Clinical Papers - Fibrin Sealants, BioGlue, Perclot, HaemoCer, Thrombin

Revealed - UK NHS tests for Transfusion related vCJD. US California new cases.

In More Bad news for purveyors of Bovine derived products and transfusion supporters, thousands of NHS patients could be secretly monitored by the Government for symptoms of the human form of mad cow disease amid concerns that there could be another wave of infections.

Experts advising the Department of Health believe patients who have received more than 80 blood transfusions are most at risk of developing the fatal brain disease because it can be passed on through infected blood.

They say monitoring these patients could give vital clues about the way the disease develops and is transmitted from person to person and could help work out whether there are likely to be further deaths. 

Thousands of NHS patients could be secretly monitored by the Government for symptoms of the human form of mad cow disease amid concerns that there could be another wave of infections

It could also inform officials whether the risk from blood donations needs to be treated more seriously.

But they are considering conducting their surveillance secretly because they fear that informing patients they are at risk and are being monitored will cause unnecessary alarm.

The proposals have been discussed by a powerful panel of leading scientists and doctors, which advises the Government on the disease, known as variant CJD.

More...

• Blood test for mad cow disease used in UK for the first time
• Flesh-eating bug that you can catch on the bus or train is spreading in the UK

The panel's report, published online, suggests conducting 'covert health surveillance' of around 30,000 patients known to have received a high number of blood transfusions.

Experts would expect to see at least 150 cases of vCJD in this group of patients, based on scientific evidence that between one in 4,000 and one in 20,000 of the population may be infected.

Experts believe patients who have received more than 80 blood transfusions are most at risk of developing the fatal brain disease as it can be passed on through infected blood

But this has so far not been seen and may either mean the risk is lower than previously thought, or that it is taking longer for cases to develop.

The 'highly transfused' group includes people suffering life-threatening illnesses including acute leukaemia, aplastic anaemia and the blood disorder thalassemia - as well as those with multiple injuries due to road accidents, or heavy blood loss from aneurysms. 

The report acknowledges that following patients without their consent is 'ethically problematic'.

But the panel, a subcommittee of the Advisory Committee on Dangerous Pathogens, has asked the Health Protection Agency to set out the various options for monitoring these patients based on seeking their consent or not. 

Chris James, chief executive of the Haemophilia Society, said: 'We are shocked to learn there was ever any suggestion of non-consensual monitoring. 

'Given the history of contaminated blood in the 1970s and 1980s, the maintenance of medical ethics is especially important to the haemophilia community.

'Any proposed framework must be reviewed by an ethics committee and open to challenge from individuals and organisations such as ourselves through a formal consultation process.' 

Latest official figures show seven NHS patients have died from vCJD after having blood transfusions.

Four are known to have been given blood from people who were infected with fatal vCJD, and the other three had previously had transfusions although it is not known whether the blood was contaminated.  

Since the first vCJD cases emerged in the mid-1990s, 175 people in Britain have died from the brain wasting disease, which is linked to eating beef infected with BSE.

Experts predicted that hundreds more could die after receiving blood infected with the disease. But they now admit they are baffled as to why these cases have failed to emerge. 

One theory is that some people have a genetic advantage and may only carry the disease without developing symptoms. However, they can still infect others if they give blood.

In one case, a patient is known to have been exposed to vCJD in a blood transfusion and is still alive 24 years later. 

A memorial plaque to victims of Human BSE on the Riverside Walk near Westminster Bridge, London

At the moment, patients are only informed that they are at increased risk of developing vCJD if they have been exposed to blood from more than 80 donors and if they are about to have brain, spinal or complex eye surgery.

But this threshold may now be raised to only inform patients if they are exposed to 300 or more blood donors because the lack of vCJD cases so far may indicate that the risk of catching vCJD in blood may be lower than previously suspected. 

Judy Kenny, of the CJD Support Network, whose husband Deryck died aged 69 in 2003 after being given contaminated blood, said: 'If the authorities are going to do any monitoring, patients should be aware of it. 

'There is no grey area - if they are thinking about unconsented monitoring, then it is wrong.'

CJD occurs when nerve-tissue proteins called prions (illustration above) turn 'bad' and gradually destroy the brain

Professor Chris Bunce, science director of charity Leukaemia and Lymphoma Research, said: 'The extent of the risk [of vCJD] to patients who receive regular blood transfusions as part of their treatment is as yet uncertain. 

'One way to ascertain the risk would be to monitor the distribution of the pathogen among people in this group. 

'But with that comes the moral question of whether patients should be informed or not, and this is the dilemma of the Health Protection Agency.'

A Department of Health spokesman said: 'No decisions have been taken on any unconsented follow-up of highly transfused patients.

'No unconsented follow-up has taken place and none would without appropriate ethical approval and on the basis of legal advice.


Meanwhile Stateside...
(Sacramento, CA) 
Friday, February 10, 2012

The Marin County Public Health Officer, Dr. Craig Lindquist, says one person who was diagnosed with a brain disorder similar to Mad Cow Disease has passed away, but that the person did not contract the disease from contaminated beef.  That makes it the classic form of the disease and not the varient form.   

There is another resident still living with Creutzfeldt Jacob Disease or CJD.  Lindquist says there is no evidence it is of the varient variety either. 

CJD is very rare, but always fatal.  It attacks the memory, hand eye coordination and vision before killing the victim within a year. 

The Mad Cow variant of the disease can be spread only by contact with the brain tissue or nervous system tissue of someone or something that is afflicted.  Twenty five years ago, nearly 170 people died of the variant form of the disease in Europe.

Doctor Richard Breitmeyer runs the lab at UC Davis that  tests  Mad Cow disease in sheep and cattle.  

BREITMEYER:  "The current science believes in the United Kingdom that was the cause of Varient CJD in people in that they had consumed meat products that were contaminated with the bovine form."

Breitmeyer's lab is one of six in the nation.

Cattle fed with bovine bone meal was found to be a significant cause of the spread of the disease in Europe.  Of the 40,000 animals tested each year in the United States since, only two tested positive.

In humans, 85 percent of those afflicted with classic CJD had no known risk factors.  Five to ten percent had a genetic history of the disease.

CRY Q3 10Q, FDA Disapproves Perclot IDE.....Perclot China Trial underway......

10Q - PerClot and HemoStase
Revenues from the sale of hemostats, consisting of PerClot and HemoStase, decreased 71% for the three months ended September 30, 2011 as compared to the three months ended September 30, 2010. Revenues from the sale of PerClot and HemoStase decreased 40% for the nine months ended September 30, 2011 as compared to the nine months ended September 30, 2010. The revenue decreases in the three and nine months ended September 30, 2011 were primarily due to a decrease in hemostat sales volume in domestic markets, partially offset by an increase in sales volume in international markets. The revenue decrease in the nine months ended September 30, 2011 was also impacted by a decrease in average selling prices, which decreased revenues by 6%.
International hemostat revenues increased 24% for the three months ended September 30, 2011 and 55% for the nine months ended September 30, 2011 as compared to the three and nine months ended September 30, 2010, respectively. This increase is primarily due to an increase in international sales of PerClot in the 2011 periods over the international sales of HemoStase in the corresponding 2010 periods. Management believes that international PerClot revenues have been favorably impacted by the Company’s ability to market PerClot for all surgical specialties, expanding the direct European sales force into Austria, and PerClot’s product performance when compared to other hemostatic agents.
The decrease in domestic sales volume for the three and nine months ended September 30, 2011 was due to the Company’s planned discontinuation of sales of HemoStase in late March 2011. The Company recognized no domestic hemostat sales in the second or third quarters of 2011, subsequent to the discontinuance of HemoStase sales, as PerClot is not yet approved for commercial distribution in domestic markets. The Company anticipates this loss of domestic hemostat sales to result in a decrease in total hemostat sales for the remainder of 2011 when compared to the corresponding 2010 periods.


The Company will not be able to sell PerClot in the U.S. in future years until U.S. Food and Drug Administration (“FDA”) approval is granted. On March 31, 2011 CryoLife filed an Investigational Device Exemption (“IDE”) with the FDA seeking approval to begin clinical trials for the purpose of obtaining Premarket Approval to distribute PerClot in the U.S. On April 29, 2011 the FDA disapproved CryoLife’s IDE filing with numerous comments and questions. CryoLife is currently addressing those comments and questions and anticipates refiling its IDE for PerClot in the fourth quarter of 2011.


Q3 Report - Brackets have been added-
Ashley Lee...

We experienced some delays in getting PerClot approved in certain international markets and some competitive issues in the EU, which leaves us to slightly lower our guidance.

Worldwide BioGlue revenues were up 10% for the third quarter and up 5% for the nine month period. These increases were predominantly driven by volume increases, particularly in Japan, due to the recent launch of the product. This was the largest year-over-year quarterly increase for BioGlue revenues, since third quarter of 2008, and we continue to remain enthusiastic about the opportunity in Japan.

Total sales in the third quarter in Japan were $651,000 and year-to-date in Japan were approximately $1.2 million. To-date, approximately 250 surgeons have been trained and over 160 accounts have ordered product. We expect another large order from Japan before the end of the year.

PerClot sales for the third quarter were $620,000 and were $1.9 million year-to-date. We experienced some delays in getting PerClot approved in certain international markets and some competitive issues in the EU, which leaves us to slightly lower our guidance. However, despite these delays, our international revenues from the sale of powdered hemostats in the third quarter still increased 24% compared to the prior year, and 55% for the nine month period compared to the prior year.

Steve Anderson...As Ashley has discussed earlier in third quarter of 2010, we announced our first technology acquisition and that we have signed a worldwide manufacturing and distribution agreement for a unique powered hemostatic agent PerClot with Starch Medical of San Jose (Shanghai), California (China).
(Chinese) PerClot is an ideal replacement for the hemostatic powder that we had been distributing worldwide. The primary difference is that PerClot’s gross margin will be 80%.....we filed our IDE for PerClot with the FDA in March of this year. The FDA had questions about our submission that we have been addressing. We will be reaching our IDE to the FDA in mid November. We expect to begin the clinical trial for PerClot (Link to current trial Xijing Hospital of Digestive Diseases, Xi'an, Shaanxi, China) during the second quarter of next year. The clinical trial will probably involve about 300 patients, 150 PerClot patients and 150 control patients. We expect that with six months enrollment and three months follow-up of these patients that we will file our PMA in the second quarter of 2013.

• In which circumstances does the FDA disapprove or withdraw an IDE?
  FDA may disapprove or withdraw approval of an IDE application if FDA finds that:
• 1. The sponsor has not complied with applicable requirements of the IDE Regulation, any other applicable regulations or statutes, or any condition of approval imposed by an IRB or FDA.
  2. The application or a report contains untrue statements or omits required material information.
  3. The sponsor fails to respond to a request for additional information within the time prescribed by FDA.
  4. There is reason to believe that the risks to the human subjects are not outweighed by the anticipated benefits to the subjects or the importance of the knowledge to be gained, that informed consent is inadequate, that the investigation is scientifically unsound, or that the device as used is ineffective.
  5. It is unreasonable to begin or to continue the investigation due to the way in which the device is used or the inadequacy of:
     (i) the report of prior investigations or the investigational plan; (ii) the methods, facilities, and controls used for the manufacturing, processing, packaging, storage, and, where appropriate, installation of the device; or (iii) the monitoring and review of the investigation.

Q & A...

Matt Dolan - Roth Capital Partners

Great. First question on the guidance, just looking at the revenue at this point it implies maybe around 10% sequential uptick in Q4. So how far below $122 million should we expect or what gets you to that type of sequential uptick, meaning, is there a category that improves something on the macro level that rebounds?

Ashley Lee

We think that the upside is in the Cardiogenesis product line and the PerClot product line as well as potentially BioGlue in Japan.

Matt Dolan - Roth Capital Partners

Okay. But given your guidance on those categories it still requires a pretty big sequential uptick?

Ashley Lee

Yeah well the possibility exists again that we could do better and then we expect to do better in Cardiogenesis, PerClot, and BioGlue in Japan. And that -- we think that that’s, we have more upside in those three areas than the rest of the business.

Matt Dolan - Roth Capital Partners

Okay. And then on the earnings guidance just to clarify, I think the delta between adjusted and GAAP last quarter was $0.05 as supposed to an $0.08 differential at mid year. So I wanted to make sure that that’s the reason for the increase in the earnings guidance? And secondly the implied guidance for Q4 cuts EPS basically in half. So I’m just trying to understand why that would be?

Ashley Lee

The primary driver in non-GAAP, the increase in non-GAAP EPS as compared to the end of the second quarter is primarily due to the shifting of some R&D expenses due to some delays and getting some studies started, as those will be shifting out of 2011 into 2012. As it relates to the fourth quarter we provided for some additional expenses in the fourth quarter this year to account for the ongoing discovery and the acceleration of the discovery in our litigation with Medafor.

Raymond Myers - Benchmark

And that was going to be my next question. So let’s get right to that. Roughly how much Medafor litigation expense should we expect?

Ashley Lee

If you go through the end of the third quarter we had spent about $1.4 million and we’re expecting a similar amount in the fourth quarter of this year about $1.4 million.....

Late wound healing problems after use of BioGlue® for apical hemostasis during transapical aortic valve implantation

Dural repair with four spinal sealants: focused review of the manufacturers' inserts and the current literature.

Abstract

BACKGROUND CONTEXT:

Deliberate or traumatic dural fistulas are typically augmented by a "sealant" or "fibrin glue" to enhance the strength of dural closure.

PURPOSE:

Little is known about the risks and complications associated with two specific "sealants" and two specific "fibrin glues" used for dural closure.

STUDY DESIGN/SETTING:

Review of the manufacturers' inserts and a focused review of the literature concerning the pros and cons for two "sealants" (DuraSeal [Confluent Surgical Inc., Waltham, MA, USA] and BioGlue [Cryolife, Kennesaw, GA, USA]) and two "fibrin glues" (EVICEL [Johnson and Johnson Wound Management, Ethicon Inc., Somerville, NJ, USA] and Tisseel [fibrin sealant; Baxter International Inc., Westlake Village, CA, USA]) were assessed.

PATIENT SAMPLE:

A focused review of the literature using four different "sealants" or "fibrin glues" was performed.

OUTCOME MEASURES:

Documentation of persistent/recurrent postoperative cerebrospinal fluid fistulas was an end point for failure for the four different "sealants" and "fibrin glues."

METHODS:

Manufacturers' inserts and a focused review of the literature concerning the relative safety and efficacy of two "sealants" (DuraSeal and BioGlue) and two "fibrin glues" (EVICEL and Tisseel) used to augment dural closure were assessed.

RESULTS:

Although DuraSeal is approved by the Federal Drug Administration (FDA) for intracranial and spinal application, two instances of paralysis are described in the literature. BioGlue is classified by the manufacturer as neurotoxic. EVICEL, one of the "fibrin glues," appeared in just two animal studies, whereas Tisseel, the other "fibrin glue," has been used in many large clinical series without adverse events.

CONCLUSION:

Despite the lack of FDA approval, Tisseel (fibrin glue) has seen wide adoption in "off-label" use. DuraSeal, which is FDA approved, was associated with two instances of paralysis. Alternatively, BioGlue was described as neurotoxic even by the manufacturer.

Cryolife Q4 - Upbeat news for shareholders 10 people in the EU until 2013 to carry Medafor Divorce, Perclot-China marriage and Bioglue EU IP

Product revenues which consists primarily of BioGlue and HemoStase increased 4% in the fourth quarter and full year of 2010 compared to the corresponding periods in 2009. For the three month and full year periods HemoStase revenue increased partially offset by a slight decrease in BioGlue revenues. Fourth quarter of 2010 also included $264,000 of PerClot revenue as we began to roll out PerClot in international markets.

Total gross margins were 60% for the fourth quarter of 2010 compared to 61% for the fourth quarter of 2009. Total gross margins excluding the write off of $1.6 million for the HemoStase inventory were 60% for the full year of 2010 compared to 62% in the full year of 2009. Preservation services gross margins for the fourth quarters of 2010 and 2009 were 39% for each period and 40% in the full year of 2010 compared to 42% in the full year of 2009.

Product gross margins for the fourth quarter of 2010 were 80% compared to 82% in the corresponding period in 2009. Product gross margins excluding the write down of $1.6 million of HemoStase inventory were 81% in the full year of 2010 compared to 83% in the full year of 2009. General administrative and marketing expenses for the fourth quarter of 2010 were $12.2 million compared to $12.6 million for the fourth quarter of 2009. These expenses for the fourth quarter of 2010 included approximately $474,000 in costs related to business development activities and $268,000 in costs related to our litigation with Medafor.

General administrative and marketing expenses for the full year of 2010 were $49.1 million compared to $50 million for the full year of 2009. The full year of 2010 included a charge of approximately $1.4 million in costs related to our litigation with Medafor $1 million related to business development activities and $729,000 related to the write off of capitalized legal expenses associated with our BioGlue intellectual property rights in Germany.....

Raymond Myers – The Benchmark Company

Okay. Good. When were you targeting PerClot approval and launch?

Product revenues which consists primarily of BioGlue and HemoStase increased 4% in the fourth quarter and full year of 2010 compared to the corresponding periods in 2009. For the three month and full year periods HemoStase revenue increased partially offset by a slight decrease in BioGlue revenues. Fourth quarter of 2010 also included $264,000 of PerClot revenue as we began to roll out PerClot in international markets.

Total gross margins were 60% for the fourth quarter of 2010 compared to 61% for the fourth quarter of 2009. Total gross margins excluding the write off of $1.6 million for the HemoStase inventory were 60% for the full year of 2010 compared to 62% in the full year of 2009. Preservation services gross margins for the fourth quarters of 2010 and 2009 were 39% for each period and 40% in the full year of 2010 compared to 42% in the full year of 2009.

Product gross margins for the fourth quarter of 2010 were 80% compared to 82% in the corresponding period in 2009. Product gross margins excluding the write down of $1.6 million of HemoStase inventory were 81% in the full year of 2010 compared to 83% in the full year of 2009. General administrative and marketing expenses for the fourth quarter of 2010 were $12.2 million compared to $12.6 million for the fourth quarter of 2009. These expenses for the fourth quarter of 2010 included approximately $474,000 in costs related to business development activities and $268,000 in costs related to our litigation with Medafor.

General administrative and marketing expenses for the full year of 2010 were $49.1 million compared to $50 million for the full year of 2009. The full year of 2010 included a charge of approximately $1.4 million in costs related to our litigation with Medafor $1 million related to business development activities and $729,000 related to the write off of capitalized legal expenses associated with our BioGlue intellectual property rights in Germany.....

Raymond Myers – The Benchmark Company

Okay. Good. When were you targeting PerClot approval and launch?

Steve Anderson

I think that PerClot’s approval will be sometime towards the end of 2012 or early 2013 the clinical study that we are going to run is includes about 300 patients and will be across a number of different specialties for a number of different indications. But I would say the soonest we could get it done at the end of 2012 probably a more timely expectation is early 2013.

Raymond Myers – The Benchmark Company

And that’s for approval or for finishing this study.

Steve Anderson

That’s approval.

Raymond Myers – The Benchmark Company

And so well let’s start with the study through this to finish the 300 patient study if you would follow your IDE at the end of March when do you think you can finish the study.

Steve Anderson

It will go pretty quickly but I don’t think that we would be finished with the 300 patient enrollment until fourth quarter of 2011.

Raymond Myers – The Benchmark Company

And that leaves about a year for FDA is that your thought?

Steve Anderson

Yeah.

Raymond Myers – The Benchmark Company

Great, your HemoStase revenue was quite strong in the fourth quarter is that related to winding down the sales and a desirable push out the last of your inventory before you can’t sell it anymore or does that more represent underlying strength in the market.

Ashley Lee

I think it represents both you know I mean you know this full area of powdered hemostatic agents is rolling and that’s why we’ve made the commitment to be in it long-term with the acquisition of the PerClot distribution rights and at the same time you know as you mentioned we do have some inventory that we are trying to sell prior to our discontinuing distributing HemoStase which is going to be in late March so it’s a combination of both.

Raymond Myers – The Benchmark Company

So should we expect similar sales on Q1 as if we saw in Q4.

Ashley Lee

For HemoStase.

Raymond Myers – The Benchmark Company

Yeah.

Ashley Lee

No.

Raymond Myers – The Benchmark Company

Lower, higher?

Ashley Lee

That would be lower than the fourth quarter of 2010 and I think that our guidance for again for the full year for all powdered hemostats is between $4 million and $6 million.

Raymond Myers – The Benchmark Company

Okay, and is some of the HemoStase that you might be selling in Q1 product that is already written off?

Ashley Lee

Potentially.

Raymond Myers – The Benchmark Company

So there could be a potential of a reversal of the prior charges?

Ashley Lee

I wouldn’t say a reversal of the prior charges we could be recognizing some revenue for which there is no associated – costs associated with the revenues so not by that finish in reversal but we could have some revenue with very high gross margin on it.

Raymond Myers – The Benchmark Company

Do you expect that to be potentially meaningful to earnings in the quarter.

Ashley Lee

I wouldn’t expect it to be meaningful to earnings in the quarter.

Raymond Myers – The Benchmark Company

Okay well.

Ashley Lee

It might be meaningful to cash flow though.

Raymond Myers – The Benchmark Company

Nice your cash flow is already very good. You’ve had a share buyback consistently through 2010 do you intend to continue that in 2011?

Ashley Lee

The buyback has continued into the first couple of months of 2011 and just to give you an idea of where we are we have purchased roughly about 1.3 million to 1.4 million stock in the first two months 2011 at an average price of you know somewhere around 5.25 [ph] that’s a guess.

Raymond Myers – The Benchmark Company

So you’ve purchased $1.3 million or shares?

Ashley Lee

Dollars.

Raymond Myers – The Benchmark Company

Dollars.....

Raymond Myers – The Benchmark Company

Yeah, thank you I’m here. Ashley and Steve could you maybe start with reminding us how many sales people do you have now and what are your plans to expand that.

Steve Anderson

In round numbers we have about 50 in the field in United States and we are direct in the UK, Germany and Austria with approximately 10 people in the field over there.


Steve Anderson

I think that PerClot’s approval will be sometime towards the end of 2012 or early 2013 the clinical study that we are going to run is includes about 300 patients and will be across a number of different specialties for a number of different indications. But I would say the soonest we could get it done at the end of 2012 probably a more timely expectation is early 2013.

FYI BioGlue paper, click on thumbnail.

  BioGlue Incidents