The "biomedical valley" of Mirandola in northern Italy is one of Europe's most dynamic health care sectors. More than 85% of the products manufactured there are for hemodialysis, cardiosurgery, respiratory and transfusion/autotransfusion applications, with some 80% of those products intended for single use only.

About 80 companies operate in the region, employing 3,500 and generating revenues estimated at $500 million annually, growing at an average rate of 6% a year over the past four years.

The bulk of this revenue is generated by the large multinationals with plants located at Mirandola, such as Baxter International, B. Braun (B. Braun Carex), Fresenius (Biofil), Gambro (Gambro Dasco), Snia-Sorin Biomedica (Bellco and Dideco) and Tyco Healthcare (Mallinckrodt Medical), which supply their marketing subsidiaries worldwide.

There is also an essential network in Mirandola of small niche companies that offer both finished products and a range of specialized services, including molding, extrusion, subcontracting, assembly, sterilization, instrument manufacturing, design, prototyping and consulting. Almost all of these are Italian companies owned by the founder, who is often also the chief executive. In an increasing number of cases, the employees also are shareholders with minority shares.

Rimos started up in Mirandola 13 years ago as a producer of sterile single-use medical devices. In 1994, it acquired RAM, a company specializing in gynecological products. "We want to continue growing," said Maria Nora Gorni, general manager. "We have recently added a product line specifically designed for artificial insemination and assisted reproductive technology."

Rand works closely with researchers at the University of Ferrara in the development of innovative therapeutic systems based on extracorporeal circulation technologies. Its Performer O. bioartificial liver system performs plasma separation, collection into a reservoir, recirculation through the bioreactor and reinfusion. It has been used successfully to treat three patients over the past four months in the Bologna and Modena transplant centers.

Gambro (Lund, Sweden) recently opened a new distribution center in Mirandola that is designed to reduce logistic costs and improve customer service across southern Europe. It is Gambro's largest distribution center in Europe. Gambro has invested another $15 million in manufacturing for blood lines and artificial kidneys. Revenue at the company's Mirandola facility for 2000 was estimated at $110 million, up 46% from 1999, with growth to $130 million projected for the current year and to $170 million by 2003.

Dideco, which is the Snia cardiosurgery subsidiary, aims to double its revenues within three years through the development of new products and acquisitions. A recent agreement with Israel-based HemoDynamics is a step in that direction, covering the distribution of complementary cardiovascular products for Europe.

One of Dideco's recent products is Lillput Phisio, said to be the first biocompatible oxygenator. Biocompatibility is provided by a coated membrane that reduces the quantities of drugs absorbed and, as a result, reduces the number of complications in pediatric patients with congenital heart defects. Each year, 75,000 such operations are performed on pediatric patients worldwide, a number that is increasing by 4% annually. About 30,000 of those patients are neonatal. Dideco claims more than 50% of this market worldwide.

Orphan drugs find a home in Europe

The European Commission (EC) in Brussels is rightly proud of its support for treatment for rare diseases. Last year the orphan drug rules which the European Union (EU) government pushed through with unusual but commendable alacrity were already bearing fruit.

By the end of the year, 71 orphan drug applications had been submitted to the European Agency for the Evaluation of Medicinal Products, 26 opinions had been issued by the Committee for Orphan Medicinal Products (COMP) and 13 applications had been granted. Orphans designated so far include potential treatments for Fabry disease, acute myeloid leukemia and Gaucher's disease.

A key part of the EU approach, similar to that of the U.S., is the promise of 10 years of marketing exclusivity for successful products. Another is the chance of winning a reduction in market authorization fees or even canceling them completely.

Although the main aspects of orphan drug legislation are well-known, other EU supports running in parallel can also make a big difference. Under the rules, for example, applicants can obtain scientific advice on conduct of tests and trials necessary – it may be difficult to find enough patients to take part in clinical trials for an orphan product. The COMP has so far appointed 66 rare disease experts to provide help to applicants.

Additionally, the EC's Research Directorate General supports research into orphan drugs with an overall $21 million budget supporting 17 projects, mainly for research into chronic degenerative and rare diseases. These currently include myopathies, infantile hyperinsulinism, defects of glycosylation, Huntington's disease, cystic fibrosis, congenital nephrotic syndromes and mantle cell lymphoma.

There also is an EU action program which, among other actions, is developing a European information network on rare diseases and training for professionals in the early detection, recognition, intervention and prevention of rare diseases. This program also supports transnational collaboration and networking between patient and support groups.

Over the past 10 years, a number of EU countries have also adapted specific measures with regard to rare diseases and orphan drugs. Here are some examples:

Austria: The Austrian Drugs Act includes a measure to waive marketing authorization and other fees for orphan drugs not authorized through the EU centralized procedure.

Belgium: Proposals are under way to exempt marketing authorization fees for orphan medicinal products and for special consideration in pricing and reimbursement negotiations.

Denmark: The Danish Medicines Agency provides specific advice to both drug companies and to researchers on design of clinical trials and development plans. The agency also collaborates closely with the Center for Rare Disorders and Disabilities.

France: The Ministry of Research has an extensive program running since 1999. A major genomic research and functional genomics program received $32 million last year and a "Genome network" was set up to help technology transfer from basic research to industrial applications. This network will receive $27 million in public funds each year over the next five years, with industry providing equivalent financing.

This year, France is addressing two fields specifically related to orphan products: new medicines (from target to candidate-molecule and validation of the active principle) and cell therapies for specific diseases and especially rare diseases. Draft legislation is under consideration to exempt companies developing orphan drugs from taxes and other contributions normally payable by the pharmaceutical industry.

Germany: German law already provides for rapid authorization of medicines of great therapeutic use, which also includes orphan medicinal products. In addition, in December 2000 a measure to promote research on rare diseases also came into effect. This legislation also promotes the creation of a national network for groups studying rare diseases.

Italy: The Network of Public Health Institutions on Rare Diseases is EC-funded and already includes 15 European countries. It operates from the Istituto Superiore di Sanita in Rome. The national Health Fund is providing financing for research into Tay-Sachs disease and adrenoleuco dystrophy in Trieste, Hirschsprung disease and neuroblastoma therapy at Genoa.

The Netherlands: A national organization is being set up which will ensure priority for a number of rare diseases and encourage drug companies to direct research toward these priority diseases. It also will promote the development of orphan products by means of tax incentives and subsidy schemes.

Despite spectacular successes in medicine development in recent years, there are still many diseases which cannot be treated satisfactorily, including about 5,000 rare diseases that affect relatively few people. Support for the development of orphan drugs for some of these diseases is clearly growing in Europe, with many European countries finally improving the climate for their development. But they still have a long way to go.

Reuse of single-use devices in Europe

While the practice of reprocessing single-use medical devices is theoretically illegal in most countries, it is, in fact, widespread throughout Europe, as in the U.S.

The European Parliament is becoming increasingly interested in the reuse debate. There is growing pressure throughout Europe for national regulators to address the fundamentals relating to the reuse of single-use devices. The latest in a series of actions by EUCOMED (Brussels, Belgium), the European medical devices industry association, is the issue of a CD-ROM which includes its position paper as well as specific country information on Australia, Denmark, Finland, France, Norway, Portugal, Spain, Sweden, Switzerland, the UK and the U.S.

The EUCOMED position paper calls on European governments to take action to protect both patients and health care workers from the transmission of Creutzfeldt-Jakob disease and hepatitis B and C. The association also is continuing an in-depth study on the negative effects of reprocessing on catheters, guidewires and angioscopes. The study has been expanded to include biopsy needles.

CJD and blood transfusion risks

Fears regarding blood donors who may have been exposed to variant Creutzfeldt-Jakob disease (vCJD) – the human form of transmissable spongiform encephalopathy (TSE), which reached epidemic levels among British cattle some years ago, have caused a number of countries to declare ineligible for blood donation anyone who has spent one year or more in Britain during the period 1980 to 1996.

The latest country to take these precautions is Ireland, which joins Australia, Canada, France, Germany, Japan and the U.S., who impose similar bans. The problem is that there is presently no blood test available to detect vCJD. A number of European governments are promoting research into developing sensitive and specific screening and diagnostic tests, and the British government has recently issued a call for proposals for state-funded research in this area.

Ortho-Clinical Diagnostics (OCD; Raritan, New Jersey) has formed a research collaboration with Caprion Pharmaceuticals (Montreal, Quebec) to develop a suitable assay. OCD also has taken an option to license Caprion's prion technologies, including the company's panel of monoclonal antibodies for detecting a structural epitope unique to vCJD.

Bayer (Leverkusen, Germany) and BioReliance (Rockville, Maryland) have recently launched a Western blot assay to screen samples from biopharmaceutical purification processes, and Q-One Biotech (Glasgow, Scotland) also has a similar Western blot assay. Investigations are under way to check if these and similar tests, originally developed for use in screening for BSE in animal-source biological products used in pharmaceutical production, could also be used in screening in blood banks for vCJD.

Transplant or dialysis: Which to choose?

There are three therapeutic strategies available to deal with chronic renal failure, said Bernard Charpentier, chief of the nephrology department at the Hopital Bic tre (Paris): a kidney transplant, hemodialysis or peritoneal dialysis. "One does not necessarily choose between one or another of these techniques, but by evaluating their potential performance, taking into account the age and general health of the patient and by explaining clearly each alternative's limitations to the patient," he said.

Comparatively, Charpentier said, a transplant offers a better quality of life but is not without risk (4% mortality). Additionally, the shortage of suitable organs can mean (in France) a wait of more than three years. The second limitation is the need for regular health checkups and for immunosuppressive therapy, which in turn implies increased risks of cancer.

Both hemodialysis and peritoneal dialysis mean substantial limitations on normal living for the patient. Hemodialysis in France normally implies three clinic sessions per week, each of four hours. Peritoneal dialysis, which is normally carried out at home, requires three sessions of five to six hours each day, every day, with the patient able to exchange the dialysis bags himself.

In all three alternatives, the motivation of the patient, his implication in the treatment schedule and total adherence to the restrictions imposed are fundamental to the success of the chosen therapy, Charpentier said.

One of the consequences of renal failure is excess phosphate in the blood (hyperphosphatemia) which, if untreated, can result in osteodystrophy, a painful condition similar to osteoporosis. AnorMED (Vancouver, British Columbia) has developed Foznol (lanthanum carbonate), a drug that regulates phosphate levels in patients with chronic renal failure. AnorMED's licensee, Shire Pharmaceuticals (Andover, England), has recently filed for European marketing clearance.

Foznol combines with dietary phosphate to form an insoluble phosphate salt in the gut that is not absorbed into the bloodstream. The worldwide market for phosphate binders for chronic renal failure patients is estimated at $400 million to $600 million.

Tissue-engineered human bone

Human feasibility trials have recently been started for both orthopedic and maxillofacial applications using autologous living bone implants grown in culture using tissue-engineered bone produced by IsoTis (Bilthoven, the Netherlands). Seven patients have been enrolled in these first trials conducted at the University Medical Center Utrecht (UMCU; Utrecht, the Netherlands) by Dr. Gert Meijer and at Westeinde Hospital (The Hague, the Netherlands) by Dr. F. P. Bernoski.

At Westeinde Hospital, four patients have received tissue-engineered bone implants for revision hip surgery, while three patients at UMCU have received implants for augmentation of the jaw. The total duration of these feasibility trials is 24 months. However, interim data are expected to yield sufficiently positive results so that multicenter clinical trials will start for both indications in 12 to 18 months.

IsoTis also plans at least two additional feasibility trials in the second half of this year for indications such as osteolysis, various bone defects and spinal fusion. In total about 40 patients will be enrolled in these new feasibility trials.

The core technology for developing these implants is a hybrid combining synthetic biomaterials and autologous cell cultures. The biomaterial used in all these applications, Polyactive, is a non-toxic biodegradeable family of copolymers licensed by IsoTis from Osteotech (Eatontown, New Jersey). By varying the composition of copolymers in the Polyactive scaffold, mechanical and physiochemical properties can be optimized for each type of tissue.

"Authoritative sources estimate the market for bone grafts is currently exceeds $500 million for the U.S. and Europe combined, and offers substantial possibilities for growth. This is not surprising, given that bone is the second-most-transplanted tissue after blood," said Clemens van Blitterswijk, president and CEO at IsoTis. The initial product launch of this tissue-engineered bone is anticipated in Europe for the second half of 2003.

European regulatory news

The reimbursement structure for medical procedures in French hospitals and clinics – both private and public sector – is to be revised as of Jan. 1, 2002, and will particularly affect medical and surgical specialists and how much they can charge for their services.

The review, which has involved some 1,000 experts, has considered the existing structure of charges, which goes back in some cases to 1972. The new schedule is supposed to take into account time taken for a procedure, the level of expertise required and any need for medical materials and additional personnel.

It is expected that some fees will fall substantially under the new system, while other, newer procedures will be accorded higher fees. For the future, the French national insurance organization, CNAM, aims to revise the reimbursement tariff every seven years.

Plaque detection catheter developed

Thermocore Medical Systems (Ghent, Belgium) has developed a catheter-based system for the location and visualization of unstable vulnerable plaque within coronary arteries. The system incorporates an array of sensitive temperature sensors mounted on a catheter to map the interior of coronary arteries based on temperature variations that point to areas where vulnerable plaques occur.

An earlier prototype version showed greater thermal variations in patients with unstable angina and myocardial infarction than in a control group with normal coronary arteries, according to Thermocore. Cambridge Consultants (Cambridge, England), a subsidiary of Arthur D. Little, is collaborating with Thermocore on the development of software for the final version of the device, which is expected to be ready for clinical trials in six to eight months, with a European product launch in 2002.

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