dramatic pharmacologic synergy in lowering blood glucose, lipids, hepatic fat, body weight and blood pressure. NuSirt, also supported by Kinexum, is targeting the standard disease indications related to the above effects, but I believe a NuSirt product would perform very well in a TAME-like trial.
New molecular entities will generally have to be approved or at least have data for disease indications before they can be aimed at lifespan indications, but TAME does present a development pathway. Is that also a regulatory pathway? We shall see, but we at Kinexum want to help in blazing that pathway. Kinexum has and will continue to support this field in other ways. We bring a wide range of expertise in scientific benchmarking, clinical trial design, measurement technology (functional and patient reported), and working with FDA and other stakeholders to address the key challenges. Kinexum will also continue to advance the concept of Metabesity—the constellation of major chronic disorders (cancer, dementia, obesity-diabetes, cardiovascular disease and the aging process itself)—with common, metabolic roots. The London Metabesity Congress last October was a terrific start to what we envision as an annual multidisciplinary gathering of experts and stakeholders who come together to work for preventions of Metabesity.
With summer about to officially begin, I wish our friends and colleagues a season of health and re-creation.
Lutz Heinemann, Ph.D., Biosimilar Insulins (cont.) …
As it is not possible to manufacture truly identical copies of complex proteins by biotechnological processes ("the process is the product"), a much more thorough evaluation of insulins manufactured by new companies has to be performed in comparison to generics (= small molecules manufactured by means of chemical synthesis). Therefore, the guidelines provided by regulatory agencies for market approval of such "biosimilar" products are quite detailed, with a strong focus on manufacturing details. From a clinical point of view, the main requirements are to demonstrate similarity of the pharmacodynamic and pharmacokinetic properties of the "biosimilar" insulin formulation in comparison to the originator insulin. This can be shown in well-performed euglycemic glucose clamp studies. Such studies must be performed in patients with diabetes. However, no large Phase II and Phase III clinical trials with large numbers of patients are needed. It also must be shown that these insulins do not induce formation of insulin antibodies above the level of the originator insulin. Reasons for immunological concerns are impurities in the formulations and/or e.g. glycosylations of the insulins that are induced by the manufacturing process.
Once such insulins are approved as biosimilar insulins (also referred to as BioIns) and can be launched (see below), they enter a market with well-established players who are fighting for market share. Gaining market share will be driven by factors such as cost advantages and political pressure. Currently >20 companies have biosimilar insulins in clinical development. It will remain to be seen how many will ultimately come to the market; however, most probably a plethora of e.g. insulin glargines might be on the market within some years, which could generate some confusion both among patients and among healthcare professionals.
Approved biosimilar insulins: Basaglar
The first approved biosimilar insulin – an insulin glargine developed by Eli Lilly and Boehringer Ingelheim (Abasaglar® in the EU and Basaglar in the US®) – has been on the market now for 1-2 years in the EU and the US. However, there has not yet been a general landslide in favour of this more affordable insulin. Nevertheless, it has gained significant market share in some countries in the EU. The decrease in prices observed varies among such countries, with a maximum price drop of up to 30%.
Approved biosimilar insulins: Admelog
More recently, the first biosimilar insulin (Admelog®) of a rapid-acting insulin analog (insulin lispro) - developed by Sanofi - was approved in the US and the EU. Studies with patients with type 1 or type 2 diabetes were published and it is on the market on both continents now [1, 2]. Also, data about the risk of developing insulin antibodies [3] and when this biosimilar insulin is used in insulin pumps [4] were published, showing no difference in the properties of this biosimilar insulin, compared to the originator insulin.
Approved biosimilar insulins: Lusduna
The next biosimilar insulin that most probably will come to the market in the EU and the US is another insulin glargine developed by Merck-US (Lusduna®). Merck has secured approval by the FDA for their version of insulin glargine; however, they refrained from launching it as they are blocked by a law suit against them by Sanofi. In the past, Eli Lilly was able to get a settlement deal with Sanofi for their biosimilar insulin Basaglar. However, Merck recently published the results of clinical trials in patients with type 1 diabetes or type 2 diabetes with their insulin glargine [5, 6].
Non-approved biosimilar insulin by Mylan / Biocon
A biosimilar insulin that most probably will come to the market is the insulin glargine being developed by US-based generics giant Mylan in cooperation with the huge Indian pharmaceutical company, BioCon. However, both EU and FDA inspectors independently raised concerns about the production facility in India. Nevertheless, both companies are confident that they can solve the issues and that they are progressing according to their plans for the launch of this biosimilar insulin. Mylan had filed an application to the FDA for their insulin glargine in pre-filled pen and vial forms under the 505(b)(2) regulatory pathway, which enables a faster than usual regulatory approval process, partly relying on the data already generated by a previous drug maker. This approval process was created by the Hatch-Waxman Amendments of 1984 as part of the Federal Food, Drugs and Cosmetics Act. The aim was to allow entry of differentiated drugs that offer alternatives at an accelerated pace and avoid duplication of existing safety and efficacy data. Again, Sanofi is not willing to give up rights on its originator insulin glargine, which is a billion dollar drug for them. Thus, Sanofi filed a lawsuit against Mylan in the US alleging infringement of its patents.
As stated, until now market introduction of biosimilar insulins has not resulted in drastic changes in the insulin market; however, as more biosimilar insulins enter the market, the increase in competition will most probably change this rapidly [7]. We will have to see if the prices start a race to the bottom as in the case of test strips for blood glucose measurement systems, which took place in recent years. This will also depend on the pressure to lower insulin prices by insurance companies and/or government healthcare systems. It is of interest to note that prices for originator insulins – which have substantially gone up especially in the US in recent years – have not be solely driven up by the manufacturers, but also by pharmacy benefit managers [8, 9]. Another question is whether one or more biosimilar insulins will get approval by the FDA for interchangeability, and qualify for automatic substitution at the pharmacy level of a lower priced biosimilar insulin with comparable properties (see below).
Immunological aspects
A matter of concern is the question if biosimilar insulins might differ in their immunogenic properties from the originator insulin. The approval requirement of a clinical study with a limited number of subjects (300) over a limited period of time (6/12 months) might not be able to clarify if such reactions do show up in certain patient groups over a prolonged period of usage. A major concern is that – at least in the case of some patients – formation of (neutralizing) insulin antibodies is stimulated. Differences in immunological responses might be induced by certain differences between the biosimilar insulins and the originator insulin [3, 10].
Another important question is the quality of different batches of originator and biosimilar insulins over time. Insulin is manufactured in batches, which could differ considerably from each other as a reflection of the complexity of the manufacturing process. The amount of information that companies are reporting about this topic is quite limited [11, 12].
Switching from one insulin to another for a given patient is a decision made by the treating physician [13]. Interchangeability means the practice of changing one insulin for another that is expected to achieve the same blood glucose lowering effect in any patient with diabetes on the initiative or with the agreement of the physician. This requires that the insulin can be regarded as interchangeable, i.e. as a property of a given insulin. The FDA has relatively lately characterized what their expectations are for such a label; however, until now no biosimilar insulin has received such a label. In contrast, substitution is a process at the pharmacy level without (!) consulting the prescribing physician whereby a biosimilar insulin is dispensed instead of the prescribed insulin. Currently, there is no "substitutability determination" in the EU, i.e., there is no automatic substitution in practice in the EU whereby a pharmacist is obliged to dispense a biosimilar insulin instead of a prescribed insulin. Interesting differences exist between states in the US when it comes to guidelines for market allowance of biosimilar insulins.
In daily practice for patients, diabetologists and nurses, the devices (most often insulin pens) used for application of insulin are of high relevance. Each manufacturer of biosimliar insulins comes to the market with a combination of e.g. their insulin glargine with an insulin pen, which – as indicated – is associated with a certain risk of confusion. The switch from the pen(s) of the originator insulin to another one is associated with an additional teaching and training burden for the diabetes team. Such aspects are of high relevance from a practical point of view.
These are early days for biosimilar insulins. They will without doubt gain more attention and momentum in coming years, mainly driven by lower cost. Lower insulin prices in turn mean more patients can afford and gain access to some form(s) of safe and effective insulin [14].
ADDIN EN.REFLIST 1. Garg, S.K., et al., Efficacy and Safety of Biosimilar SAR342434 Insulin Lispro in Adults with Type 1 Diabetes Also Using Insulin Glargine-SORELLA 1 Study. Diabetes Technol Ther, 2017. 19(9): p. 516-526.
2. Derwahl, K.M., et al., Efficacy and Safety of Biosimilar SAR342434 Insulin Lispro in Adults with Type 2 Diabetes, Also Using Insulin Glargine: SORELLA 2 Study. Diabetes Technol Ther, 2018. 20(1): p. 49-58.
3. Home, P., et al., Anti-Insulin Antibodies and Adverse Events with Biosimilar Insulin Lispro Compared with Humalog Insulin Lispro in People with Diabetes. Diabetes Technol Ther, 2018. 20(2): p. 160-170.
4. Thrasher, J., et al., Safety of Insulin Lispro and a Biosimilar Insulin Lispro When Administered Through an Insulin Pump. J Diabetes Sci Technol, 2018. 12(3): p. 680-686.
5. Home, P.D., et al., Efficacy and safety of MK-1293 insulin glargine compared with originator insulin glargine (Lantus) in type 1 diabetes: a randomized, open-label clinical trial. Diabetes Obes Metab, 2018.
6. Hollander, P.A., et al., Efficacy and safety of MK-1293 insulin glargine compared with originator insulin glargine (Lantus) in type 2 diabetes: a randomized, open-label clinical trial. Diabetes Obes Metab, 2018.
7. Heinemann, L. and A.W. Carter, Will Biosimilar Insulins Be Cheaper? Diabetes Technol Ther, 2017. 19(9): p. 513-515.
8. Carter, A.W. and L. Heinemann, If PBMs Guard Access to Drugs, Then Quis Custodiet Ipsos Custodies? (Who Will Guard the Guardians?). J Diabetes Sci Technol, 2016.
9. Carter, A.W., In the Biosimilar Marketplace Will There Be 50 Ways to Leave Your Insulin? J Diabetes Sci Technol, 2016.
10. Owens, D.R., et al., The emergence of biosimilar insulin preparations--a cause for concern? Diabetes Technol. Ther, 2012. 14(11): p. 989-996.
11. Carter, A.W., L. Heinemann, and D.C. Klonoff, Quality Control of Insulins and Biosimilar Insulins: What Do We Know? J Diabetes Sci Technol, 2016. 10(4): p. 811-815.
12. Carter, A.W. and L. Heinemann, Insulin Concentration in Vials Randomly Purchased in Pharmacies in the United States: Considerable Loss in the Cold Supply Chain. J Diabetes Sci Technol, 2017: p. 1932296817747292.
13. Dowlat, H.A., et al., Interchangeability among reference insulin analogues and their biosimilars: regulatory framework, study design and clinical implications. Diabetes Obes. Metab, 2016.
14. Perrin, C., M. Ewen, and D. Beran, The role of biosimilar manufacturers in improving access to insulin globally. Lancet Diabetes Endocrinol, 2017.
Robert Claar, Opportunities in Japan (cont.) …
Human iPS cells were first implanted for the treatment of age-related macular degeneration (autologous implant in September of 2014 and allogeneic transplant in March of 2017). Additional iPS cell clinical trials were approved in Japan for Parkinson's disease in 2017 and severe ischemic cardiomyopathy in 2018, with more programs under development, including for thrombocytopenia and spinal cord injury.
Breakthrough research in iPS cells is what got this started, but that is not the whole story. This article explores the current status of regulations and opportunities in Japan. The environment has now been established for fast-tracked clinical research and approvals in the regenerative medical field. What does that mean for companies in Japan and companies interested in coming here to accelerate their development programs?
In November of 2013, Japan announced new regulations which became law in November of 2014. The new Act on Pharmaceuticals and Medical Devices (PMD Act) established regenerative medical products (RMPs) as a distinct third category, after drugs and devices. A new office was established for the review and regulation of this new category in the Pharmaceuticals and Medical Devices Agency (PMDA): the Office of Cellular and Tissue-based Products.
RMPs are defined as processed (more than minimal manipulation) live human or animal cells that are intended to be used for the reconstruction, repair, or formation of structures or functions of the human body, the treatment or prevention of human diseases or for gene therapy.
The goal of the RMP inclusion in the PMD Act was specifically to enable early conditional approvals. Now, conditional approval is possible based on a limited number of cases to 'demonstrate safety and anticipate efficacy', while ongoing evidence can be studied in post-marketing registration studies within 7 years from conditional approval.
The stated goal is to enable treatment access for patients with unmet medical needs. Certainly, the government of Japan was also very keen to trigger economic growth based on the Yamanaka effect, and wanted to create a framework that enabled speedy but safe development for RMPs.
At the same time as the PMD Act, Japan created the Act on the Safety of Regenerative Medicine (Safety Act) under regulation by the Ministry of Health, Labour and Welfare (MHLW). The goal of the Safety Act is also very clear. Japan needed to rein in potentially unsafe practices at cosmetic and other clinics where doctors were administering to patients willing to pay for expensive, unproven stem cell therapies and cancer vaccines, etc. The Safety Act doesn't outlaw these practices, but requires that all facilities and programs be properly registered.
The Safety Act categorizes RMP programs into 3 classes by risk level, which in turn determines the level of certification and oversight required:
- Class I: iPS cells, ES cells, other allogeneic cells, gene therapy, other engineered cells and high risk programs
- Class II: Autologous cell therapies
- Class III: Autologous cell therapies without transdifferentiation
Programs are further categorized as Medical Care, which are patient pay commercial programs, and Clinical Research. As of this writing, the current total number of RMP programs in Japan is 3,704. Of these, there are 144 registered Clinical Research Programs nationwide.
The requirements before initiating first-in-human clinical studies include product, CMC and non-clinical study factors. In terms of product factors, the applicant must investigate the main and secondary pharmacological actions in vitro and in vivo and confirm the mechanism of action of the therapy, the characteristics of source cells and the rationale for animal models to be used in non-clinical studies.
CMC requirements include an explanation of the structure and other product characteristics, process for the management of impurities and an explanation of the method of ensuring quality consistency of the investigational product.
Required non-clinical study results include pharmacodynamics, immunological cross-reaction data, in vitro safety pharmacology and toxicity. The minimum anticipated biological effect level (MABEL) needs to be defined based on the results of these non-clinical studies in the most appropriate animal models.
Besides certification and oversight, the Safety Act also includes one accelerating aspect. It enables medical institutions to outsource cell culturing and processing activities to certified companies. This was seen as time consuming and a development bottleneck for some medical facilities.
The current number of approved cell culturing and processing facilities, including medical institutions and companies in Japan is 62 for Class I programs and an enormous 2,510 facilities for Class II and III programs. In addition, the MHLW has approved 5 companies from Korea and 1 company from Taiwan. There is an opportunity for more overseas CDMOs to obtain MHLW certifications under this regulation.
The sheer number of facilities requiring materials, media, systems support and logistics must represent a significant business opportunity, if one is to believe the gold rush adage of profits being made by those supplying the miners.
We see that five years after the new regulations, many companies and medical facilities are active in cell processing and clinical studies, and a robust ecosystem has grown around this clinical and research activity. The initiation of studies has become easier and the possibility for early conditional approval makes Japan particularly attractive.
However, the fact remains that Japan still has only 4 RMP approvals: JACE and JACC from J-TEC (a FujiFilm subsidiary), HeartSheet from Terumo and TEMCELL from JCR Pharma.
So, what does the future hold? It is helpful to look at the IND / Clinical Trial Notification submissions to see what approvals are likely to come soon. It's also interesting to note the following 3 foreign capital firms with ongoing clinical trials in Japan: Novartis Pharma, Janssen Pharmaceutical and Caladrius Biosciences.
Our view is that Japan is an attractive market with many ongoing clinical programs and a significant number of new approvals coming in the near future. Information from the PMDA showing an increase in the number of development consultations for RMPs indicate that the number of clinical research programs and clinical trials will continue to grow.
We are on the cusp of regenerative medicine breakthroughs in Japan, and five years into the new regulatory regime, in many ways it still feels like we are at the starting gate.
Japan enables early initiation of development programs based on supportive regulations, highly motivated researcher physicians and an advanced ecosystem of medical facilities and companies. Japan also offers the possibility for approval based on limited data which can come from physician-initiated studies.
It's true that there are only 4 approvals so far, and it's also true that not every RMP program in Japan will utilize the conditional approval pathway available for regenerative medicine. While this pathway enables a quicker route to patient access and commercialization, some companies feel there are drawbacks versus a traditional development path. Those include all-case post-marketing surveillance and limited ability for commercial rollout to a broad number of medical facilities until the full approval is obtained.
Another interesting factor is that Japanese regenerative medicine companies with global reach are not starting all their programs in Japan first as a matter of course. They are certainly focused on Japan development but are choosing their first region for each of their programs based on epidemiology and market needs. Fujifilm and Healios are examples of Japanese companies with overseas RMP programs.
For an overseas company looking at coming to Japan, regardless of whether you intend to develop your asset yourself or license to a Japanese company, and whether you plan to develop based on the conditional approval or traditional pathway or decide along the way, two factors will be absolutely critical to your success. First is selecting and partnering with KOL doctors. Second is collaboration with the PMDA.
Doctor relationships at important facilities are necessary for generating medical society support, political support and validation for your program. Onboarding your investigator team early with a full understanding of their motivations, personal and facility capabilities, relationships and network is of great and lasting importance. Their involvement in Japan can also support your ex-Japan activities and networks.
Positive PMDA collaboration is also necessary for success. Ensuring your Japan-based investigators are fully supportive and willing to advocate in front of regulators is one factor. Another is to remember that RMPs are hard to regulate, and every program is new and unique. Despite the PMDA's good intentions, they will struggle to regulate and approve new and unfamiliar programs.
Sponsor companies should think of the PMDA as a partner that requires support in order to move programs forward. Partnership and collaboration among the sponsor company, KOL doctors, the PMDA and experienced consultants is necessary for success.
Japan is open for RMP business, and I hope we can help more overseas companies launch their programs here.
Bart Van der Schueren, Ph. D, M.D., The European Regulatory Framework (cont.) …
European regulators rightly understood that harmonization was needed between its 28 (soon to be 27 because of Brexit) member states in terms of the requirements to obtain marketing authorization. This "one stop" for regulatory approval within the European Economic Area (EEA; i.e., the 28 (soon to be 27) member states of the European Union (EU), Iceland, Liechtenstein and Norway) has the obvious advantage of saving valuable time that was previously lost because of fragmented requirements and processes in each member state. In addition, it expands access to a much wider expertise available across all countries and a better monitoring of the safety of medicinal products throughout their life cycle.
It was this need for harmonization that led to the founding of the European Medicines Agency (EMA) in 1995 for the protection of public and animal health through the scientific evaluation and supervision of medicines. The EMA's Committee for Medicinal Products for Human Use (CHMP) is responsible for conducting the initial assessment of EU-wide marketing authorization applications, assessing modifications or extensions ('variations') to an existing marketing authorization, considering recommendations of the Agency's Pharmacovigilance Risk Assessment Committee (PRAC) on the safety of medicines on the market, and when necessary, recommending European Commission changes to a medicine's marketing authorization (including its suspension or withdrawal from the market). The centralized procedure is mandatory for human medicines for the treatment of HIV/AIDS, cancer, diabetes, neurodegenerative diseases, auto-immune and other immune dysfunctions and viral diseases. In addition, it is mandatory for all medicines derived from biotechnology processes, advanced therapy and orphan medicines. Potential marketing authorization holders (MAHs) of other medicinal products may opt for a centralized or decentralized procedure in one or more EU member states simultaneously.
Recognizing that his need for harmonization between member states created EMA is a key to better understanding how it differs from the Food and Drug Administration (FDA) in the U.S. The FDA developed as a consumer protection agency and has the advantage of centralization and common rules across the American States. The EU regulates medicinal products through a network of centralized and decentralized agencies throughout its member states and has to strike a difficult balance between harmonization while preserving national autonomy. This affects how marketing authorizations are assessed. Within the European system, two member states are nominated to assess a marketing authorization (rapporteur and co-rapporteur). They independently assess the marketing application in terms of quality, pre-clinical, pharmacokinetic and pharmacodynamic and clinical data until day 80. Subsequently, their assessment and a list of outstanding issues are presented to all other member states for comments and a consolidated list of outstanding issues precluding marketing authorization is returned to the aspiring MAH. Its responses are then assessed and discussed at CHMP, until a positive benefit risk balance can be established and CHMP can adopt a positive opinion for marketing authorization. In addition, the post-approval measures and risk management plan are agreed upon between the PRAC and the aspiring MAH.
The total assessment time amounts to 210 days (or 150 days when accelerated), excluding 'clock-stops,' during which the aspiring MAH formulates responses and conducts additional analyses. Ultimately, the applicant also has the opportunity to defend its position to all EU member states and Norway and Iceland during an oral explanation. The final decision is reached either by consensus or vote in which a majority is defined as 17 of the currently 28 members + 5 co-opted members (individual members of CHMP selected for their expertise). Norway and Iceland can comment, but do not have a vote within the system.
This process is different from what happens under the FDA, where medicines are approved by divisions with jurisdiction over therapeutic areas and modalities, and the agency is more broadly responsible for the safety and security of the food supply, all cosmetics, dietary supplements, health care products that use radiation and medical devices. In contrast, EMA only regulates medicinal products.
The European attempt to harmonize drug approval has proven to be successful. It remains however fundamentally different from the system in the US and also does not guarantee that a marketed drug with a demonstrated positive benefit risk will make it to patients. This is the ultimate challenge in a continent where health care is provided and reimbursed by each individual member state. There are attempts to improve the collaboration between payers and the regulatory agency. However, it is easy to understand that this is a challenge in view of the heterogeneity of the financial capability of each member state. Nonetheless, the European system has clearly demonstrated its value and will continue to do so for member states that opt in. Brexit confronts EMA with the challenge of moving from London to Amsterdam and losing one of its most valuable members. However, it is ultimately a spirit of cooperation that will ensure Europeans to have access to the best and most innovative medicinal products. Honi soit qui mal y pense.
The views expressed by the author are his personal views and may not be understood or quoted as being made on behalf of or reflecting the position of European Medicines Agency (EMA) or one of its committees or working parties.
Lana Pauls, MPH, My Career Continuum (cont.) …
The Beginning:
I started my career at the FDA in 1990 as a Project Manager, interestingly enough, working from time to time directly with Kinexum founder, Dr. Zan Fleming, for approximately 6 years (I stayed in touch with Zan until he left the Agency in mid-1998). One of my most memorable experiences as a project manager was when a Medical Officer in the review division told the sponsor that they had to re-do a $1.7 million trial because she "didn't like the design." This happened in my first week on the job, and I was simply awestruck. At this point, from a sponsor's perspective (and mine), working with the Agency seemed like navigating a black hole, as there was no 'true' project management, and absolutely NO transparency or consistency across the review divisions. The sponsor heeded the advice and repeated the trial. This made me think the Agency had omnipotent powers.
With the implementation of the original Prescription Drug User Fee Act (PDUFA) in 1992, project management was institutionalized, and processes, procedures and communications slowly began to improve. PDUFA also increased funding, and established timelines for reviews. In approximately 1999, the Center for Drug Evaluation and Research (CDER) implemented a Quality Assurance (QA) unit to help increase consistency and transparency.
PDUFA II to PDUFA VI continued to implement increasing consistency and transparency, by mandating new timelines, development of guidances, pilot programs, and public meetings.
Over the years, I held a variety of leadership roles in project management, quality assurance, strategic planning and training, and observed the Agency evolve from an omnipotent regulator to a supportive regulator giving tractable guidance to the pharmaceutical industry. I cannot deny that there is still a sense of mystery from the sponsor's perspective, especially for start-up pharmaceutical companies. However, my perspective certainly changed over the years, and I now truly believe that the FDA and Pharma are "on the same side" in terms of delivering safe and effective life science products to patients.
The Next Step:
After 26 years at the FDA, culminating in a leadership position in Post Marketing, I joined IQVIA (formerly known as QuintilesIMS) as a Director of Global Regulatory Affairs (GRA), in which role I provided regulatory affairs strategies and supported regulatory CTD submissions to the FDA and other regulatory authorities.
IQVIA, with over 59,000 employees is the largest Contract Research Organization (CRO) in the world.
When I moved to IQVIA, I thought that the mystery would diminish because of the volume of "working knowledge" and established SOPs. Although hundreds of SOPs were in place for the vast number of employees on payroll (I was required to sign off on over 70 SOPs in my first week), the actual day-to-day work was not necessarily well-defined, and often inconsistent across individuals on the same team, as well as across project teams. This "industrialized approach" and multiple silos (each having its own "piece of the pie" sometimes interfered with morale, and could lead to differing interpretations of regulations, causing inconsistencies in final work product and delays. In addition, GRA was not centralized, and existed as a sub-group among multiple Operating Divisions, which again contributed to inconsistencies and sometimes confusion. This experience impacted my perspective of how a large CRO views FDA's opinions and comments and its relationships with current and potential clients.
Current State:
After two years with the large CRO, I decided to work either within a smaller company, or as an independent consultant. I have found a productive and enjoyable application of my expertise and experience in consulting for Kinexum clients, helping Kinexum implement systems and processes and engage with its clients, and conducting assignments through my Regexel, LLC. I have great respect for my Kinexum colleagues, who are dedicated and collegial professionals, and see the value for clients of the Kinexum approach, which can assemble a team of experienced functional experts to advise regarding the complex, interdisciplinary work of life science product development.
The common bottom line throughout my career has been the motivation to more effectively and speedily bring safe and effective products that save lives and improve the quality of life for the American public, and this has brought, and continues to bring me, deep satisfaction.
Upcoming Conferences
New Kinexum team Members
Kinexum provides strategic regulatory, clinical and non-clinical, manufacturing and other translational advisory services for life science product development.
Our experts typically have decades of experience in government, industry and/or academia, and have broad experience with a range of modalities (including small and large molecules, devices and digital health) and therapeutic areas (including diabetes, cardiovascular, GI, oncology, neurology, wound healing and infectious diseases). We manage and salvage complex assignments, and file regulatory submissions and negotiate with the FDA and agencies in other major markets.


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The rapid convergence of social networks, mobile phones and global positioning technology has given Duke University engineers the ability to create something they call "virtual sticky notes," site-specific messages that people can leave for others to pick up on their mobile phones.
A team led by Roy Choudhury has developed a new software system that enables users to obtain location-specific, real-time information – either passively or directly – from other mobile phone users across the world. It will be as if every participating mobile phone works together, allowing each individual to access information throughout that virtual network.
Interested in trying that new Mexican restaurant? Tap into the virtual sticky notes floating in the ether within the restaurant and find what other network users thought of it.
Heading to the airport and need to know where the traffic jams are? Sensors in the phones detect movement and can relay back to the network where traffic is the heaviest.
The potential of this new application, which has been dubbed micro-blog, is practically limitless said Roy Choudhury.
"We can now think of mobile phones as a 'virtual lens' capable of focusing on the context surrounding it," Roy Choudhury said. "By combining the lenses from all the active phones in the world today, it may be feasible to build an internet-based 'virtual information telescope' that enables a high-resolution view of the world in real time."
The application combines the capabilities of distributed networks (like Wikipedia), social networks (Facebook), mobile phones, computer networks and geographic positioning capabilities, such as GPS or WiFi.
"Micro-blogs will provide unprecedented levels and amounts of information literally at your fingertips no matter where you are, through your mobile phone," Roy Choudhury said. "We have already deployed a prototype, and while some challenges remain to be addressed, the feedback we've received so far indicates that micro-blog represents a promising new model for mobile social communication."
Mobile phones are already more than just communications devices, Roy Choudhury points out. Increasingly they are coming equipped with cameras, GPS service, health monitors, and even accelerometers, devices which measure speed.
In simple terms, people who use the micro-blog application will enter information – photos, comments, videos – into their mobile phone, where it will be "tagged" by the user's location. Passive information, such as location or speed, can also be recorded. All this information is then sent to a central server, where it is available to all participants.
"So if you're planning a trip to the beach or a restaurant, you can query the micro-blog and get information or see images from people who have been or are currently there," Roy Choudhury said. Another application consists of individual, localized pockets of information.
"Say you are in a museum," Roy Choudhury said. "As you pass a particular painting, your phone could download comments from art experts providing relevant information about that painting."
The current prototype works with the Nokia N95 mobile phone, but Roy Choudhury said the application will eventually be written for any kind of programmable mobile phone. He also believes that these, and other as-yet-to-be imagined applications, will be commonplace within five years.
However, Roy Choudhury said there are three solvable issues that still need some work. The first is the trade-off between precise geographic location and battery power.
"GPS, while it can be accurate down to several meters, can also drain a mobile phone battery in seven hours," Roy Choudhury said. "On the other hand, WiFi and GSM technologies are widely available and don't use as much energy, but they aren't nearly as accurate. We believe that an approach blending these technologies will probably solve that problem." (GSM is an international cell phone standard that enables global roaming.)
Another issue is more societal than technological: What kinds of incentives would inspire users to enter information when queried by strangers, since that would involve their time and battery power.
Finally, location privacy needs to be addressed. Since mobile phones are transmitting data – including location – back to a central server, users must trust the administrator to keep this information private. Roy Choudhury believes that these issues can be addressed by assigning different modes – private, social or public – much like social networks already do.

subset: commoncrawl


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St. Helena Island Open Farm / Pasture Land
Beaufort County, South Carolina
21.01 +/- Acres
Parcel #/ID: R300 029 000 0164 0000
This 21 +/- acres of primarily open pasture land on St. Helena Island just outside of Beaufort, SC is quite the gem, featuring separated fenced pasture areas, mature hardwood trees, a pond, open field areas, and hidden future homesite area. It lies in a rural agricultural section of Beaufort County, surrounded primarily by open farmland, timber/recreation tracts, rural residential, and is seconds from saltwater. The tract has been set up for a homesite, pond, fields, and fenced pasture areas, featuring multiple live oaks and palmetto trees along the classic Lowcountry landscape. There is a well already in place, and a septic permit has been previously acquired for a new home here. There are 70 +/- acres that adjoin that could possibly be added on if desired. This tract is in a quiet area off of Scott Hill Rd, only minutes to Lands End and Fort Fremont, and a short drive to other beaches, such as Fripp Island, Hunting Island State Park, and Harbor Island. It is also a short, easy drive back into Lady's Island and Beaufort.
Estimated Acres:
21.01 +/- acres
Property Highlights:
Great opportunity for an equestrian estate. Two separated pastures in place on opposite sides of property.
Great opportunity for mini ranch/farm and holding a mixture of horses, cattle, and/or other farm animals.
Potential for hunting and many other recreational activities, to go along with a new homesite area if desired. Small pond in place.
Potential for dove field(s). Farming, gardening, ranching, and many agricultural activities are all possible with beautiful, primarily high and dry, hard to find, open land featured here.
Quiet area, not far from multiple local attractions, saltwater rivers, boat landings, beaches.
Conservation Easement in place, allows for construction of new home / outbuildings, agricultural / recreational activities, no future subdividing or commercializing (Including adjoining 70 acre tract). See attached doc.
Drainage ditches and road system already in place. Fences/gates in place. This parcel has already been thought out, set up, and is ready to build or to customize as your own!
Conservation Easement in place. Document attached. Does not allow for further subdivision. Allows for new homesite and outbuildings.
Taxes: $56/year (2018)
|Road Frontage:
Septic Needed
|Appointment Only
Sign on Property
Utilities: Electricity, Well, Septic Needed
Zoning: Agricultural
Terrain: Level
Road Frontage: Paved
Showing: Appointment Only, Sign on Property
Listing ID#: 1228619


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Foods that Improve Your Mood
What you eat is an important part of how you feel! There are foods that can improve your memory and brain health, foods that can help you sleep more restfully, and now foods that will just make you feel better. These mood-boosting foods are loaded with the vitamins and nutrients your body needs to feel happy and healthy. Add a few to your diet and spend more time with a sprightly smile on your face!
Milk contains a good amount of tryptophan, which the brain needs in order to make serotonin. Seratonin is a neurotransmitter that greatly affects mood, and is known to have calming, happy-making effects. In addition, milk contains anti-oxidants that destroy free-radicals associated with stress.
Chicken and turkey are high in phenylalanine, an animo acid that the brain converts to dopamine; dopamine is a neurochemical known to elevate mood and motivation. Additionally, eating proteins helps slow the absorption of carbohydrate in the blood, which can leave you feeling more upbeat and productive.
Fish like mackerel and salmon are great sources of omega-3 fatty acids which boost serotonin levels and prime serotonin receptors (essentially enhancing your brain's receptiveness to the neurotransmitter). It's also rich in vitamins B6 and B12, which are an important part of the synthesis of serotonin.
Dark Chocolate
As we've mentioned before, dark chocolate is a great mood booster because it contains a fair amount of tryptophan, stimulates the brain's opioid production, and because it tastes great! With the increased serotonin and dopamine, you will feel calmer and happier, and with the great-tasting treat, you'll just feel good anyway.
These little blue berries are full of great antioxidants that will reduce stress-causing free radicals, in addition to vitamin C, which reduces the body's release of cortisol (a natural hormone that triggers the "flight or fight" response to stress), and thus, makes you calmer and happier.
Whole Grains
Complex carbohydrates like whole wheat pasta and whole grain rice boost serotonin levels, making you feel calm and at ease. Plus, they're digested very slowly, keeping you full, energized, and happy for much longer than simple carbohydrates like white bread would.
Photo Credits: Shiny Cooking, Cooking Light, The Food Enquirer, Culinary Cafe, Men's Health


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Once a Vision, make it a Common Vision
This starts as ahead of schedule as building up the vision itself. The base thought must energize. Somebody needs to be a piece of having any kind of effect. Having a chance to change an industry. To perceive and compensate in addition makes a difference.
- Begin with little gatherings to assess the significant components. You can move speedier in the information accumulation. Then drive assessment to organize with less included. You can likewise join more considerations rapidly, and survey complex examples all the more effectively with a little gathering. This gathering can make an impermanent and chosen reason for input assignments from basic regions of the organization.
- Ensure you have told everybody what you are doing a top line? why have "specialists" from essential territories as benefactors, and work to safeguard that basic administration. They should contribute and purchase in. Clean the "draft" vision and its essential drivers. The consequences for the organization's incomes, costs, framework and individuals with this little gathering. Impart advance routinely, with the goal that input starts coming early to such an extent that when the aggregate item is shared. Force is now assembled. This will convert your vision into a common vision.
- Offer this draft with key pioneers over the firm, and have them acquaint the draft with their kin both to study. Increment purchase in, and in addition to deciding the basic detail important to actualize the arrangement. It is essential to have done the homework going this exceedingly well. So that as the gathering of people extends, the work item is understood as strong, promising. Every individual and office can see their part in conveying it.
- Understand that change, even great change comes hard, particularly at first. Nonetheless, you display it, make sure the partners see it. That this exertion has full help from the highest point of the organization. That it is upheld by the conclusion pioneers too.
Few more suggestions
- To change implies disturbance. Individuals require motivation to change. Frequently today, for example, in the Internet or innovation enterprises, the commercial centre has prepared us. That change and speed of progress are basic both to survival and to achieving the gold toward the finish of the rainbow. In different businesses, this isn't generally so. Individuals frequently would rather not change regardless of whether it implies they will end up plainly wealthier. Change operators regularly think that it's simpler, albeit maybe less pleasant. To change coming up short organizations than right now fruitful ones. In the primary case, everybody is focusing on survival. In the last mentioned, everybody is happy with the way things are done now. For instance, with the present state of affairs.
- Consolidate purposes to alter the course of the vision. Incorporate however many of the accompanying as expectations. An emotional plan to change an industry, end up plainly number one, be the most imaginative, and so forth. A sensational motivation to change survival is in danger. Yet guaranteed on the off chance that we demonstration now. An acknowledgement and reward framework for those partaking. What's more, gold toward the finish of the rainbow?
- Understand that now and again, outsiders might be important to prepare. This relates to the aptitudes important to assess, examine, and deal with the key activities to an organized fruition. Also, to help introduce the abilities required for interminable change and learning.
- Set up the change administration aggregate independently. Yet fixing nearly to individuals who deal with every day?. This enables every day to work, yet to contribute to. Welcome the points of interest they will pick up at the introduction of the progressions.
- Deal with those that can't deal with change.
After a decade of immense study in this field, I have chosen to contribute as an entrepreneur with a wealth of experience across industries and market segments by helping through blogs. I have a proven record of building e-commerce platforms and a ready network of marketing and sales channels to reach a large audience. Moreover, I take a pragmatically unconventional approach towards describing how making small modifications in a person thinking, can yield massive results in their day-to-day lives.


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ETA Students Shine for Evert Tennis Academy!
by IVAN PASQUARIELLO | VIEW 132975
ETA students at Evert Tennis Academy competed in a total of nine USTA Florida Level 6 Tournaments finals. The most important part of the students' preparation for the event has been focusing on the mental aspect of the game.
Evert Academy's Director of Mental Conditioning, Doctor Vernice Richards, was pleased to acknowledge the students' progresses and commented saying: "For the past few weeks, athletes have been working on effectively using the time between points; both emotionally and cognitively.
They are learning how to manage their emotions after points and in preparation for the big, most important and decisive points. This work is certainly shown by the results they earned this past weekend." So let's take a look at the winners, and remember to check out the updated results for Evert Tennis Academy on their Facebook and Twitter pages! Emily Baru - Girls' 10 Singles Championship Draw Consolation Winner at the USTA Florida Rick Macci International Spring Break Challenger Level 6 - Boca Raton, FL.


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One of my destinations were the Japanese Alps but since I wanted to visit Kyoto too, the best option for me was staying in Nagoya. That meant I only had one day to visit Kyoto and that it was impossible to see everything.
The top 4 obvious things I wanted to do:
- Kinkaku-ji (Golden Pavilion)
- The Arashiyama Bamboo Grove
- Gion (Kyoto's most famous geisha district)
- Tetsugaku no michi (The Philosopher's Path and one of the cherry blossom viewing spots)
Doing the top 2 was pretty evident and if we weren't too tired, we could've added the geisha district too. That was the plan however this trip taught me that plans were made to be broken: I went to the Ginkaku-ji temple (Silver Pavilion) and not the Kinkaku-ji temple. Make sure you do your research as one letter can make all the difference.
The blessing behind my mishap is that it immediately brought me to the Philosopher's Path to see one of Kyoto's cherry blossom viewing spots. This path follows a canal which is lined by hundreds of cherry trees and it may have been #4 on my list but it sure went up 2 spots after witnessing the real deal.
This same path had also led me to the Honen-in temple which wasn't on the plan but ended up being my #1 in Kyoto. One thing I've noticed once I've set foot in Japan is that there's a lot of people everywhere, all the time. I've found peace for the very first time in Japan thanks to the Honen-in temple. This small temple wasn't crowdy and gave me time to meditate and pray in front of the Amida Buddha statue.
For the second half of the day, I had to choose between the Golden temple and the Bamboo Grove and since I already had my moment of peace at the Honen-in temple, I decided to go to the Arashiyama Bamboo Grove.
The fact is that the deserted pictures of the Bamboo Grove we see everywhere are very misleading. This place was so jam-packed with tourists I hadn't enjoyed it as much as I wanted to. It is unique and something I've never seen before but don't get your hopes up too high and hopefully your expectations might still be met.
If I were to ever have a do over again in Japan, I'd spend the night in Kyoto. The Golden Pavilion and the geisha district are still places I'd want to view and perhaps if I went really early in the morning or stay very late in the evening, I might have a shot at having a picture of an empty Bamboo Grove in Arashiyama.
Here's an useful tip in case you'd end up at the Ginkaku-ji temple instead of the Kinkaku-ji temple like I did: there's a direct bus that goes from the Silver to the Golden temple: bus 103 (keep in mind the 10 minute walk to the bus stop).
Me next stop: Japan 2016 Part III: Shirakawa-go


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Bread Winners Inc.'s freshly opened spot (just 3 bebe weeks in fact) is just a quick three minute drive from campus down on McKinney and is ready for SMU biz. Sara and I made the long haul last Tuesday to check out the new space.
The interior is beautifully decorated, with dark woods and fun patterns adorning walls and ceilings, Henry's Majestic feels like a cozy escape. The rustic, chic interior is centered around an impressively stocked bar and gorggggeous fireplace.
Enough about my interior design drooling, let's talk about food.
The menu is influenced by many a culture, from Asian to French, Italian, and Texan of course. Options are available for the adventurous eater as well as those wanting a familiar warm meal on a cold Dallas night.
Oysters Majestic – Butter and bacon, how can you go wrong? Kimchi butter adds an intriguing depth of flavor to this rather traditional Dallas area favorite. The pancetta and salt balances out the butter surrounding the big, plump lumps of oyster.
Sara and I had oodles of fun with the Cured Meats and Cheese Board. Her favorite mix was the blue cheese and apricot jam, while I preferred the salami slice with the cheddar cheese and grain mustard. Mixing and matching the different pieces was beyond entertaining, and it definitely helped that everything on the plate tasted de-lish. Even the chicken liver mousse (don't wince), which we were both a bit nervous about, proved to be light, airy, and a lovely complement to the smoky flavor of the manchego option.
HM slow roasts their rotisserie chickens fresh every day on an in-house spit. The chicken is far from dry and covered in a sweet, sticky sauce. Warning: half chickens are your serving size so prepare to be couch-laden post dinner.
Texas Pho – basically the same Vietnamese we all know and love with big hunks of Texas brisket as the meat portion. The broth is a blank slate that is made to be built upon by the add-ons offered by the restaurant, jalapeños, limes, egg, etc. Perfect for warming your bod during the predicted MIZ weather this weekend.
And now to the best part of every meal: dessert. They called this one a Beer and a Shot; a chocolate pudding infused with a strong stout and bourbon whipped cream. Sara and I are agreed – PHE-NOM. The stout flavor was just subtle enough to act as a highlighter for the rich chocolate flavor instead of taking over the dish. I'll be back for you soon, dearest.
Henry's Majestic also boasts a diverse, carefully crafted cocktail list that would elevate any date night or brunch with the gals. Ask for recommendations from the waiters, they know what's up.
Head over to Henry's and taste for yourself during happy hour, every Tuesday through Friday from 4-7.
Happy devouring dolls,
– A and SWM


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Join the owner of the Sea Hunter, Avi Klapfer and Sea Save Foundation Co-Founders – Georgienne Bradley (Scientist, Writer & Producer) & Jay Ireland (Filmmaker & Photographer) for this 12-day trip!
A World Heritage Site, Cocos Island National Park has been called one of the best diving spots in the world and is considered a "must do" by seasoned divers. This island's world-renowned waters explode with life, including innumerable whitetip reef sharks, schooling hammerhead sharks, silvertips, silky and Galapagos sharks, dolphins, mantas and marbled rays, sailfish, and the occasional tiger shark. Jacques Cousteau pronounced Cocos "the most beautiful island in the world."
"I am definitely a Cocoholic," says Jay Ireland. "I can't get enough of the high-adrenaline Cocos Island action. I never know what to expect, but I know it's going to be good. I have been lucky enough to dive some of the most fantastic destinations in the world, but nothing beats Cocos Island."
Georgienne Bradley has worked with Jay Ireland to raise awareness about this island since 1992. It was then that she brought back some of the first images of shark finning and presented them to then President Jose Maria Figueres. Awareness needed to be raised and laws changed. Postage stamps, two books and myriad magazine articles later, the duo are returning to the island.
Together they have logged over 3,000 dives at Cocos and contributed to the UNESCO petition which made Cocos Island a World Heritage Site. They love to share their stories about the island with others. When asked why they are returning, Bradley answers, "Cocos Island never disappoints. The underwater ecosystem is brimming with life. It's a photographer's dream. Topside is paradise. As you circumnavigate the island, you can see over 300 waterfalls! I never get used to the sight of walls of hammerheads. How could you? It makes me feel so alive!"
Ireland and Bradley will lead a fundraising trip for Sea Save Foundation aboard the luxury yacht, the M/V Sea Hunter with the Undersea Hunter Group, one of the world's preeminent adventure dive operators, for a 12 Day / 11 Night Cruise – May 3-14, 2019 – the height of the season.
The Sea Hunter is an intentional blend of work ship and luxury yacht. The 130-foot vessel was designed to pamper up to 20 discriminating passengers in 8 spacious, well-appointed staterooms. The ship's chefs prepare fresh, international-level, four-star cuisine. The DeepSee submersible might also be available to take you down to unbelievable sites that only a few have had the pleasure of viewing.
PRICING for Remaining Spots:
Cost per person includes –
Not Included –
+ Deposits are nonrefundable
+ Trip insurance is advised
Click here to organize your insurance with DAN (Diver Alert Network)
Click here for FREQUENTLY ASKED QUESTIONS about Cocos Island
Join Sea Save on this fabulous adventure while supporting ocean conservation! Proceeds benefit Sea Save Foundation, a 501(C)3 organization working to generate consciousness and encourage stewardship of natural ecosystems. Their campaigns protect our oceans by raising awareness, educating people about marine beauty and advocating change to resolve current challenges.
Don't miss the opportunity to be part of our exciting Cocos Island expedition!
Call us at 310 458 1020 or send an e-mail to firstname.lastname@example.com !
Located in the Eastern Tropical Pacific, 300 miles southwest of Cabo Blanco, Costa Rica, lies the renowned Cocos Island Marine Park. A rugged yet incredibly verdant island, this World Heritage Site is the spectacularly beautiful crown jewel of Costa Rica's many National Parks. In 1994, after several return visits to the island, Jacques Cousteau pronounced Cocos, "The most beautiful island in the world."
The island has an irregular coastline, which makes precise estimation of its land area more a matter of opinion than a surveyor's science, but it is roughly five miles by two miles (8 x 3 kilometers).
Cocos Island was formed during a volcanic upheaval about two-and-a-half million years ago and is composed of basaltic rock, labradorite and andesite lava flows. Its landmass is punctuated by four mountain peaks, the highest of which is Cerro Iglesias, at 2,080 feet or 634 meters above the sea.
There are only two bays with safe anchorages and sandy beaches: Chatham is located on the northeast side and Wafer Bay is on the northwest. Just off Cocos are a series of smaller basaltic rocks and islets. The largest satellite is Isla Manuelita (formerly Nuez). Thanks to the breathtaking marine life in its waters, Cocos Island was named one of the ten best scuba diving spots in the world by PADI (Professional Association of Diving Instructors) and a "must do" according to diving experts.
Costa Rica has two international airports. For optimum convenience, we recommend that you fly directly to San José rather than the more distant Liberia International Airport. Please kindly email your confirmed flight itinerary once purchased to firstname.lastname@example.com.
Pack lightly since you will be dressing for warm tropical weather. Please check with your airline for weight allowances and baggage policies. Airlines have ever-changing baggage limitations that can affect divers and photographers, so always check for updates on regulations.
All passengers must have a valid passport to enter Costa Rica. Most U.S., Canadian, EU and Japanese citizens do not require a visa. If in doubt we recommend checking with the nearest Costa Rican consulate to see if you will need a visa.
We strongly recommend each guest purchase comprehensive accident, medical, baggage and trip cancellation and interruption insurance when space is received. Trip insurance will protect you from financial disappointment if you are prevented from making your scheduled trip due to illness or family illness, or in the event that unforeseen circumstances prevent the airline or yacht from making its scheduled trip.
Please note, it is mandatory that you have a dive specific insurance that covers evacuation. We strongly recommend that passengers have valid Divers Alert Network insurance to provide coverage in the event of an accident. Cocos Island is a very remote area and the cost involved in evacuating a diver is very high. The D.A.N. policy is a vital protection to have. Please do not hesitate to contact us if you need assistance with obtaining dive insurance (at least one week prior to the trip).
We have also provided a link to DAN for your convenience at http://www.DiversAlertNetwork.org/partner/1669207/trip.
FEES & TAXES (Per Pax)
There is a National Park Fee of USD $560 which is included on your invoice.
All divers must bring proof of certification by a national certifying agency. The certification must allow the diver to dive to the recreational dive limit of 130 feet (40 meters). The Dive Master will request to see your certification before you are allowed to dive. If you are certified for Nitrox and other specialties as well, then remember to also bring those certifications.
Upon arrival in San Jose, you may take a taxi to your hotel. There are always taxis available at the airport and minivans for those who have a lot of gear. For accommodations in San Jose, Sea Save is recommending Hotel Sleep Inn Paseo Las Damas. You can make your reservations at http://www.sleepinnsanjose.com/. The night before departure, Sea Save Trip Leaders will inform you at the above hotel of your precise pickup time for transport to our dock and your awaiting vessel. The evenings on shore are at your leisure. Hotel nights and meals before and after the cruise are not included in the charter.
On the day of departure to Cocos, generally between 8 AM and 1 PM, you will be picked up from your hotel and transferred to the seaport village where you will board the vessel. The drive takes about 3 hours, including a stop on the way for a snack or lunch. The price of this meal is not included in your trip package. The ride will give you an opportunity to view some of the lush tropical forests and rich farmlands of the region.
At the end of your Cocos adventure, you will usually disembark the boat at 8 AM and be transferred back to your hotel in San Jose. The transfer takes approximately 2 hours, give or take.
Spanish is the official language, but English is widely spoken within regions associated with tourism.
Colones are the national currency, with 1 USD equal to approximately 571 (colones) as of March 2018. check xe.com for most current conversion rate. International credit cards and US dollars are widely accepted in regions associated with tourism. Hotels and banks will exchange US Dollars for Costa Rican colones. US dollars as well as Visa, MasterCard and American Express are accepted on the vessels. Personal checks or travelers checks are not accepted onboard.
Costa Rica and Cocos Island are 1 hour behind US Eastern Time during the North American winter and 2 hours during the North American summer.
Most of the action is at 60-90 feet /18-27 meters, and most dives are between 60-130 feet / 18-40 meters. The safety limit is set at 130 feet / 40 meters and a dive computer is necessary. Visibility averages 60-100ft/18-30m.
Average temperature is 79 F to 84 F (26 C to 29 C), although it can be a few degrees lower under the occasional thermocline.
To increase safety and bottom time while maintaining safe non-decompression dives the use of Nitrox is recommended. The vessel offers full onboard TDI training in Nitrox, with rental of Nitrox computers. Nitrox fills are free for Nitrox certified divers.
When all passengers are boarded, the vessel will take 32-36 hours to reach Cocos Island. Crossings are normally calm, but to prevent motion sickness we advise you to take the necessary precautions. At the conclusion of your trip, we will return to Puntarenas where a bus will be waiting to return you to your San Jose hotel.
You will need the following gear: 3-5 mm (1/8″ to 3/16″) wetsuit, mask, fins, snorkel, regulator with visible pressure gauge, a mandatory dive computer, buoyancy compensator, depth gauge, dive gloves, weight belt (without weights), dive light, and dive watch.
Weights for your weight belt: 2, 3, 4, and 6 lbs. (1, 1.5, 2 and 3 kilos). Also provided, air or Nitrox tanks — 80 cubic ft. aluminum (12 liters).
Please note, tanks are standard yoke (INT), not DIN. Please notify our offices in advance if you need an adaptor.
You can rent a complete line of ScubaPro dive gear: BCD, regulator, wetsuit, mask, fins, snorkel, and Aladdin Nitrox dive computers.
There is a limited supply of 15 Liter steel tanks. If you would like to rent one, make sure to reserve it well ahead of time.
The menu aboard offers a delicious combination of American and local cuisine. Meals are varied and well balanced, and delicious snacks are offered between dives. Food is abundant with plenty of fresh tropical fruit and salads and is served buffet style. Please let us know of any special dietary needs or requests, but try to be lenient, as storage and preparation space is limited on board.
Soft drinks & Beer: Free, Bottle of wine: $15 – $35.
Hard liquor is not available on board but guests are welcome to bring their own, which should be purchased prior to boarding.
We recommend casual and cool cotton attire while on board. Nights can be chilly and/or drizzly so bringing a sweater, light jacket or windbreaker is recommended. In San Jose, dress is slightly more conservative, like long jeans and collared shirts. For women, we recommend holding off wearing shorts and beach type clothing until you are aboard the vessel. We suggest packing in a soft duffel bag for easy luggage storage. Booties or hiking shoes are recommended if you want to visit the island.
There is usually one or two visits to the island itself during a trip.
The vessel has both 110 and 220 volts ac. The cabins have 110 volts ac only.
The vessel has standard US and European sockets (but not British style sockets).
There is a variety of nightly entertainment available on board: slide shows, DVDs, music, games and much more. Please feel free to bring along your favorites.
SEA SAVE FOUNDATION THANKS YOU FOR YOUR SUPPORT! SHOULD YOU HAVE ANY ADDITIONAL QUESTIONS ANY TIME, PLEASE DO NOT HESITATE TO CONTACT US AT email@example.com


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30 Home Gym Must-Haves
The home gym can be a blessing for a busy mom. There are no closing hours, no waiting to use the equipment and no need for a sitter to watch your kids. Unfortunately, it can often be confusing to know what items you really need in your home gym. That's why we've rounded up a list of 30 amazing must-haves to add to your home gym.
1. Compact Refrigerator with Wipe-Off Board Front: Looking for an easy way to remember your routine? Try writing it on your mini fridge! That way, when you reach in to grab a bottle of water or a sports drink, you can be reminded of your routine and goals for the week. (via Wal-Mart)
2. Body Solid Vinyl Dumbbell Sets: If you've been trying to get sexy arms for summer, these dumbbells are the perfect match. Pick up a set in every weight and then use our free-weight exercise for toned arms to whip those arms into shape! (via Amazon)
3. Dragonfly TPE Lite Mat: Doing ab exercises or a yoga routine on a hard floor can feel like torture! So try adding this amazing mat to the mix. (via Everything Yoga)
4. Rejuvenation 55 cm Complete Support and Stability Ball: The stability ball can be used for everything from ab exercises to squats. Looking for a way to incorporate this ball into our routine? Try our total body stability ball workout. (via Dick's Sporting Goods)
5. Rep Fitness Medicine Ball: The medicine ball is an excellent way to increase the intensity of your workouts. Whether you use it to pump or your squats or add resistance to a waist-wittling wood chop, you just can't go wrong with this medicine ball. (via Amazon)
6. VIZIO 24 Inch HDTV: What better way to work out to your favorite exercise DVDs than on this high-quality HD TV? This television is small enough to fit perfectly into your workout space, yet still large enough to make your favorite fitness DVD feel like a one-on-one with a personal trainer. (via Amazon)
7. TRX Suspension Trainer Pro Kit: Always wanted to try TRX training but hate the thought of those expensive classes? Now you can try this amazing workout at home for half the cost! (via SPRI)
8. Champion Weighted Jump Rope: If you're looking for a mega calorie burning workout that's totally mobile, try adding this gem to your fitness arsenal! This weighted rope offers both cardio and resistance in the convenience of a portable rope. It's also a great addition to our ultimate playground workout routine! (via ESports Online)
9. The STEP: This adjustable bench is the perfect match for our High Energy Step Workout. Not into step aerobics? This bench can also be used for step-ups and as a bench for tricep dips and even pushups. (via Amazon)
10. Seca 700 Physician's Balance Beam Scale with Height Rod: Yes we know, weighing yourself is likely the last thing you want to start your morning with, but it's important to do in order to stay on track. This scale is unlike your typical bathroom scale. It gives you an accurate weigh-in every time. (via Amazon)
11. Gliding Disks: These disks are perfect for adding a little variation to your average pushup, and the colors will add a fun touch to your workout room. (via SPRI)
12. BOSU Balance Trainer: The BOSU ball can be used for so many amazing things! Use it to add intensity to lower body workouts or flip it over and strengthen your core while working on your upper body. Either way you work it, no workout room is complete without a BOSU Balance Trainer. (via Amazon)
13. GoFit Pro Massage Foam Roller: Tough workouts deserve a little R&R, and this foam roller is your body's best friend. Use it to massage out the kinks and keep you feeling as amazing as you look. (via REI)
14. ProForm Performance Treadmill: It's a fact that running burns a crazy amount of calories and is a great way to work your legs and butt. Unfortunately, the weather can often suck the joy out of running. That's why this treadmill is the perfect home gym addition. Now there really are no more excuses! (via Wal-Mart)
15. Pilates Power Ring Pro: If you've been trying to get those thighs toned and tight, this little ring will help you get there fast. Use it to trim your inner thigh area or as an addition to really pump up your Pilates workout! (via SPRI)
16. Momentum: Designs That Move You: Who knew a bracelet could be inspiring? These adorable pieces of jewelry have inspirational quotes to keep you motivated when you don't think you could possibly last another second in plank pose. (via Designs That Move You)
17. Everlast Boxing Gloves: These gloves may look sweet, but add them to your favorite kickboxing workout and you'll be ready to put the smack down on those extra pounds. (via Target)
18. Free Standing Ballet Bar: Love Barre workouts but never seem to be able to make those crazy class schedules? Now you can add an in-home barre workout to your routine with this standing ballet bar. (via Amazon)
19. Slastix Resistance Bands: If you travel or simply have limited space in your home gym, these toning bands will be your best friend. With as much resistance as the average dumbbell, these amazing bands offer a serious workout without hogging all of your space. (via ESports Online)
20. Heart Rate Monitor Watch: If you're working hard to get that body into bikini shape, then you need this heart rate monitor. Not only will it ensure that you're keeping within your fat-burning zone, but it will even let you know how many calories you burned during your workout! (via Amazon)
21. InStride Pro Electric Mini Stepper: This mini stepper is the perfect addition to your home gym. Just pop it in the corner and get to stepping! (via Wayfair)
22. Wireless Bluetooth Speaker: If cranking the tunes through your headphones isn't quite enough to keep you motivated during a workout, then this speaker will be a life saver! It only requires a little bit of space but it will pump up the volume and get you rockin'! Need a workout pick-me-up playlist? Try one of these! (via Amazon)
23. Shaun T's FOUCUS T25 Base Kit: If lack of time has been your excuse for getting into shape, sorry, but your excuse has been squashed! T25 gives you a full body, kick-butt workout in only 25 minutes. (via Amazon)
24. TurboFire DVD Workout: If you loved Turbo Jam but felt like it was time to up the intensity, Turbo Fire has you covered! This amazing routine will burn fat and tone your body in all the right places. (via Amazon)
25. 'Good Vibes Only' Print: Need to add a little character to your home gym? Let the good vibes roll with this inspirational print. (via Etsy)
26. 'Be Stronger Than Your Excuses' Print: This print will help to remind you that the only thing stopping you from reaching your goals is yourself! (via Etsy)
27. 'Why You Started' Print: When the going gets tough, this print will be there to remind you to keep going. (via Etsy)
28. Honeywell Super Turbo Air Circulator: Even in a home gym, workouts can be tough with all of this humidity. Cool off while you're getting hot with this portable floor fan. (via Target)
29. Fuel Performance Adjustable Plyometrics Box: If you're not adding plyo to your regular routine, you should be! This plyo box fits perfectly in the corner or even in a closet, but really adds intensity to exercises like box jumps and step-ups! (via Amazon)
30. Lebert Equalizer: Add this amazing equalizer to exercises such as tricep dips and elevated pushups, to take your muscle toning to a whole new level. (via Amazon)
So if your home gym is lacking a few key essentials, get it up to par ASAP! With these amazing home gym must-haves, you'll be on your way to your best shape ever!


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GREAT BEND (GH) — A Great Bend man who shared pornography involving children under age 5 was sentenced Tuesday to nearly 14 years in federal prison.
Charles A. Gann, 49, pleaded guilty to one count of distributing child pornography. In his plea, he admitted that an investigator with the Kansas Internet Crimes Against Children Task Force was able to use a file-sharing program to download child pornography from Gann's computer.
Gann, who faced from 5 to 20 years in prison, received a 165-month sentence from District Judge John W. Broomes.


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A NEW group is hoping to clean up Girvan's act after being inspired by determined Ayr volunteers.
Town Action Group (TAG) Girvan, has now launched after one resident felt determined to "brighten" up the tired looking streets of her town after seeing TAG Ayr transform locations up the road.
Lynne Sykes made contact with Maxine of TAG Ayr to start the Girvan version of the group, and last week a team of 16 volunteers helped fill 36 bags as they completed their first project of cleaning up the Harbour area.
Lynne told the Advertiser how she wants to bring back a sense of civic pride back to Girvan.
She said: "It's all gathered momentum very quickly, the folk in Girvan have been brilliant. We had 16 turn up on Sunday including school age kids. We did really well we tided up the Harbour area, it's where buses stop, it's been looking neglected and wasn't looking great. It was mainly overgrown weeds some rubbish and leaves lying."
The clean up was held a success, but Lynne and others were shocked to find what appeared to be at first a dead bird lying in amongst the leaves, but was instead a polystyrene ornament.
Lynne joked: "The kids were cleaning this area and I thought it was a dead cat, or a pheasant. We were panicked as we didn't know what it was going to be. I got one of the guys to go in and it turned out to be someone's ornament of a chicken."
The group is now focused on taking on other projects, but Lynne hopes it will inspire others to pick up after themselves.
The mum who also works as a nurse believes some time out every a week can make the difference in a town.
Lynne said: "I hope it changes the mind set that people think a bit more about where they live.
"People have to take control. My 11-year-old son said the skatepark he goes to is a mess, I told him to get his friends together and do something about it, it's about changing attitudes.
"I work night shift. Sunday was just a couple of hours, there is no fundraising needed, just a couple of hours each week is all that's needed."


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Arunachal: Honoris Causa Doctor of Literature Award conferred to Kiren Rijiju
The Arunachal University of Studies has conferred upon the Honoris Causa Doctor of Literature Award to Union Minister of state for Home Affairs, Government of India, Kiren Rijiju. The award was bestowed to him by the Pro-Chancellor of University Vishva Lochan and Vice-Chancellor Prof. V.K. Kawatra.
Rijiju while expressing his happiness over the development of the several higher learning educational institution and AUS as one of them. He lauded the authority of the Arunachal University of Studies for imparting quality higher education to the upcoming generation of the state which will become the foundation in transforming economic conditions of North East and Arunachal Pradesh making it more prosperous in coming years.
He further said that the University is gradually becoming one of the largest & most progressive Institution of the region under self-sponsored category in the field of higher education. He also mentioned that if such establishments were made in 1970's then the present education scenario in the region could have much better been altogether different.
He expressed his satisfaction and said that the University is duly recognised from statutory bodies and is developing a world class infrastructure. It is noteworthy to mention that Arunachal University of Studies is the only UGC recognised University of Eastern Arunachal Pradesh and has created laurels in the field of education with its excellent education methodology, infrastructure and is continuously promoting the cause of quality education with the help of its 12 constituent faculties.
The Arunachal University of Studies is abridging the education gap in the region which has been felt from quite sometime time and is creating more appropriate linking between the school education and higher education.
It is like dream coming true and He said he feel happy to have become a part of growing institution and assured of wholeheartedly cooperation for the development of the University and appeal all stake holders to come together in developing the education sector and education scenario in building of human resource development of the state.
AUS Director Trilochan Singh inform that that announcement of the degree was already done on 2nd Convocation of the university on January 31 2018 and since he was absent and the degree was handed over to him at his office at New Delhi recently.


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NXP Semiconductors is set to launch its EdgeVerse platform brand that expands the company's rapidly expanding portfolio of scalable and secure edge computing solutions. EdgeVerse is thought to be the industry's most comprehensive edge computing portfolio under a common brand platform.
The platform combines NXP's complete portfolio of industrial, IoT, and automotive embedded processors, security, enhanced short-range connectivity solutions, turnkey production-ready solutions, software solutions for Machine Learning (ML), audio/video experience, and device management software platforms. It includes the embedded processing portfolio of NXP i.MX and Layerscape applications processors, K32, LPC and Kinetis microcontrollers, i.MX RT crossover processors, and automotive microcontrollers and processors.
Part of the platform, the security portion includes a range of products from discrete secure elements to processors with advanced integrated security, classified by easy to understand security levels. Additionally, the offering addresses AI at the edge by providing tools and engines for machine learning, inferencing, and easy connectivity to the cloud. It includes NXP's eIQ machine learning software development environment, Immersiv3D audio experience suite, and EdgeScale device management platform, which users can employ with existing models, or quickly design, train, and optimize new models for deployment across the breadth of NXP's portfolio.
As part of the EdgeVerse platform, the EdgeLock SE050 Plug & Trust Secure Element family secures Industrial 4.0 and IoT applications from edge to cloud. The Common Criteria (CC) EAL 6+ certified EdgeLock SE050 is said to make it easy to implement high-performance security for sensing and control. Additionally, it streamlines the deployment of IoT services and onboarding of edge devices to public and private clouds, edge computing platforms, and infrastructure.
The EdgeVerse platform is available today while EdgeLock SE050 is expected to be available by July 31. For more information, visit the EdgeVerse page.


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Handbook of Organized Crime in the United States
Handbook of Organized Crime in the United States
Robert Redfield, the eminent American anthropologist, once remarked that the surest sign of the emergence of a new subdiscipline in science was analogous to what he had found to be characteristic of the establishment of small folk societies: a social structure organized by a kinship system made up of clans which shared a common folklore and mythology about the origins and values of the group. This timely and comprehensive volume of essays, demonstrates that by Redfield's definition, the study of organized crime has established itself at last as a coherent subdiscipline, if not yet as a functional community, of research interest.
When in the 1950s organized crime burst anew into the popular culture, questions of its character, structure, and dimensions were the exclusive province of government law-enforcement officials, some journalists, and a very few scholars such as Daniel Bell and Donald Cressey. This volume demonstrates how far we have come since then. Not only criminologists, but sociologists, anthropologists, historians, economists, political scientists, and legal scholars along with journalists and jurists have joined with criminal justice professionals to define, describe, analyze and recommend solutions to what is clearly a world-wide rather than peculiarly American social phenomenon. But despite decades of research, investigation, and any number of books and films--both documentary and dramatic--the study of organized crime remains a morass of conflicting claims and often spurious assertions held together more by controversy than by any consensus.
Within the loosely knit social structure of students and pundits of organized crime, we established a kinship system dividing ourselves into a number of . . .


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New CSR Experienced Manager Card being introduced
From 30 March 2018 the Construction Skills Register (CSR) is introducing a new Experienced Manager Card. The card is available to experienced managers and senior managers who do not have a construction related degree, professional membership or relevant NVQ.
The Experienced Manager card is one of a number of cards available following the removal of occupational assessments for managers and senior managers from 30 March 2018. Other options include the Academically Qualified Person card or the Professionally Qualified Person card.
Applicants for an Experienced Manager card must provide:
1. An employer's declaration confirming their experience,
2. Evidence that they have signed up to a relevant NVQ such as:
- Level 6 NVQ Diploma in Construction Contracting Operations Management
- Level 6 NVQ Diploma in Construction Site Management
- Level 7 NVQ Diploma in Construction Senior Management, and
3. Complete one of the following manager/senior manager level health and safety courses appropriate to the level they operate within their organisation:
- Essential Health & Safety for Managers
- IOSH Managing Safely in Construction
- Essential Health & Safety for Senior Executives
- IOSH Safety for Executives and Directors
The card will be valid for 4 years and cannot be renewed. Cardholders are expected to have achieved a relevant NVQ prior to the expiry of the card.


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We've found 3 Toyota Corolla for sale in Louisiana at low prices, and some others at auction. Some of these Corolla may be sold. Most of these bargains were manually chosen specially for people with low budget searching for where to buy a cheap Toyota Corolla in LA at prices below $1000, $2000 or under $5000 dollars. These Toyota vehicles weren't automatically fetched from data feeds scattered through the web. If you are selling a used Corolla in LA at a very cheap price, and would like to list it here for free, please join us. At Autopten, we are constantly searching for those car dealers from Louisiana selling the most affordable used cars to promote and help them to get in touch with buyers able to buy these vehicles.
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