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Drug-device convergence

Technological advances herald a major oportunity


For years patches, inhalers and pumps have accounted for the lion's share of the drug-device combination market, but there are signs that new, innovative products are emerging from the R&D pipeline.

Drug-device combinations have been around for more than 50 years, with transdermal patches delivering drugs, stents coated with anticoagulants, inhaled medicines and drugs bundled alongside diagnostics all coming under the FDA's broad definition of the term.

All told, the global market for drug-device combinations (excluding companion diagnostics) in 2012 was around $66bn, and is predicted to grow at a near 8 per cent to 2019, outpacing the background growth of the pharma and medical device markets to reach $115bn, according to recently published data from Transparency Market Research (TMR).

But the size of that market belies that fact that combination products that have been around for decades account for a massive proportion of sales. Transdermal patches make up the biggest share at around $25bn in 2012, while inhalers made up another $20bn. 

Start adding implantable and ambulatory pumps and other delivery devices such as pre-filled syringes and autoinjectors - which represent multi-billion dollar markets in their own rights - and it becomes apparent that while industry pipelines have yielded many innovative product developments - such as 'bioactive' materials linked to drugs or biological components - commercialised projects remain thin on the ground.

Bioresorbable implants are expected to drive the combination products market in the coming years

One reason is that for years drug device combination developers were caught between two regulatory pathways - for drugs and medical devices - and it was not until 2002 that the FDA set up the Office of Combination Products (OCP) specifically to handle the convergence of the two technologies.

Since then the FDA has refined its approach, for example introducing guidance on Good Manufacturing Practice (GMP) for single-entity and co-packaged drug-device combinations last year, although it continues to come under criticism for the complexity of the regulatory framework. 

Small-molecule drugs, biologics and devices are all handled by separate centres at the FDA, and combination products by definition will fall under the dominion of at least two different units, and there continue to be calls for a unified approach to regulation. 

With marketing applications still handled via different approval pathways, it has been suggested that for some developers the prospect of requiring approval through the more rigorous drug/biologics route acts as a disincentive. 

In some cases the decision is straightforward. It's clear for example that in a product like a drug-eluting stent the device is the primary therapeutic element, while for a pre-filled syringe the drug is the main component. For other products, the classification is not always so easy to determine.

The dividing line between drug and device has material implications for developers, as medical devices have a typical development time of five to six years, around half that of pharmaceuticals and at a much reduced investment in terms of R&D spend. The impact of the uncertainty is hard to gauge, but while the OCP saw the number of applications rise between 2003 and 2009, there have been progressive fall offs year-on-year since then. From a peak of 377 applications in 2009 applications have declined to 266 in 2012, according to agency figures. In 2011, an Institute of Medicine (IoM) report asked for a complete overhaul of the device regulation system, citing the review of combination and companion products as a key area for improvement.

Meanwhile, the European Medicines Agency (EMA) revised its guidance on drug-device combinations in 2010, although additional changes are in the works as the updated Medical Devices Directive - introduced in the wake of the breast implants scandal that hit Europe two years ago - emerges from the legislative process. At the moment the impact of those changes is still being weighed.

TMR notes in its latest report that clinical trials for drug device combination products are more comprehensive and expensive compared to those required for individual drugs and devices.

“With the advances in medical technology, medical devices have changed their definition to more complex devices which assist in improving the efficiency of drugs in therapeutic treatments,” it notes.

Implanted therapies
Much of the promise in combination products comes from their ability to target delivery of actives - such as chemical or biological drugs or even stem cells - directly to the tissues where they are needed. The evolution of drug-eluting stents is a perfect case study for this approach. 

The advent of bare-metal cardiovascular stents in the mid-1990s was a major advance in the management of patients with coronary artery disease, used after balloon angioplasty to prevent cleared arteries from collapsing or restenosing. Despite the step forward, around a quarter of stented arteries closed within six months, mainly because of regrowth of tissue.

The first generation of drug-eluting stents - spearheaded by the approval of Cordis' sirolimus-laden Cypher device in 2003 - reduced restenosis rates to 10 per cent by blocking some of that regrowth, although separate concerns about an increase in clotting within the stents held back their use.

A second-generation of products using more effective drugs such as everolimus or zotarolimus, thinner metal alloys and more biocompatible polymer coatings started to arrive in the late 2000s and these have been followed by devices with fully biodegradable polymers that - after several months - stops delivering the anti-restenosis drug and reverts to a bare metal stent.

The next steps for the technology look set to be drug-loaded stents that are fully biodegradable - disappearing entirely after the normal endothelial function of the disease artery is restored, with candidates from Reva Medical and Abbott Labs in late-stage trials. The advantages of this approach are that a foreign body is not left in the body indefinitely, and this reduces the need for chronic direct anti-platelet therapy (DAPT).

The evolution of loaded stents has also heralded new approaches to diseases, for example intraocular implants for ophthalmic applications and using drug-eluting beads to treat tumours and other peripheral diseases. Among recent product developments, pSivida Corp and Alimera Sciences are gearing up to file for US approval of their sustained-release ocular implant Iluvien (fluocinolone acetonide) for diabetic macular oedema, despite no less than three earlier rejections by the FDA. The companies have however successfully brought the drug to market in Europe and recently secured reimbursement approval in France.

A drug-eluting bead approach for the treatment of cancer is being pioneered by Biocompatibles, which already markets beads carrying doxorubicin (Debdox) and irinotecan (Debiri) for localised delivery of chemotherapy to tumours. The company has phase 2 trials ongoing with a new form of bead - called Paragon - that is administered via the hepatic artery to treat primary liver cancer and metastatic colorectal cancer.

Among somewhat more conventional drug-device combinations, Cerevast Therapeutics is developing an ultrasound device that is placed on the head of a stroke patient - called the Clotbust ER - that is designed to enhance the effectiveness of clot-dissolving therapy with tissue plasminogen activator (tPA) in stroke patients. Last year a phase 2 study indicated the approach was safe, and it is now in an 830-patient phase 3 trial to see if it can improve patient outcomes.

Activaero and Chiesi's Flavorestin nebuliser device that delivers the corticosteroid budesonide to patients with severe asthma has also shown promise in trials, and is due to be submitted for approval in Europe in the coming months.

Other combinations have run into obstacles, however. Last year, an FDA advisory committee unanimously voted against approval of Delcath Systems' Melblez catheter system that delivers the cytotoxic drug melphalan directly into the livers of patients with liver metastases from ocular melanoma on the grounds of toxicity and a lack of a survival benefit in trials. 

Given the fragmented nature of the drug-device combination sector it is notable that earlier this year device giant Medtronic bought into the sector via the acquisition of biomaterials specialist Tyrx for $160m plus earn-out and milestone payments.

Tyrx recently won approval for an antibacterial 'envelope' called AIGISRx (pictured above) that is used to reduce infection rates in patients who have pacemakers/defibrillators or spinal cord modulators fitted. These complications are estimated to cost the US healthcare industry more than $1bn a year. Tyrx is also developing Pivitab, a surgical mesh using the same antibiotic-impregnated bioresorbable polymer used in AIGISRx, for use in hernia surgeries.

TMR predicts these types of bioresorbable implants will be a driver for the combination products market in the coming years.

“Technological advances such as biodegradable implants coupled with increases in access and recognition of these technologies in emerging market, will serve as an opportunity for investors to invest,” it notes.

Article by
Phil Taylor

freelance journalist specialising in the pharmaceutical industry

21st March 2014

From: Research, Healthcare



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