Thirteen leading medical journals in Australia, Britain, Canada, Denmark, the Netherlands, Norway, New Zealand and the United States issued editorial warnings last month, saying that the promise of big financial rewards may be corrupting human clinical trials. The editorials – running in The Lancet, The New England Journal of Medicine, the Journal of the American Medical Association and 10 other medical journals – specifically criticized pharmaceutical manufacturers for their increasing use of contract research organizations (CROs) instead of academic institutions, often because the CROs are cheaper. And CROs also are less independent, according to the journals.
In the U.S. last year, 60% of pharmaceutical research grants went to CROs, and the editorials asserted that the CROS do not provide sufficient oversight of clinical trials. "The results of the finished trial," warned the 13 editors, "may be buried rather than published if they are unfavorable to the sponsors' product." And they also expressed the fear that substantial financial rewards may compromise the objectivity of scientists and could place patients at risk.
The warning came as Bayer (Leverkusen, Germany) faced possible class-action suits over Baycol/Lipobay, which has been linked to more than 50 deaths, and as GlaxoSmithKline (London) became the subject of a U.S. claim that it deliberately hid from regulators the side effects of Paxil, its multi-billion-dollar antidepressant.
The 13 medical journals themselves promised to raise their own standards for the publication of research. From now on, they said, all authors and peer reviewers will have to reveal any possible conflicts of interest.
New cardio sub-sectors to watch
Cardiovascular technologies have long been at the heart, so to speak, of medical device development, and that arena recently has produced two emerging sub-sectors: drug-coated stents and septal occlusion devices. Interestingly, the two technologies offer a sharp contrast in purpose: Stent technology is intended to maintain an open supply of blood in the vasculature, while septal occlusion attempts to shut off unwanted movement of blood in the heart.
The use of drugs to decrease the rate of in-stent restenosis is seen as just one approach to the problem – with radiation entering the competition last year and gene therapy on a more distant future horizon. Whatever the approach here, the intent is to maintain continued normal blood flow at the stent site by preventing the reclogging of tissue around it. While radiation has decreased the rate of restenosis, the drug/device combination has demonstrated near-zero results in the most recent reports of early clinical trials.
Thus far, Cordis (Miami Lakes, Florida), a unit of Johnson & Johnson (New Bunswick, New Jersey), is seen as having the lead in bringing a drug/stent combination to market sometime next year. In an attempt to play catch-up, Guidant (Indianapolis, Indiana) and Cook (Bloomington, Indiana) in late August set aside competitive concerns and formed an agreement to combine their efforts. Cook will have access to Guidant's stent technologies and will contribute to that company its polymer-free paclitaxel coating, with the drug coating itself licensed from Angiotech Pharmaceuticals (Vancouver, British Columbia).
When the pact was announced, John DeFord, PhD, Cook's president and CEO, said that the agreement was in part an effort to avoid patent battles between the two companies. However, Boston Scientific (Natick, Massachusetts) has raised its own legal challenge to the agreement, issuing a Notice of Dispute to the companies, saying that it has the only right other than Cook to commercialize stent products using Angiotech's paclitaxel coating. This has put Angiotech in the middle, with that company issuing a release attempting to distance itself from the dispute.
In another approach, Implant Sciences (Wakefield, Massachusetts) and CardioTech International (Woburn, Massachusetts) in early September announced their own agreement to develop a drug-eluting stent – a stent that releases the drug Rapamycin over a period of several months. Michael Szycher, MD, PhD, president and CEO of CardioTech, said this coating "is not just a coating – it is a microporous structure," utilizing biodurable polymer, trade-named ChronoFlex. This, he said, provides for improved healing over time around the stent as a way to retard restenosis. Dr. Clara Bajgar, manager of medical device development at Implant Sciences, said that besides working on cardiovascular applications for the drug/device treatment, the company is developing applications such as drug-eluting stent grafts "with enhanced anti-restenotic properties for the treatment of abdominal aortic aneurysms."
The second emerging area – septal occluding devices – received a boost last month with FDA panel backing of the occlusion devices being developed by NMT Medical (Boston, Massachusetts) and AGA Medical (Golden Valley, Minnesota). These systems offer less-invasive alternatives to surgery for plugging small holes in the heart which prevent its proper function. In infants, some of these congenital defects will prevent the child's growth and development and so must be closed fairly quickly. Other forms of septal holes may be asymptomatic initially, but can result in serious heart failure in later years.
In an early September meeting, the Circulatory Systems Devices Panel voted to recommend approval of NMT's CardioSeal Septal Occlusion System for treatment of congenital ventricular septal defects of the heart, and of AGA Medical's Amplatzer Septal Occluder (ASO) system for two indications in this area. The technical terms for AGA's applications are treatment of atrial septal defects (ASD) in secundum position and closure of the fenestration following a fenestrated fontan procedure.
Larry Haimovitch, president of Haimovitch Medical Technology Consultants (San Francisco, California), who follows the cardiovascular sector for The BBI Newsletter and its sister publications, Cardiovascular Device Update and Medical Device Daily, said that the panel approvals, "aren't going to dominate interventional cardiology news" when compared to the current market battles over stents – which he termed "stent wars." But he said that, with approval of expanded applications, the devices would address a fairly large population of people needing treatment for patent foramen ovales (PFOs), holes between the left and right atria which do not close, allowing a reverse flow of blood. NMT has estimated a population of 80,000 to 90,000 in the U.S. with PFOs and a worldwide population of 450,000. Besides PFOs, other terms for these leakages of blood in the heart are PDA (patent ductus arteriosus), ASD (atrial septal defect) or VSD (ventricular septal defect).
NMT's CardioSeal system consists of an occluder, or closure, system and a catheter-assisted delivery device. It describes the occluder as an alloy framework on which polyester fabric is attached. The placement and attachment is made by means of what the company calls a Qwik Load loading system for delivering the occluder which is then held in place by natural pressure. AGA describes its ASO device as a "self-expanding, self-centering, repositionable, double-disk" system comprised of nitinol metal braid with polyester patches sewn into the disks. It too is delivered by means of a catheter. Haimovitch noted that the ability to place these devices less invasively puts them at a clear advantage over standard surgical procedures.
Additionally, for older patients, surgery is not appropriate and so blood-thinners are often used to reduce adverse events such as carotid stenosis or stroke. But Haimovitch pointed to increasing evidence that anticoagulation therapy may not offer as much benefit to these patients as previously believed and that, especially for active patients who are more subject to cuts and bruises, the use of blood thinners may result in excessive bleeding. "It appears [these] closure devices may provide a much better solution," he said.
Besides their specific cardiovascular applications, the devices may have broad potential uses in the neurological arena, especially in the reduction of stroke. NMT has indicated it has longer term plans for expanding to this sector. Supporting this, Haimovitch noted new research evidence indicating that up to 10% of strokes may have their basis in a septal defect of the heart.
"That's really significant and unrecognized in the neurology community," Haimovitch said. "Now we have a pretty elegant solution from the interventional standpoint that seems to really solve the problem, as opposed to major open heart surgery." He also noted that the less-invasive option may be especially important for those patients already prone to stroke. Overall, Haimovitch characterized the treatment of PFOs as the broadest possible opportunity, calling it "the big enchilada" in terms of long-term development of the technology in the cardio sector. Thus he called the NMT and AGA devices "a very, very interesting new technology for a significant problem."
DEHP report 'incomplete,' says AdvaMed
The Advanced Medical Technology Association (AdvaMed; Washington) last month challenged an FDA report on the effects of DEHP-treated vinyl in medical products, saying the report offers some important information but not a complete picture of the potential benefits and risks. The agency had issued what it called a "first step" report concerning DEHP (di[2-ethylexyl]phthalate), a softener used in various vinyl medical devices, focusing on potential adverse effects on infants, while saying there was no evidence of those effects in human studies.
In response, James Benson, AdvaMed executive vice president of technology and regulatory affairs said that the FDA report, in terms of risk/benefit analysis "took into account one side of the equation."
AdvaMed said that in many applications, DEHP-plasticized PVC material has shown to be the optimal choice for meeting device performance functions such as strength, durability, biocompatibility, clarity, flexibility, weldability and suitability for sterilization. Where technically feasible and clinically appropriate, PVC and DEHP-free materials are options in some medical devices, it said.
The organization also expressed disappointment that the FDA's assessment did not fully incorporate all available data on DEHP. AdvaMed provided the agency with the results of a new study that looks at reproductive and development effects on neonatal rodents exposed to high dosages of DEHP. The FDA, which was consulted on the study's design, incorporated only some elements of the study results in its safety assessment, AdvaMed said.