Data Supporting FDA Approval for Cardiovascular Devices Called into Question

Key Points:

Device data submitted to FDA have unreliable endpoints, little randomization
Discrepancies found in patient numbers and ages
Call for more rigorous scientific standards as basis for approvals

Studies used to support US Food and Drug Administration (FDA) approval of cardiovascular devices often are scientifically inadequate and may be prone to bias, according to a study in the December 23/30, 2009, issue of the Journal of the American Medical Association. The review of 123 summaries of safety and effectiveness data found that 65% of implantable or invasive devices were approved based on data from a single study.
Researchers led by Rita F. Redberg, MD, MSc, of the University of California, San Francisco (San Francisco, CA), analyzed the methodology and primary endpoints used in studies submitted to the FDA as supportive evidence for 78 cardiovascular devices that received pre-market approval between January 2000 and December 2007.
Of the 123 studies, 80% reported the number of participants enrolled, 27% were randomized, and 14% were blinded. Some device groups had a higher proportion of randomized and blinded studies. Of 24 studies of cardiac stents, for example, 54% were randomized and 46% were blinded.
No Endpoints for Some, Discrepancies for Others
Overall, 14% of the 123 studies had no primary endpoint stated. Of those with primary endpoints, the vast majority were surrogates, which may not be reliable predictors of actual patient benefit, the authors write.
Seventy-eight percent of studies that included data for which both the number enrolled and analyzed were stated contained some discrepancy between the 2 numbers. The major discrepancy noted was that more patients were enrolled than analyzed. Other discrepancies occurred in relation to mean age and number of patients enrolled by sex and race. Such discrepancies may introduce bias, because patients with less favorable outcomes may be lost to follow-up, which might cause safety concerns to be overlooked.
The researchers also found that 15% of the primary endpoints were noninterpretable. The most common reason was that no target goal for device performance was stated (78%), and in one instance the results themselves were not stated. Follow-up periods varied by type of device with the longest median follow-up time for primary endpoint analysis being 365 days for intracardiac devices and endovascular grafts and the shortest follow-up time being just 1 day for hemostasis devices.

Clinicians Look to FDA for Guidance

Dr. Redberg and colleagues point out that the FDA has much more experience with drug approvals than with device approvals, which only began in 1976 with the FDA Device Amendment. In addition, there has been a significant increase in the number and complexity of devices. Nevertheless, the FDA approval process is crucial to a vast spectrum of players in the health care system from clinicians to insurers.
“The importance of the ‘seal of FDA approval’ cannot be overstated. Many manufacturers immediately encourage widespread use of their devices based on FDA approval through direct-to-consumer advertising, detailing to physicians, and continuing medical education venues,” the authors write. They add that since FDA-reviewed data are the only evidence clinicians can analyze to evaluate the basis for the agency’s decision and form the sole basis for systematic reviews and guideline development, the study reinforces the need for improved access to complete FDA reviews for both pharmaceutical and device data.
“To uphold the FDA’s mission of ensuring ‘safe and effective’ medical devices, it is essential that high-quality studies and data are available,” they conclude.

US researchers develop intravenous blood-clotting agent

New York (Dec 28, 2009) : Whether in war-torn Iraq and Afghanistan or on the world's roads, many thousands of people bleed to death each year as a result of traffic accidents, gunshot wounds and bombs.
Traumatic injury is the leading cause of death for people aged 4 to 44, US researchers wrote this month in the journal Science Translational Medicine. But they think they have found a way to halt
internal bleeding with the help of nanotechnology.
A team led by Erin Lavik, a biomedical engineer at Case Western Reserve University in Cleveland, Ohio, has developed synthetic blood platelets from biodegradable polymers already used in treatments approved by the US Food and Drug Administration (FDA), whose regulatory purview includes biologics and blood products.
If injected into a trauma patient, the synthetic nanoparticles could bind at the site of injury with natural blood platelets, thereby hastening clotting. In tests, the synthetic platelets halved
bleeding time in wounded rats. Lavik and her colleagues said that injecting the nanoparticles was like adding sand bags to a levee along a flooding river.
When blood starts to flow from a wound, the researchers explained, natural platelets try to staunch it by binding together using fibrous protein molecules. The synthetic platelets augment this process by binding to the natural ones.
To prevent the synthetic platelets from clumping into dangerous clots, each one is built with a surrounding "shield" of water. In the test animals, surplus synthetic platelets were flushed out of the body within 24 hours.
The researchers said they had been looking for a means to stem internal bleeding that medics could carry in their field packs. "The military has been phenomenal at developing technology to halt bleeding from external or compressible injuries," Lavik remarked, pointing out that the nanoparticles could complement existing therapies

Vascular Solutions Wins Appeal In Disparagement Litigation With Marine Polymer; To Accept $3.2 Mln In Damages

Monday, medical device company Vascular Solutions, Inc. (VASC:News ) said that the First Circuit of the U.S. Court of Appeals has affirmed the earlier judgment in its favor in its product disparagement litigation with Marine Polymer Technologies and $2.7 million in damages to be paid to Vascular.
In the two-week trial in April 2008, the jury has issued a permanent injunction prohibiting Marine Polymer from making disparaging statements concerning the safety of Vascular Solutions' D-Stat hemostat products. The jury had also awarded $4.5 million in damages to Vascular Solutions and found five statements made by Marine Polymer regarding Vascular Solutions' D-Stat products false.
The Appeals Court,however, has determined that due to differences in opinion among the judges Vascular may either accept a $2.7 million award of damages, plus interest, or insist upon a new trial limited to the issue of determining the reasonable amount of damages.
Adding interest at the statutory rate, Vascular said that it calculates the $2.7 million award to currently total approximately $3.2 million. Today's appellate decision is subject to Marine Polymer Technologies' ability to petition for rehearing by the First Circuit and appeal to the U.S. Supreme Court. The permanent injunction issued against Marine Polymer at the conclusion of the earlier trial will remain in effect.
Independently, the Appeals Court found that the evidence "provides ample proof of malice. And the most inflammatory of the five statements, and the most glaringly unsupported, are the two that associated D-Stat Dry with specific and serious outcomes in percentages that would be remarkable for a relatively straightforward medical task -- to stop bleeding at a modest-size doctor-created incision."
Howard Root, CEO, Vascular Solutions, said, "In order to conclude this litigation, we intend to accept the $2.7 million award of damages, plus interest, and to forgo the cost and distraction of an additional trial on damages. We expect the final steps in this litigation to be concluded during the first half of 2010, and the approximately $3.2 million in damages and interest to be collected by Vascular Solutions without substantial additional expense."
VASC is currently trading at $8.40, down $0.05 or 0.59, on the Nasdaq.

ZymoGenetics shares fall on regulatory delay

Shares of ZymoGenetics Inc. dipped Tuesday after the company said additional studies are likely needed to gain European regulatory approval of its only marketed product, Recothrom.
Sales of the drug, which is used to control bleeding during surgical procedures, climbed to $8.5 million from $1.8 million during the third quarter. While approved in the U.S., it is not yet approved in Europe. Seattle-based ZymoGenetics licensed all rights outside of the U.S. to Germany-based Bayer in 2007.
In a Securities and Exchange Commission filing Monday, ZymoGenetics said Bayer pulled its application with European regulators as a response to indications that the drug candidate would take an additional study to gain approval.
The Committee for Medicinal Products for Human Use said Bayer's submission did not meet the necessary standards.
The stock fell 13 cents, or just under 2 percent, to $6.61 in afternoon trading. ZymoGenetics shares have traded between $2.55 and $7.31 over the last 52 weeks.

Synthetic Blood Platelets Are Twice As Effective

Scientists working with small particles at the nanoscale have recently revealed that they have developed a new type of synthetic blood platelets, which have twice the clotting capabilities of the standard variety. In the experiments they conducted on lab mice, the science group, which are based at the Case Western University (CWU), in Cleveland, managed to obtain an increased efficiency using their innovation than they could squeeze out of traditional clotting methods.
Technology Review reports that the nanoparticles could be the next major innovation in this field, considering that the regular drugs were so significantly exceeded in terms of performance. “We're helping to form the clot,” CWU bioengineer Erin Lavik, who has also been the leader of the new investigation, explains briefly. The scientist reveals that plans are to create blood clotting particles that are so effective that they could be used by paramedics right at an accident site, or by doctors working on injured soldiers in battlefields around the globe.
Early safety tests turned out to be very promising, but the CWU team admits that there is still a lot of work to be done until the new nanoparticles are ready to be mass-produced, and administered to patients. Speaking about the challenges associated with the development of a good blood clotting method, University of Pennsylvania Medical School physician Mortimer Poncz said, “There's a balance between the two edges of the sword--bleeding too much and clotting too much. You don't want to stop bleeding in the leg but die of a heart attack or have stroke.” He has not been involved in the new study.
The new nanoparticles are about one third the size of normal platelets. They can run through the bloodstream without experiencing obstacles, but also have the same stickiness that makes their natural counterparts so effective at stopping bleeding. While existing drugs can indeed boost the immune system's proprietary response to injury, they can also be terribly expensive, so a cheaper, more effective method was very high up on researchers' priority lists.

Medafor publish commentary of Cryolife battle

Medafor have published a pdf document on their website detailing their current view of the on-going battle with Cryolife. In the document they accuse Cryolife (amongst a host of contractual and legal issues) of attempting to initiate a lawsuit to force a sale after the Board rejected a second offer by Cryolife to purchase Medafor. Medafor have also engaged in a lawsuit charging their previous CEO and Chairman, Dick Zerban and Cryolife CEO, Steven Anderson alleging the wrongful transfer of shares. The full document is available on the first page of the Medafor website.

Zymogenetics cuts back staff to focus on Recothrom

ZymoGenetics is cutting all of its immunology work along with 15 percent of its jobs, or 52 positions. That's in addition to the 161 jobs the developer cut in April when it decided to bow out of the cancer research business. All ongoing immunology discovery research programs will be discontinued; however, the company will keep the research capabilities necessary to support the ongoing development programs for current product candidates.
According to the regulatory filing, cutting new immunology research will allow the developer to focus on its sole marketed product, Recothrom Thrombin, a treatment for surgical bleeding. It will also give ZymoGenetics more resources for developing and commercializing its pipeline of clinical and preclinical product candidates. In a statement emailed to Xconomy, a spokesperson said that the company has abandoned the strategy of discovering and licensing out many early-stage candidates. Now it will focus on fewer programs that it will advance to later stages. The spokesperson added that the company is focusing on drug candidates that have the most potential over the next three to four years.
ZymoGenetics's reductions will result in an annual expense savings of $8 million to $10 million, in addition to the estimated $30 million in savings generated by the April restructuring. This round of layoffs leaves the developer with about 300 employees, according to Xconomy.

ProFibrix Initiates Phase II Clinical Trial of its Lead Topical Hemostat Product Fibrocaps(TM)

SEATTLE, Washington, and LEIDEN, The Netherlands - ProFibrix B.V. today announced the start of the company’s Phase II clinical trial for Fibrocaps(TM), the company’s lead topical Hemostat product, with the successful treatment of the first patients for mild to moderate bleeding during liver surgery. ProFibrix expects to complete the study before the end of 2009.
Fibrocaps is based on a mixture of two essential blood clotting proteins, fibrinogen and thrombin, and is a unique dry powder topical tissue sealant that rapidly stops bleeding after or during surgery. Fibrocaps has major advantages over existing liquid tissue sealants: it is ready for immediate use, is stable at room temperature, highly effective and fast acting.
ProFibrix expects to submit an Investigational New Drug Application (IND) for Fibrocaps to the U.S. Food and Drug Administration in the first half of 2010, and conduct a combined phase II/III pivotal study in various surgical indications.
Jaap Koopman, PhD, Chief Executive Officer, said: “The successful treatment of the first patients with our lead product Fibrocaps is an important milestone for the company. With focus and dedication we have made enormous progress over the past two years, and we are on track to bring Fibrocaps to the point of market approval.”

About ProFibrix
ProFibrix was founded in 2004 and is headquartered in Leiden, The Netherlands, with a subsidiary in Seattle, WA. The company leverages its expertise in fibrinogen technology to develop and market innovative products for the hemostasis and regenerative medicine markets. Human fibrinogen plays a pivotal role in blood clotting and tissue healing. ProFibrix is led by a team with extensive commercial, clinical and scientific experience in the hemostasis field.