FDA Accepts Novozymes Master File

Novozymes Biopharma, part of Novozymes A/S, world leader in bioinnovation, announced that the US Food and Drug Administration Center for Biologics Evaluation and Research (FDA/CBER) has accepted a Type IV Master File for its recombinant albumin, albucult. The dossier which contains proprietary information on the manufacture and safety of albucult, can help support the company's customers in applications such as drug formulation and medical devices. By providing customers with access to a single source of information filed with the FDA as part of their product applications, Novozymes can help to accelerate the regulatory process for products that use albucult.
Derived from Novozymes' proprietary yeast expression technology, albucult delivers unprecedented performance and quality benefits to a range of applications including drug and vaccine manufacture, device coating, sealants, IVF media and cell therapy applications. albucult complies with the excipient monograph standard for recombinant human albumin, published in the United States Pharmacopoeia - National Formulary (USP-NF) and confers a range of unique advantages including sustainability of supply and improved biocompatibility. In addition, albucult ensures batch-to-batch consistency which can significantly reduce lot testing burden for clients.
Wayne Prestwood, principal regulatory associate at Novozymes Biopharma, comments: "The company is always looking for the most effective ways of supporting our customers' applications through regulatory processes and we are delighted to have a master file for albucult accepted by CBER. By ensuring that the information required by the FDA as part of our customers'review processes is readily available, we can help speed up their regulatory approvals, enabling their products to be delivered to market faster."

Oyster glue's secret ingredient

The natural cement produced by oysters to build extensive reef systems contains significantly more inorganic material than the glues of other marine species, and could spur development of new synthetic adhesives for biomedical devices or antifouling coatings for ships, say researchers in the US.

Jonathan Wilker and his team at Purdue University and colleagues at the University of South Carolina have been investigating how oysters bind to reefs and each other, in a bid to develop synthetic composite materials with properties that imitate the oyster glue.

The team analysed the chemical composition of oysters' adhesive using infrared spectroscopy, electron paramagnetic resonance spectroscopy and thermogravimetric analysis. They found higher protein content in the adhesive material than in oyster shell (10 per cent as opposed to 2 per cent), and evidence of protein cross-linking, iron species and radical species.

Cryospray Against Airway Tumors Leads to Unexpected Complications

Spray cryotherapy with liquid nitrogen has been used effectively for ablating esophageal tumors. Some facilities even perform the technique in an outpatient setting under sedation. However, spray cryotherapy for treating advanced airway lesions—when other treatment options are limited—is more recent, and few reports of its effectiveness have been published (J Thorac Cardiovasc Surg 2010;139:781-782).

To assess their efforts to date, thoracic anesthesiologists at Memorial Sloan-Kettering Cancer Center in New York City reviewed 24 spray cryotherapy procedures in 22 patients; all treatments involved airway-obstructing tumors. Ten of the patients (45%) experienced unexpected and serious respiratory or cardiovascular events; of these, three required reintubation and mechanical ventilation overnight. One patient suffered cardiac arrest and died in the operating room (Table).

Table. Complications From Cryospray Complication N=30 (% of procedures) Pneumothorax 2 (2.8) Hypoxemia 5 (20.8) Reintubation 3 (12.5) ST-segment changes 3 (12.5) Bradycardia 6 (25) Tachycardia 3 (12.5) Hypotension 7 (29) Death 1 (0.04)

“We did not expect to see such an incidence of cardiac complications during this procedure,” said Alessia Pedoto, MD, lead author of the study presented at the 2010 annual meeting of the Society of Cardiovascular Anesthesiologists (abstract SCA41), in New Orleans.

The spray cryotherapy technique delivered liquid nitrogen by catheter through an endoscope at 2 to 4 psi at –196 C, causing rapid freezing and thawing of tissue—resulting in cell death and hemostasis (Figures 1 and 2). A minimum of three cycles of five seconds each was administered to each patient, with a complete visual thaw between each cycle. All patients underwent general anesthesia for combined rigid and flexible bronchoscopy.

Among the 24 procedures, hypoxemia developed in five (20.8%); ST-segment changes developed in three (12.5%); bradycardia in six (25%); and hypotension in seven (29%). More than one complication occurred per procedure.

“Bleeding and pneumothorax have been reported in very small series and we had two cases of pneumothorax we thought were related to the use of jet ventilation with cryospray,” Dr. Pedoto told Anesthesiology News. “We speculate that the use of cold liquid nitrogen is associated with an increase in airway pressure when the spray is used, affecting the heart and the conduction system,” she said.

According to the researchers, spray cryotherapy is a novel technique that can be used to re-establish airway patency in patients with symptomatic airway tumors. The advantages it might offer over airway laser therapy include no fire hazard and improved hemostasis. They said that further study is needed for better selection and improved safety of patients.

QuikClot goes Japanese

WALLINGFORD, Conn.--(BUSINESS WIRE)--Z-Medica Corporation, a medical device company developing innovative hemostatic agents, today announced that it has signed an exclusive distribution agreement with Nihon-Kohden, Japan's leading manufacturer, developer and distributor of medical electronic equipment . The agreement allows Nihon-Kohden the exclusive right to distribute Z-Medica’s QuikClot line of hemostatic agents to hospital, military and law enforcement markets throughout Japan. The companies have been working together since early 2009 to obtain regulatory approval. Such approval for the sale of Z-Medica’s full line of QuikClot hemostatic gauze products was approved by the Japanese Ministry of Health, Labor and Welfare in March 2010.
“We are very pleased that we have signed this distribution agreement with Nihon-Kohden because of their longstanding positive reputation and vast reach throughout the Japanese market,” said Brian Herrman, Chief Executive Officer, Z-Medica. “We believe that clinical practitioners outside of the US will find QuikClot to be a useful tool in achieving hemostasis in a fast, safe and convenient manner, and we intend to continue expanding our international distribution through best-of-breed partners such as Nihon-Kohden.”
QuikClot is a surgical gauze impregnated with kaolin, an inert material with no known contraindications, and can achieve hemostasis in severe bleeding situations in as little as three minutes. QuikClot is widely used throughout several clinical specialties, including cardiology, interventional radiology, critical care, dermatology, emergency medicine, orthopedics and OB/Gyn, and after months of testing against 12 other hemostatic products in the marketplace, the military version of the kaolin gauze (“Combat Gauze”) was chosen as the exclusive product for use by all US Military Forces in 2008. It continues to be the exclusive product used by all USA military forces for first line treatment of bleeding hemorrhage.
“We are very pleased to have this opportunity to market in Japan QuikClot which helps many patients who suffer from bleeding,” said Hiroshi Aida, General Manager of Import Business Operation, Nihon Kohden. “QuikClot also helps medical professionals with much shorter time for achieving hemostasis. It is a nice addition for our product portfolio.”
Z-Medica and Nihon-Kohden have been working together since early 2009 in order to gain the recently granted regulatory approval. The QuikClot line of products to be distributed by Nihon-Kohden in Japan include:
QuikClot Combat Gauze is a soft, white, sterile, nonwoven 3” by 12 feet rolled or z-folded gauze impregnated with kaolin. Each roll of QuikClot Combat Gauze is individually wrapped in an easy rip, military grade foil pouch. Indicated for temporary external control of traumatic bleeding, QuikClot Combat Gauze is flexible and pliable and contours to all wounds. Recommended as the number one hemostatic agent by the COTCCC (Committee on Tactical Combat Casualty Care Committee), QuikClot Combat Gauze is the only product carried by all branches of the US Military to control life-threatening hemorrhage.
QuikClot Emergency Dressing is an easy-to-use dressing which can achieve hemostasis in as little as three minutes, helping to prevent loss of life and limb. Because QuikClot requires very little training to administer, it can be effectively used by medical personnel, civilian first-responders and medical professionals in the field and in clinical environments. This dressing comes in various sizes, including a 4-ply 4” by 4” (10cm x 10cm) and a 6-ply 2”x2” (5cm x 5cm) format.
QuikClot Interventional Hemostatic Bandage consists of a soft, white, double sterile, hydrophilic pad impregnated with kaolin. It is double-wrapped in a blister package and foil pouch for aseptic technique. QuikClot Interventional Hemostatic Bandage is applied topically as an adjunct to manual compression and is indicated for the local management and control of external bleeding from vascular access sites and percutantous catheters or tubes utilizing sheaths up to 12 Fr.
QuikClot Trauma Pad consists of a soft, white, double sterile, three-ply 12”x12” (30cm x 30cm) pad impregnated with kaolin. It is double-wrapped in a peelable foil package for aseptic technique. QuikClot Trauma Pad is indicated for temporary external use to control traumatic bleeding and is also x-ray detectable to ensure proper removal.

About Z-Medica

Z-Medica Corporation is a medical device company developing innovative hemostatic agents. The company manufactures and markets its QuikClot® family of products for hemostasis for use by healthcare professionals, first responders, law enforcement officers and the military. QuikClot products rapidly enhance the body’s natural coagulation process, helping to achieve hemostasis faster. Z-Medica’s QuikClot® Combat Gauze™ product was chosen by the Committee on Tactical Combat Casualty Care (TCCC) as the United States Military’s sole source supplier for first-line hemostatic treatment, based on tests conducted by the Naval Medical Research Center and the U.S. Army Institute for Surgical Research. It continues to be the exclusive product used by all USA military forces for first line treatment of bleeding hemorrhage. QuikClot® products are also widely used by first responders, in hospital emergency rooms, interventional cardiology and radiology laboratories and other healthcare environments where bleeding requires fast and effective control. Z-Medica, named one of the Top 100 Technology “Companies to Watch” in 2008 by the Connecticut Technology Council, is a privately-held company based in Wallingford, CT. More information about Z-Medica Corporation is available at www.z-medica.com.

About Nihon Kohden

Nihon Kohden is Japan’s leading manufacturer, developer and distributor of patient monitors, defibrillators, ECGs, EEGs, EP/EMGs, hematology analyzers and other medical electronic equipment, with subsidiaries in the United States, Europe, and Asia, and distributors in nearly every country in the world. Nihon Kohden is a publicly held company listed in the First Section of the Tokyo Stock Exchange. In addition to designing medical equipment for hospital and clinic use, Nihon Kohden actively contributes to the advance of medical technology.

FDA rules CollPlant wound dressing a device

The US Food and Drug Administration (FDA) has ruled that the CollPlant Holdings Ltd's (TASE: CLPT) wound dressing product, Vergenix, will undergo the certification process by the Center for Devices and Radiological Health (CDRH), which oversees medical devices.
Vergenix Wound Dressing is wound care sheet composed of pure recombinant human collagen scaffold that provides a moist wound healing environment. The product, a type I collagen, is produced by transgenic tobacco plants. It is designed to treat acute and chronic wounds, such as pressure ulcers, venous ulcers, diabetic ulcers, surgical wounds, abrasions, and second-degree burns.
US licensing procedures for medical devices are shorter than the procedure for pharmaceuticals. CollPlant believes that while Vergenix is based on human recombinant collagen produced through advanced biotechnological techniques, the FDA decision that the CDRH will review the product is very important for the company, as the regulatory procedures are significantly simpler, shorter, and cheaper than for biological and pharmaceutical products. This is a breakthrough since Vergenix will be a pioneering product for CollPlant's subsequent products.
CollPlant's share price rose 9.9% by mid-afternoon to NIS 1.20, giving a market cap of NIS 126 million.
Published by Globes [online], Israel business news - www.globes-online.com - on August 29, 2010

US Military faces challenges from Chinese Knock-offs

As anyone who has served in combat knows, if a buddy is wounded, the first two things you need to do are make sure he can breathe and his bleeding is stopped.
For the past several years, troops serving in Afghanistan and Iraq have used an advanced Combat-Application-Tourniquet (C-A-T) developed by Composite Resources in Rock Hill, S.C. The tourniquet features a nylon strap and a plastic rod to tighten the strap to stop bleeding.
The regulation C-A-T costs about $28. But about two years ago the Army detected cheap knock offs made by a Hong Kong company that had entered the military's supply chain in Afghanistan and Iraq. The imitation sold for about $8.50.
They're accurate looking fakes, right down to the label and national stock number.
But as Col. John Kragh, a doctor at the U.S. Army Institute of Surgical Research at Fort Sam Houston, pointed out in June, the rod on the fake tourniquet "is bendable to a point where it cannot work right. It's like bending Gumby's arm."
He said the fake tourniquet could be fatal because it cannot stop bleeding. Kragh added a decentralized ordering system probably accounts for the presence of the fake tourniquets in the field, with low-level supply personnel ordering the knock offs over the Internet based on price.
The Defense Department issued a warning about the knock-offs in April, Kragh said, and the Food and Drug Administration this month put out a safety alert about the tourniquets, which are also used by civilian first responders.
The lesson here is a good deal isn't always that; it can even be deadly.

Poll Result - Which Geographical Manufacturing Area for Hemostatic Devices Causes Concern?

Controversies

2007 Chinese Export Recall

The 2007 Chinese export recalls were a series of scandals involving tainted food and products exported from China, starting with tainted pet food imported from China to the United States that poisoned pets. The recalls sparked international concern that many products made in China do not meet minimum quality standards. Soon after, the US halted imports of seafood from China after tests detected the presence of drugs unapproved in the US.China has gone on record to admit that nearly a fifth of products made in China do not reach minimum standards. Also, some children's toys made in China were found to contain excessive levels of lead, prompting widespread concern. In 2006, shipments of cough syrup and other medicines, imported from China to Panama and laden with the toxin diethylene glycol, caused mass poisonings and killed 83 people.
On December 19, 2007, The US House of Representatives passed legislation (H.R. 4040) that would significantly amend the current U.S. safety establishment for consumer products imported from China.

2008 Chinese heparin and milk scandals

In March 2008, major recalls of heparin were announced by the U.S. Food and Drug Administration (FDA) due to contamination of the raw heparin stock imported from China.
The raw material for the recalled heparin batches was processed in China from pig's intestines by the American pharmaceutical firm Scientific Protein Laboratories. The U.S. Food and Drug Administration was quoted as stating that at least 81 deaths were believed linked to a raw heparin ingredient imported from the People's Republic of China, and that they had also received 785 reports of serious injuries associated with the drug’s use. According to the New York Times, "Problems with heparin reported to the agency include difficulty breathing, nausea, vomiting, excessive sweating and rapidly falling blood pressure that in some cases led to life-threatening shock."
Upon investigation of these adverse events by the FDA, academic institutions, and the involved pharmaceutical companies, the contaminant was identified as an "over-sulphated" derivative of chondroitin sulfate, a popular shellfish-derived supplement often used as a treatment forarthritis. Since over-sulphated chondroitin is not a naturally occurring molecule, costs a fraction of true heparin starting material, and mimics the in-vitro properties of heparin, the counterfeit was almost certainly intentional as opposed to an accidental lapse in manufacturing. The raw heparin batches were found to have been cut from 2-60% with the counterfeit substance, and motivation for the adulteration was attributed to a combination of cost effectiveness and a shortage of suitable pigs in China.
When the FDA conducted an inspection of Baxter's Chinese Heparin supplier, it found serious deficiencies at the facility which the FDA detailed in a warning letter.
The FDA has stated that it does not have the funds nor bear the responsibility to inspect on a regular basis overseas manufacturers of active pharmaceutical ingredients such as heparin.
In November 2008, the FDA seized eleven lots of heparin from Celsus Laboratories Inc., a manufacturer in Cincinnati, Ohio.

One year later, the 2008 Chinese milk scandal refers to a food safety incident in mainland People's Republic of China involving milk and infant formula which had been adulterated with melamine, an organic base combined with formaldehyde to form plastic. The result was catastrophic - By 22 September, nearly 53,000 illnesses, over 12,800 hospitalizations, and four infant deaths had been reported, caused by kidney stones and other renal failure.The chemical appeared to have been added to milk in order to cause it to appear to have a higher protein content. The same chemical was also involved in a series of pet food recalls in 2007. In November 2009, two individuals were executed for endangering public safety and producing and selling toxic food.

2009 Made in India scandal

In June 2009, the Nigerian Government Drug Regulatory Authority (NAFDAC) reported about the detention of a large consignment of fake anti-malarial generic pharmaceuticals labeled Made in India but produced in China. The Laboratory analysis conducted by NAFDAC revealed the drugs to be fake and had it not been intercepted, about 64,200 adults would have been affected. The consignment containing Maloxine and Amalar tablets, used for the treatment of Malaria, were valued at 32.1 million Naira and were produced, packed and shipped from China. After Indian Authorities took up the matter, The State Food and Drug Administration (SFDA) of China was asked to investigate the matter[10]. In December 2009, 6 chinese traders were sentenced to death for their involvement.
In July 2009, customs officials in the South Indian port city of Chennai seized spurious cosmetics and mobile phone batteries worth Rs. 30 million, imported into India from Scheko in China. The 40 foot container was held up at the port for more than 75 days and opened on 13th July when the importer did not file a bill of entry. It was reported to contain over 187,000 batteries with Nokia holograms and stickers, and 126,000 cosmetic items including face packs, lipsticks and hair gels.

Further Reading - "These are not isolated cases," Han Yi, director of the administration's quality control and inspection department, told the state media. Underlining his concerns, officials said hundreds of bottles of fake human blood protein were found in hospitals......

Also - Federal drug regulators, in announcing Wednesday that the mystery contaminant in heparin was an inexpensive, unapproved ingredient altered to mimic the real thing, moved closer to concluding that Americans might be the latest victims of lethal Chinese drug counterfeiting.

And - There also seems to be agreement that our regulatory agencies can’t rely on China to police its own factories. The Chinese have lurched between vows of reform and disregard for American concerns about the quality of the country’s products.

Prepare your Hemostat's - Here Come the Anti-Coagulants

Aug 24 (Reuters) - Rival drugmakers are racing to develop
new oral anticoagulants to replace difficult-to-use warfarin for
the prevention of stroke in patients with atrial fibrillation, a
common irregular heart rhythm.
Industry analysts estimate the market will be worth well
over $10 billion in annual sales, making so-called Factor Xa and
direct thrombin inhibitors among the most valuable and closely
watch new drugs in development.
Medical experts and investors will focus on clinical trial
results for two of them -- Bayer (BAYGn.DE) and Johnson &
Johnson's (JNJ.N) Xarelto, and Bristol-Myers Squibb (BMY.N) and
Pfizer's (PFE.N) apixaban -- during the European Society of
Cardiology congress in Stockholm next week.
The table below shows a selection new oral anticoagulants in
development. Pradaxa and Xarelto have already been approved for
use in Europe and some other markets to prevent thrombosis after
surgery, but not yet for stroke prevention:

DRUG COMPANY MECHANISM STATUS

Pradaxa Boehringer Direct thrombin launched EU
Xarelto Bayer/J&J Factor Xa launched EU
apixaban Bristol/Pfizer Factor Xa Phase III
edoxaban Daiichi Factor Xa Phase III
YM150 Astellas Factor Xa Phase III
otamixaban Sanofi Factor Xa Phase III
betrixaban Merck Factor Xa Phase II
letaxaban Takeda Factor Xa Phase II
Source: Thomson Reuters

FibroGen - Recombinant Human Type III Collagen

SAN FRANCISCO--(BUSINESS WIRE)--FibroGen, Inc., today announced results of a 2-year clinical study demonstrating that surgical implantation of biosynthetic corneas formulated with the company’s proprietary recombinant human type III collagen (rhCIII) restored vision and promoted nerve regeneration (restoring sensitivity) in patients who had corneal damage and significant vision loss. The results of this phase 1, investigator-sponsored study were published today in Science Translational Medicine.1
“These clinical results suggest that our collagen could potentially provide an important option for patients by reducing risk of disease transmission and increasing supply of corneal implant material in the face of the worldwide shortage of human donor corneas”
Corneal damage and disease are major causes of blindness worldwide. In countries where tissue banking is available, such as the US, treatment is by implantation of human donor corneas. However, there is a severe shortage of human donor tissue worldwide. Patients who do receive donor human corneas, however, can still suffer complications, such as tissue rejection. Corneal prostheses, made from synthetic plastics are used in limited cases, but only where human donor grafts are contraindicated or have been repeatedly unsuccessful. These synthetic alternatives are not designed to replace donor tissues or promote tissue regeneration.
FibroGen pioneered the development of recombinant collagen production technology and is the only producer of rhCIII. Since 2005, FibroGen has collaborated with Dr. May Griffith of Linköping University, senior author of today’s publication, to develop biosynthetic corneas molded from chemically cross-linked rhCIII. The biosynthetic implants are designed to mimic the human cornea, which is composed mainly of the protein collagen.
“Recombinant human collagen is a viable replacement for naturally occurring human collagen that does not have the limitations of human donor tissue or animal-sourced collagens, such as risk of disease transmission and availability of donor supply,” said Dr. Griffith. “Our study provides proof-of-concept that corneal implants composed of recombinant human collagen can promote tissue regrowth and restore vision.”
“These clinical results suggest that our collagen could potentially provide an important option for patients by reducing risk of disease transmission and increasing supply of corneal implant material in the face of the worldwide shortage of human donor corneas,” said Thomas B. Neff, Chief Executive Officer of FibroGen. “This product concept continues to be improved and additional studies are planned.”
About the Phase 1 Study

In the clinical study, 10 patients with corneal disease underwent resection, followed by surgical implantation with rhCIII-based biosynthetic corneas. Two-year post-surgery results demonstrated that 100% of the transplanted corneas remain viable at two years, cells from the patients’ own corneas had grown into the implant, and nerves that had been severed during surgery regrew. In addition, the blink reflex and tear film were restored. In terms of visual acuity, at 24 months, best spectacle-corrected visual acuity improved in six patients, remained unchanged in two patients and decreased in two. None of the patients experienced any rejection reaction or required long-term immunosuppressive therapy, serious issues associated with the use of human donor tissue.
Unmet medical need for a biosynthetic corneal implant

Loss of vision due to corneal disease or trauma affects over 10 million individuals worldwide, but lack of access to good quality donor tissue severely limits the number of transplant procedures that can be done, particularly in the developing world. In the US, an estimated 42,000 corneal grafts are performed annually using optical tissue from cadavers; however, graft rejection can occur, and failure rates are significant. In addition, the mandatory use of steroids with cadaver-sourced corneal material limits their successful use to certain patient populations. Fully synthetic prostheses (without biological activity) have been developed, but their use has been limited to cases where human donor tissue fails repeatedly or cannot be used. Moreover, apart from the US, in most countries, tissue donation and banking systems do not exist.
About FibroGen’s recombinant human collagens

FibroGen is the only producer of highly purified, fully characterized recombinant human type III collagen (rhCIII) intended to replace similar animal- or human-derived materials currently used in a variety of medical, pharmaceutical, and consumer applications. FibroGen uses proprietary recombinant methodology in a yeast expression system with human DNA sequences to develop synthetic versions of human collagens essentially identical to the native protein. Mixtures of various collagen types found in animal-sourced collagen are nearly impossible to segregate. FibroGen has been able to produce specific types of recombinant human collagen (e.g., types I or III) consistently and reproducibly. FibroGen has developed simple, scalable purification processes that provide highly purified and reproducible lots of protein in any desired quantity, and employs a series of rigorous analytical tests to ensure lot-to-lot consistency and high quality.

Facts about blood needs in the U.S.

• Every two seconds someone in the U.S. needs blood.
• More than 38,000 blood donations are needed every day.
• A total of 30 million blood components are transfused each year in the U.S. (2006).
• The average red blood cell transfusion is approximately 3 pints.h
• The blood type most often requested by hospitals is Type O.
• The blood used in an emergency is already on the shelves before the event occurs.
• Sickle cell disease affects more than 80,000 people in the U.S., 98 percent of whom are African American. Sickle cell patients can require frequent blood transfusions throughout their lives.
• More than 1 million new people are diagnosed with cancer each year. Many of them will need blood, sometimes daily, during their chemotherapy treatment.
• A single car accident victim can require as many as 100 pints of blood.
• One donation can save the lives of up to three people.

Go to www.redcrossblood.org to find out more about blood donation and to see if you are eligible.

Kensey Nash Q2 - Edited

Joseph Kaufmann

Our total revenue for the quarter of $21.9 million exceeded prior year by 7% and increased 10% sequentially. Total net sales of $15.1 million exceeded prior year by 12% and increased 14% sequentially. This growth was due to sports medicine, which increased 58% year-over-year and 9% sequentially; and our cardiology products, which are primarily Angio-Seal components, also increased 14% year-over-year and 3% sequentially.

As far as the Angio-Seal collagen sales, again, our third and fourth quarter collagen sales to St. Jude were very good. And we look at the comp compared to last year and our first quarter, it's primarily again due to timing. We expect our second quarter sales to St. Jude will reflect this and will show the improvement.........

It's products, it's quality, it's all that things that you think of every day, and that we think with hopefully some of the new products that we're brining to the marketplace, the biologic products, we believe are going to be a major factor in all of healthcare going forward. And Kensey Nash is going to be a major player in this space, not only in sports medicine, but also in general surgery and in other areas that we're very well positioned with the technology we have built here over the last five to 10 years or so within our organization....

Josh Jennings - Jefferies & Company

And then just last one just on the St. Jude supply agreement. Anymore color you could provide in terms of what happens? I know that's a tiered supply agreement for the component parts, but after 2011, it seems that that minimum 25% does that end in 2011 and you could renegotiate for 2012? And then lastly, is there any risk of the Angio-Seal royalty rate going away at some point?

Joseph Kaufmann

On the supply agreement, it's a two-year deal that starts at January 2011, so it goes out for '11 and '12. And then after that it will be determined whether it will be expanded, increased, decreased, or renewed, I don't know at this time.

As far as royalties are concerned, we are a royalty on Angio-Seal sales. As long as there is at least one claim on any patent, we're entitled to the full 6% royalty, there aren't any step-downs. So as long as there is patents in place that are being utilized, then that's when we continue to receive the royalty.