New Publication Answers Questions About the SIPPET Study

Inhibitors are the most troubling complication of hemophilia A treatment today. In this week’s blog, I share with you a new publication concerning the SIPPET study, which sheds light on factor VIII products and inhibitors.
New Publication Answers Questions About the SIPPET Study


An article written by noted hematologist Dr. Flora Peyvandi and colleagues was recently published in the medical journal Haemophilia. This article directly addresses and answers several questions that were raised about the 2016 publication of the Survey of Inhibitors in Plasma-Product Exposed Toddlers, or SIPPET study.1

With this new article, SIPPET: methodology, analysis and generalizability, the authors respond to the 17 most common questions associated with the design, methodology, and results of the SIPPET study, including1:
  • Is the inhibitor risk higher in SIPPET than in previous reports?
  • Could differences in treatments between countries have affected the results?
  • Could the results have been affected by the way the study was randomized?
  • Do the SIPPET results also apply to other recombinant factor VIII (rFVIII) products
    beyond the 1st and 2nd generation products used in the study?
  • Is there a difference in inhibitor risk between the different brands within the plasmaderived and recombinant groups?
Original SIPPET Study
The SIPPET study, conducted by Dr. Peyvandi and colleagues, was the first randomized trial to compare the incidence of inhibitors in plasma-derived factor VIII (pdFVIII/VWF) products and rFVIII products in previously untreated patients (PUPs).2

Results from this landmark study showed that there was an 87% higher rate of inhibitor development in patients who received rFVIII compared with patients who received pdFVIII containing von Willebrand factor (VWF).2

Based on the results of the SIPPET study, the National Hemophilia Foundation’s Medical and Scientific Advisory Council (MASAC) now recommends that pdFVIII/VWF be considered as one of several treatment options in PUPs.3
Visit www.inhibitorinfo.com to Learn More About Inhibitors
Inhibitors are the most serious and challenging hemophilia A treatment complications. All patients with hemophilia A are at risk for developing inhibitors, regardless of age and disease severity.
Inhibitorinfo.com is a comprehensive website that provides important information and resources about inhibitors and the risk of inhibitors. There is a discussion guide patients can download and use to talk with their hematologists about inhibitors. Visitors can also read about the results of the SIPPET study and watch leading hematologists talk about its implications.
When visitors sign up for updates at inhibitorinfo.com, they will receive access to the full SIPPET study, as well as updates about hemophilia, inhibitors, and the latest clinical data.
References: 1. Peyvandi F, Mannucci PM, Palla R, Rosendaal FR. SIPPET: methodology, analysis
and generalizability [published online ahead of print March 17, 2017]. Haemophilia. doi:
10.1111/hae.13203. 2. Peyvandi F, Mannucci PM, Garagiola I, et al. A randomized trial of factor VIII
and neutralizing antibodies in hemophilia A. N Engl J Med. 2016;374(21):2054-2064. 3. National
Hemophilia Foundation. MASAC Update on SIPPET. National Hemophilia Foundation website.
https://www.hemophilia.org/Newsroom/NHF-Community-News/MASAC-Update-on-SIPPET.
Published March 9, 2016. Accessed April 27, 2017.
This is a paid public announcement from Grifols and does not constitute an endorsement of
products or services. When you click on the links in this blog entry, you will be directed to
the Grifols website. LA Kelley Communications always advises you to be a savvy consumer
when contacting any company; do not reveal identifying information against your will.
BN/A8/0517/0275

Blood: Time to Donate!

 

National Hemophilia Foundation recommends recombinant factor as the standard of choice for treatment of hemophilia, but did you know that many factor products used to treat
hemophilia are developed from human blood, specifically human plasma? In fact, one person with hemophilia can require up to 1,200 plasma donations for a one year’s supply of factor
products. Plasma products are especially important for those undergoing immune tolerance therapy to treat inhibitors, for those with von Willebrand disease and for those in developing countries.
 
And plasma can come from you! Think of making a blood donation, during this time of Thanksgiving and holidays.
 
First, learn a bit more about plasma, Plasma is the straw-colored liquid that makes up
approximately 55 percent of total blood volume. A single liter of plasma yields
coagulation factors essential for blood clotting, immunoglobulins used to
combat viruses and bacterial infections, and albumin, a major plasma protein
that regulates blood volume and other essential functions.
 
In addition to treating hemophilia, plasma-derived therapies
are used in everyday medicines, emergency and critical care situations, as well
as preventive medicine. Albumin, for example, is used to treat burns, shock,
trauma, liver conditions and cardiopulmonary illnesses; immunoglobulins are
indicated for Rh incompatibility, pediatric HIV, hepatitis, and animal bites.
 
Plasma is an expensive raw material and represents between 40 to 60 percent of the cost
of plasma-derived product production. This is due primarily to its biologic
nature: plasma protein therapies are not interchangeable, have no generic
variations or substitutions, and are defined as sole-source biologic products
by global regulators.
 
Since plasma is biological in nature, complex regulation and
oversight measures are in place—including collection, processing, and storage
and handling requirements—to ensure plasma donor health, as well as product
purity and efficacy for patients.
 
The majority of the world’s plasma comes from plasma donors
in the U.S. Collectively, the Food and Drug Administration (FDA) and its Center
for Biologics and Research (CEBR) are responsible for regulatory oversight of
the U.S. blood supply. Blood collection centers are either registered or
licensed by the FDA, and are held to quality standards comparable to those of pharmaceutical
manufacturers. Blood establishments located outside of the U.S. that import or
offer for import blood products are also required to register with the FDA.  
 
CEBR regulates the collection of blood and blood components
used for transfusions, as well as for the manufacture of pharmaceuticals
derived from blood and blood components. CEBR develops and enforces quality
standards, inspects blood establishments and monitors reports of errors,
accidents and adverse clinical events.
 
Manufacturing processes begin with fractionation,
followed by purification and virus inactivation. Fractionation is a time
consuming and complex process that extracts, or “fractions off,” specific
plasma proteins that have a proven health benefit. Fractionation requires
multiple processing steps, which involve manipulating solution pH, temperature,
ionic strength and alcohol concentration.
 
Once fractionated, plasma proteins are further subjected to
virus inactivation, a complex purification processes that includes prion
removal, nanofiltration, solvent/detergent
treatments and incubation, to ensure sterility and purity of the final product.
The complete manufacturing process, from plasma collection at a donor
center to the FDA’s lot release, takes seven to 12 months.

 

So donate now! Next year at this time, your donation could be used to save a life!
 
Sponsored by ASD Healthcare.
 
Great Book I Just Read
The Climb to Hell  [Kindle]
Jack Olsen
 
Olsen sure can write a page-turner. In 1957, one of the most audacious and stunning rescues to ever take place occurred on the north face of the Eiger, one of the most notoriously difficult challenges to scale, located in the heart of the Swiss Alps. The Eiger is feared for its avalanches, fast-changing weather, and sheer facade. When two poorly-prepared Italians set off to make history by being the first Italians to scale it, they become stuck for eight days, in zero-degree weather, unable to get off the mountain. This launches an international rescue effort, that leads to surprising outcomes, including national rivalry, clashing personalities, extreme risk taking and uncertain success. Fantastic story, well told and must-reading by all mountaineers. Four/five stars.

Under the Tuscan Sun: A Company Branches Out

Beautiful hills of Tuscany

If you’re my Facebook fan, you might know
I spent last week in Italy. I know, poor me. It was quite a change from two
weeks in India. All I need is Indonesia and I will have done my Eat, Pray, Love
hemophilia pilgrimage. Except I managed to eat in India, pray in Italy…. The
rest has yet to be seen!

I spent a few days in Florence before
heading slightly north for the real purpose of my trip. Florence is a city I studied
intensely as a teen. While other girls were going to dances, I studied the
Renaissance and became quite an “expert” at a young age. I copied paintings of
the masters, as I loved art, and when I first arrived at age 17, knew more
about where to go than our high school guide. So returning for my fourth time,
I resolved to wander the streets and churches, revisit the masters, and stand
in awe of the treasures of Italy. Nothing man-made captures my stunned, silent
respect and worship like the statue of David.
On day four I headed to Lucca, to visit a
pharmaceutical company called Kedrion. Kedrion came to our attention in the US a few years ago when it was contracted by Grifols to handle distribution of Koate-DVI, a
plasma-derived factor VIII product. Originally produced by Bayer, it was
divested, along with all the Bayer plasma division, to Talecris. Eventually
Talecris was bought by Grifols. But the US government, leery that Grifols now
had two plasma derived FVIII products, required Grifols to have a different
company handle distribution of Koate-DVI. Enter Kedrion.
Kedrion may be new to the US, but not to
Europe. Kedrion is a leading global pharmaceutical company specializing in the
development, production and distribution of a wide range of protein products
derived from human plasma. The company’s products are used to treat hemophilia,
immune deficiencies, infectious diseases and other serious medical conditions in
over 60 countries. The company owns four production facilities: two in Italy,
one in Hungary and one in the United States (currently leased to Grifols).
I was thrilled to be offered a tour of
the production plant. The plant is nestled among the Tuscany hills in Lucca, an ancient
city famed for its fortress-like walls that protect the denizens, once Romans
in 180 BC. The scenery—snow capped mountains rolling away to the sea; petite,
puffy clouds touching down on factories and churches— is breathtaking from the
patio of the Renaissance (how appropriate) hotel, perched on a mountain and once
owned by the Marcucci family, which also owns Kedrion.
I had dinner the night before the tour
with Paolo Marcucci, CEO of Kedrion, and wife Paola Pardini, whom I have met
before and who sponsor 17 children through Save One Life. With us was also
Danilo Medica, Italy country manager for Kedrion, who I had also met before at
a WFH event. Social events are always lovely with Italians, who know the fine
art of socializing, eating and drinking, and offering sincere and mutual respect
and hospitality.
Laurie at Kedrion plant, with
Charles Waller

So my purpose in visiting was to see the
plant, and learn more about this newcomer to the US market. Also, Kedrion has
been for a few years now our largest single donor of factor products to
Project SHARE, my factor donation program. We are now collaborating on ways to
secure even more factor to donate to the regions of the world where the 75%
live—those people with hemophilia with little or no access to treatment. Like…
some of the places I had just seen in India.

First, a snapshot: Kedrion was founded by
the Marcucci family; current CEO Paolo is son of the founder. It offers technology transfer of plasma collection to Macedonia,
Turkey, and Iran, as well as plasma-derived product sales to about 60 countries. It has 15 plasma
collection centers (nine of which are in the US). About 95% of its products are
plasma derived. Kedrion is one of the few factor manufacturers that is
considered part of a government healthcare system. About 75% of the company
is owned by the Marcucci family; 25% is owned by government.
Kedrion experienced enormous growth in the
past few years. Its business used to be only in Italy until just 2007; now it’s
been global for five years. A dominant 60% of its business is international,
part of this switch attributed to production acquisition sites in the US. It
has a FV product in the pipeline, even though there are only 5-6 patients with
FV deficiency in Italy. Clearly, Kedrion continues to have its eyes set on the
world.
And hemophilia in Italy? There are 3,481
hemophilia A patients; 1,688 are severe, 1,320 mild, and 473 moderate. In 2013,
FVIII consumption was about 555 million IU, with plasma-derived product use
actually increasing, driven by IT therapy for inhibitor patients.  Still, recombinant products dominate the
hemophilia market, at 66% of sales.
PLANT
TOUR
On a frosty Wednesday morning, I removed my jewelry, washed my hands thoroughly, suited up, and entered the plant with my
hosts, to tour how plasma products are made. The plant fractionates 1 million
liters (about 264,172 gallons) every year, using 24,000 liter tanks. First I
watched a film on the plant: how plasma arrives, is checked, monitored and
inventoried. How plasma is separated by centrifuge creating cryo paste for
fractionation. There are 480 employees in Lucca, and the plant operates 7 days
a week, 24 hours a day. It will be closed over Christmas for maintenance and
cleaning. The instruments and suites where products are made are cleaned daily.

On this tour I was able to watch albumin
being made. Albumin is the part of plasma used to bulk-up factor concentrates,
to allow them to be injectible. Alessandro, plant manager and our guide, explained
about different classes assigned to manufacturing suites (A-D), based on sterility
and cleanliness. As each product goes through each manufacturing phase, the
requirements for cleanliness gets more and more complex.

It’s not
just that things must be sterile. In the suite, people come and go; there is
air, exhalations, and ventilation. The air itself, pressurized like in an
airplane, to push air out if there is a breach, must be monitored constantly. You
want a low level of environmental pollutants such as dust,
airborne microbes, aerosol particles and
chemical vapors. Levels of contamination are specified by the number of
particles per cubic meter at a specified particle size. Instruments protruding
out of the wall measure constantly the ambient air, and would signal an alarm
if the air contained undesirable things in it at a level considered potentially
harmful.
We watched as lab employees handled the
sterile vials into which the albumin would be placed, all by machine to reduce
human contact. The rubber stoppers were placed, and the machines sealed it with
the foil. I learned something new: I always
thought the rubber stopper might be at risk to cause a breach of integrity of the vial
if the vial got too hot or cold. But Alessandro assured me these stoppers are
powerful and not likely to contract or expand with different temperature. It
really is about temperature control to keep the protein from degredating and
becoming less effective, less powerful.
Speaking of power, the plant must have
power at all times. What of there was a black out, someone asked? Kedrion is
self-sufficient in power, Alessandro explained. They produce energy themselves
using methane gas production.

Last, we learned about the “KQP”: Kedrion
Quality Program, an eight step system, using among other things, regular
qualified donors, NAT testing, pathogen inactivation, and TSE agents, to assure
that the products are safe.
The Italian Health System is complex,
making me realize we aren’t the only ones with healthcare budgetary woes. With 19
regions that are traditionally independent, 645 public
hospitals, 50 HTCs, and an ongoing economic crisis, the federal government is trying
to consolidate hospitals, and is asking for additional cost reductions from
industry. And yet Kedrion must continue to fractionate Italian blood and return
plasma-derived products back to the various regions.
One concern is that Italy’s not
self-sufficient in any product. Consumption is growing faster than production, but
consumption includes imported products at much higher per unit prices. In the
face of an economic crisis, slashed healthcare budgets, the question is: can
Italy use the products it has already to alleviate demand?
So that’s the point of my visit: in April
2013, Italian laws have changed regarding plasma. Previously Italian plasma had
to be used by Italians, but now the law allows Italian regions to recover costs
by selling the plasma products to other countries. Or maybe, donating? To India,
to Africa? We will see.
The name Kedrion comes from the Greek
language for lemon tree (or juniper or citrus, depending on your source). Its
symbol represents the deep roots Kedrion has in Italy, where the company was
built on Italian plasma and by a family dyanasty, and its branches go out into
the air, the world. I’m hoping they continue to branch towards developing
countries, to patients waiting to know this unique company and benefit from its
products.
To learn more about Kedrion: www.kedrionusa.com
Great Book I Just Read
Brunelleschi’s Dome by Ross King [Kindle]

The perfect book for reading while in
Florence. My hotel was about 200 feet from Santa Maria del Fiore, and when I
stepped into the cobblestone streets each morning, the massive façade, capped by the
astounding dome, greeted me. This book goes into great detail about what it
took to create the 37,000 ton dome, one of the largest cupolas in the world,
completed in 1436. It took 16 years to complete (over 100 for the Cathedral itself!),
and the architectural construction was filled with competition, craftiness and creativity. Brunelleschi
invented all kinds of new ways to transport marble, to hoist the marble. He was
a genius of architecture, and this Dome today still awes and impresses. This
story is compelling, and shows the potential of man to create and persist. Brunelleschi
was foiled many times, faced many obstacles, but finished it, leaving behind
one of the most prominent and important symbols of the Renaissance. A must read
for anyone going to Florence. But a fabulous book on any account. I climbed the
436 stairs to the top and was rewarded with a breathtaking view of Florence, one
of my favorite cities. It boggles the mind how this could have been created, at
such a time, with such vision. You’ll never look at a church steeple or
basilica the same again once you read this. Five/five stars!

The Future of Plasma Products

This past week I attended a fascinating event: The Plasma Protein Therapeutics Association (PPTA) in Washington DC. The PPTA is a nonprofit organization whose mission is “to promote the availability of and access to safe and effective plasma protein therapeutics for all patients in the world.” Attending were representatives and the heads of the major plasma producers in the world, including Baxter, Grifols, Octapharma, Talecris and CSL Behring. With only about 300 people present, it provided a more detailed and intimate look at issues affecting plasma.

The theme was “Access to Care.” Larry Guiheen, President of Biopharmaceuticals, Baxter, and also chair of the PPTA Board, kicked off the meeting with an overall look at the state of the world: Access means different things in different countries, he said, referring to the poor versus the rich countries. Health care goals of all countries include improving the overall quality of care, and providing access to care. Healthcare should be viewed as an investment in poorer countries (or what manufacturers call emerging markets); it’s expensive at first but someday it will pay off. What therapies will a government support? Those with the highest impact–meaning, I think, that lower cost drugs will allow governments to buy the more drugs, allowing for expanded treatment for all citizens. And plasma products generally are lower cost than recombinant ones. He added, the key to access is reimbursement of care.

Larry continued by saying, in the US, plasma is a key ingredient to health care. The US is an exporter of plasma, where self-sufficiency [in creating its own plasma] is key, but sometimes a country actually limits care. He pointed out that one limitation are trade barriers, which need to be broken down. China used to have barriers to importing plasma. Overall, he concluded, global plasma production capacity is increasing, plants are expanding, and collection centers are expanded.

Mark Skinner, president of the World Federation of Hemophilia, gave a wonderful presentation on the work of the WFH: there are now 115 national member organizations (NMOs). There are 219,000 patients with bleeding disorders identified.

I gave a presentation on my visit to Zimbabwe in December, to contrast the difference in access to care issues in a country with no hematologist and economic collapse, to a country with excellent care but increasing access hurdles, the US. I also gave my presentation on the Current Storm, which in a nutshell outlines the changing landscape of the hemophilia industry under the tightening screws of payer reimbursement restrictions.

A lively panel discussion with executive representation from the plasma manufacturers (and one lawyer to prevent any violation of antitrust laws) ensued on the last day of the conference. The panel came alive at the mention of paid versus voluntary donors. (There is excellent background on this issue in the book Blood, by Douglas Starr) Wolfgang Marguerre, chairman of Octapharma, a Swiss-based factor manufacturer which has just recently set up shop in the US, warned about shortages of supply: if there is an indication or new product for multiple sclerosis treatment that uses plasma products, there will not be enough plasma for the US population.
We need more volunteer donors, he stressed. “We have to use our influences to get them to understand our message,” he strongly pointed out. “The time has come to end ideological warfare against these types of donations.

Mark Skinner noted that the World Health Organization (WHO) allows only voluntary donations, and this is not sufficient to meet world demands. He asked, how can we reconcile WHO policies and the needs of our population?

Marguerre added, “There is confusion about [the role of] transfusion. [Authorities believe] Plasma is special and needs to be voluntary.”

Jan Bult, president of the PPTA, then asked the board their opinions of self-sufficiency, the ability of a country to produce its own plasma for its own people. I was shocked to learn that only the US and Germany are capable of doing this! In large part, because the US pays its donors, something that is considered forbidden, unethical and dangerous in many countries, and by some groups here in the US.

Dr. Gregor Shultz, chairman of the board of Biotest, pointed out that Japan had been trying for 20-30 years to create self-sufficiency and still can’t do it. Self-sufficiency won’t work there. Larry Guiheen added, “We pay donors, and other countries must too if they want to be self-sufficient.”

Japan became a focus of the discussion, and I learned that in Japan, the Minister of Health could be held personally liable if something goes wrong with blood supply. And the HIV scandal still haunts Japan, which then affects their regulatory department. The Japanese government can restrict imports of blood products when demand for these products hurts domestic production. And the government prefers blood products from Japanese blood. Blood is also labeled “voluntary” or “involuntary” yet no compensation is given.

Obviously, plasma production and supply was viewed from a marketing point of view: restricted markets mean the manufacturers cannot sell their products there. As a businesswoman, I enjoyed the presentations and discussions immensely and learned a great deal about the plasma business. As a humanitarian, I appreciated perhaps more than anyone present the positive impact plasma products have on the patients with hemophilia in the developing world. They are the future of care for so many countries, and we need these products. I feel that the US is one of the engines, if not the engine, that drives the hemophilia industrial world. We need out manufacturers to continue to produce plasma products, and keep the incentives that motivate them to product it, for choice, access to care, and for our brothers in the developing world.

Congratulations to Jan, Julie Birkofer and the entire PPTA staff who hosted this engaging, interesting and stimulating conference. I look forward to attending next year!

(Photos: Jan Bult opening PPTA meeting; Wolgang Marguerre of Octapharma; Mark Skinner of WFH; Kerry Fatula, director of West Penn. Chapter of NHF with CSL Behring representatives; Laurie and Jan Bult)

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