Drug-device combinations are now becoming widely recognised by interventional radiologists as a promising therapy treatment. This development has led to new techniques and procedures that have improved and expanded existing interventional practices and have also resulted in a greater response from patients who desire minimally invasive treatments.
This year's Josef Roesch Lecture at the recent CIRSE meeting in Rome was given by physician Dr Lindsay Machan of the Department of Radiology, Vancouver Hospital and Health Sciences Center, Vancouver, Canada. Machan, who is also the co-founder of Angiotech Pharmaceuticals and consultant to the scientific advisory board of multiple medical device companies, presented his talk entitled 'Drugs and Devices - Challenges and Opportunities for Interventional Radiology' to an almost full theatre.
Machan began his discussion by explaining that the longevity of interventional procedures is, or perceived to be, less in comparison with major surgical procedures, despite the powerful advantages fluoroscopically guided minimally invasive procedures has to offer patients. However, adding pharamacologic or biological activity to a device could, according to Machan, potentially improve the efficacy and longevity of minimally invasive procedures.
"In some cases procedures which are at present palliative could even become curative," said Machan. "In addition to extending the number of patients to whom they can be applied, the procedures are even made more attractive to patients and referring clinicians and more acceptable to paying agencies."
Drug-device combinations - not just for interventional procedures
Citing a paper by Wu P et al., Machan stated that drug-device combinations are not just being applied to minimally invasive procedures, there are being developed for many other areas of medicine. Such areas include antimicrobial wound care products, bone graft substitutes, antimicrobial catheters, antibiotic bone cements, photodynamic therapy, regional gene therapies, plus many others. Interestingly, the global market for drug-device combinations was approximately US$5.4 billion in 2004 and is anticipated to increase at an average annual growth rate of 13.6% to US$11.5 billion in 2010, as stated in 'Report RB-205 Drug Device Combinations, Business Communications Company'.
Drug-devices for minimally invasive therapy
Stents, largely drug-eluting stents, are possibly the most well-known biologically active devices developed for minimal invasive therapy. Others, as Machan highlighted, include drug-releasing embolic particles, coated embolic coils, targeted embolisation agents, pharamacologic agents to optimise ablative procedures, ultrasound and energy assisted thrombolysis, implantable venous valves, coated stent grafts, anti-infective central lines, and self-sealing biopsy devices.
"The range and diversity of biological activities associated with these devices is breathtaking," Machan commented. He then outlined various techniques and their positive effects, for example, he explained that coating a stent with a sclerosant or substance which induces a mural reaction could potentially improve long-term outcomes by addressing endoleaks in particular, device migration and disarticulation. Utilising ultrasound or heat (ie. focused energy) causes the systematic release of subtherapeutic doses of otherwise toxic drugs at therapeutic concentrations around the site of a percutaneous intervention, heightening tissue ablation and possibly preventing local recurrence.
"Drug-eluting stents have been described as a transforming technology," said Machan. "They have decreased the number of referrals to cardiac surgeons as well as changing the types of patients being referred. They have also transferred the business of medical devices and the science by validating the concept that adding biological activity to a medical device can improve its performance, and by showing that it is possible to have such a device approved for clinical use while being financially viable."
These hurdles as outlined by Machan, had to be overcome in order for postulated therapies made possible through the merger of physical, biological and medical advantages taking place over the past ten years, could be reduced to practice.
SIROCCO and GREAT trials
According to Machan, several lessons have been learned about the use of drug-eluting stents outside the coronary circulation. The outcomes of the multi-centre, prospective, randomised, double blind, two-arm SIROCCO trial (A Clinical Investigation of SIROlimus Coated Cordis SMART Nitinol Self-expandable Stent for the Treatment of Obstructive Superficial Femoral Artery Disease) demonstrated that the same inhibition of intimal hyperplasia can be achieved as in coronary arteries at six months. Of the 36 patients included,14 in the sirolimus-eluting arm and 17 in the control were analysed by duplex ultrasound at 18 months. In the slow sirolimus-eluting group (five patients) there was 0% restenosis, although in the fast sirolimus-eluting group (nine patients) three patients (33%) demonstrated restenosis. The restenosis rate in the control group (17 patients) was 30%. This cohort showed 0% restenosis at six-month follow-up, and this finding was continuing to hold at 18 months." Despite this, citing Duda SH et al., Machan pointed out that a durable effect is quickly lost due to the very different milieu of the superficial femoral artery.
In the GREAT (The Palmaz Genesis PeRipheral Stainless Steel Balloon Expandable Stent in Renal Artery Treatment) trial, designed to assess the safety and performance of a low-profile stent for the treatment of obstructive renal artery disease by looking at six-month renal artery patency uniformly of balloon-expanded sirolimus stents, it was seen that although a reduction of restenosis was achieved, less so than in other drug trials, this did not positively impact the clinical outcome for the patient. Fifty-two patients were enrolled and the results showed that although the target revascularisation rate was 3.77% vs. 11.5%, in favour of the sirolimus-eluting arm, this difference was not significant.
"For the first time in endovascular stenting, we have a potentially commonly used technology which is so expensive to develop and test with the rigor required of pharmaceutical agents, that even if efficacy can be demonstrated in preclinical testing, economics may prevent many applications from becoming clinical reality," Machon explained.
Challenges of drug-device combinations
As drug-device combinations have a more complex regulatory pathway than simple devices, challenges are often presented to device companies in which most cases are related to the lack of financial resources supporting the development of a device and seeing it through to approval status (Table 1). Interventional radiology is an attractive field to practitioners as Machan explained, largely because of the diverse number of methods of treatments that can be performed.
Imaging
More complex imaging will be required to provide more sophisticated assessments of the endpoint of the therapy as well as keeping track of the distribution of injected materials, as Machan explained. A real-time solution is therefore necessary for optimum and precise monitoring and one solution offered by Machan is fusion imaging. This form of imaging allows data sets from one modality such as MR to be simultaneously displayed with real-time imaging, such as fluoroscopy. These techniques require particular imaging skills and knowledge, which according to Machan, are already obtained by the interventional radiologist.
Conclusion
Many drug-device combinations have been developed and have enhanced minimal invasive procedures and hence achieved patient satisfaction. In his conclusion, Machan stated that financial and regulatory restrictions will be in place over the development of combined therapies at a far greater extent than was seen with the development of simple, non-coated devices. Having said that, Machan reiterated the fact the interventional radiologists possess skills, such as sophisticated imaging, that they can exploit use to their advantage. It is therefore necessary to for interventional radiologists to take the lead and drive such minimally invasive treatments such as drug-device combinations in order to continue to use these devices to their full capacity before they become overtaken by financial and regulatory issues and possibly left behind.
Published: Nov 2006
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