The European Union directives covering therapeutics and medical devices at present exclude specifically medical devices incorporating or derived from tissues or cells of human origin other than derivatives of human blood or plasma (covered by Directive 2000/70/EC amending Directive 93/42/EC). Other products such as bioengineered skin substitutes, bone replacements, cartilage repair systems and novel wound dressings using material of human origin are not presently eligible for the CE mark.
But for several years now, interested groups of users, standards organizations, trade associations and European regulators have pushed for the setting up of a regulatory framework for these therapeutic products and it seems that the project is at last moving.
Three separate departments in the European Commission (Brussels, Belgium) are involved in clarifying the situation. The Directorate General Health and Consumer Protection has put forward a proposal for an European Directive on the donation, procurement, testing, processing, storage and distribution of human tissues and cells (COM(2002)319) for use in the human body. The proposal sets standards for accreditation and monitoring systems for tissue banks including requirements on traceability of donations. Its coverage will set out common requirements regardless of whether the material is processed in tissue banks, hospitals or by commercial organizations.
The Directorate General Enterprise (Division G4) for the medical device sector is engaged in reviewing feedback from public consultations with involved groups on therapeutic products arising from tissue engineering. In particular, DG4 has sought out views on the need for, and possible framework of, new legislation distinct from the existing Medicines and Medical Device Directives. Results from these consultations are expected soon.
Division F2 of the Enterprise Directorate General that covers the medicines sector is considering modifications to the definition "medicinal products" and Annex A in the Directive on Medicinal Products for Human Use (Directive 2001/83/EC), which includes somatic cell therapy medicinal products. The latest version of the draft modifications is likely to widen the range of healthcare products within its scope and may even change the regulatory status of some existing medical devices.
As they stand, the proposed modifications could, for example, apply to heparin-coated cardiovascular devices or to antibiotic-coated catheters where the medicinal substance is ancillary to the primary purpose of the device. Additionally, some cell-therapy products of human origin could come within the Medicinal Products Directive if they are based on the administration of cells as the primary mode of action.
Of course, interdepartmental consultations, discussions and negotiations are the normal way of doing business in the European Commission, but differing viewpoints on the final content of a resultant Human Tissues Directive already has resulted in several European countries introducing statutory or voluntary codes of practice for the safety of these products, contributing to the present regulatory barriers to tissue engineering. It is likely that these will as a result need revising once a European Commission directive on the subject has been adopted.
Chris Mason of the department of biochemical engineering at University College, London, speaking at the recent Medical Device Technology European Conference in Birmingham, England, emphasized the need for companies involved in tissue engineering to move from today's "cottage industry" low-volume production techniques to automated mass production scale-ups that can deliver the lower prices necessary to show real cost benefits.
He identified as likely future major players in this sector Baxter Healthcare (Deerfield, Illinois), Johnson & Johnson (New Brunswick, New Jersey), Medtronic (Minneapolis, Minnesota), St. Jude Medical (St. Paul, Minnesota) and Sulzer Carbomedics (Austin, Texas) in the U.S. and Novartis (Basel, Switzerland) and Smith & Nephew (S&N; London) in Europe. Mason particularly cited S&N, which had been a long-term partner of Advanced Tissue Sciences (ATS; La Jolla, California). After the financial collapse of ATS, Smith & Nephew rapidly stepped in and acquired the rights to the company's skin product, Dermagraft, indicating a continuing commitment to this potentially substantial market sector.
Size not everything, says Schering CEO
Over the past decade, the pharmaceutical industry has been heavily impacted by successive waves of major mergers. Today the sector can be divided into four levels. After the two giants, Pfizer (New York) and GlaxoSmithKline (London), there are companies like Aventis (Strasbourg, France), Roche (Basel, Switzerland) and Novartis (also Basel) that concentrate on large market sectors, followed by specialized companies that target specific sectors and then the biotechnology firms.
"Consolidation will continue in the first two groups where economies of scale are still possible," said Hubertus Erlen, president of Schering (Berlin) "Eventually there will be a few large companies even bigger than today, and a number of specialist operations."
Schering, which classes itself in the "specialized operations" group has concentrated on four speciality areas: medical imaging, hormone therapy, therapeutics for cancer and thrombotic diseases and dermatology. "We have concentrated on a specific group of medicines and therefore in terms of marketing we have no need for enormous sales teams," Erlen said. To market today a hypertensive, an antibiotic or a new Viagra will require marketing teams numbered in their thousands in Europe and the U.S., Erlen pointed out, whereas Schering needs only 300 worldwide for its radiology products.
Last year diagnostics and imaging products constituted 27.5% of total sales of around $5 billion, with half in Europe and a quarter in the U.S. Erlen said, referring to the company's strategic plan to 2010, that Schering is counting on growth opportunities in existing sectors. He did not consider that it was necessary to enter other therapeutic areas. "We do not have a diversification strategy since there is plenty of growth in these (existing) sectors," he said.
The company is developing with Collateral Therapeutics (San Diego, California), which it acquired last year, a novel therapeutic approach for the treatment of myocardial ischemia, intracoronary angiogenic gene delivery, suitable for patients for whom a surgical procedure would be risky. Phase I trials showed the procedure to be safe and effective, and a second round of trials are now under way.
In a completely different area, Schering, which developed the first contraceptive pill for women, is collaborating with Akzo Nobel (Arnheim, the Netherlands) to develop a male contraceptive pill, expected to be ready in five to seven years. At the end of last year Schering reduced its shareholding in Leiras (Helsinki, Finland) from 75.1% to 49%, relinquishing management control to Nycomed Pharma (Vienna, Austria), previously junior partner and now majority shareholder with a 51% stake. Leiras produces slow-release contraceptives implanted in the upper arm.
New technologies speed up GSK pipeline
Jean-Pierre Garnier, chief executive at GlaxoSmithKline (GSK; London), said that GSK would double the number of projects entering Phase I clinical trials and triple potential drugs moving into Phase II trials this year. The use of new technologies had in some cases taken two years off the time needed to get a molecule into clinical trials, he said. "We have entered a formidable undertaking, to try to change the trend of declining productivity in the industry that has been going on for 20 years, and our metrics seem to indicate that we have turned a corner. Whether we can solidify this is too early to say," Garnier said.
Using constant exchange rates, GSK beat its target for full-year earnings growth before exceptional items for 2002 with a 13% increase of profits to $1.26 per share ($1.17) with sales up 7% to $34.2 billion, although fourth-quarter sales only increased 1% to $9.15 billion and pre-tax profits flat at $2.15 billion.
In common with a number of companies reporting large deficits in their pension funds over the past year, GSK has recorded a $2.1 billion deficit under the new accounting rules, compared to $737 million at the end of 2001. The company injected $499 million into the fund at the end of last year in an effort to halt the rapidly growing shortfall.
Separately, GSK reported a joint evaluation project with Vectura (Bath, UK) of the company's PowderHale formulation system in dry powder inhaler devices for inflammatory and constrictive airway diseases. The Aerocine technology from Vectura is part of the PowderHale system and the evaluation project will earn Vectura option and development fees during the initial program of work, together with royalties if GSK exercises its option to license the technology for its respiratory product pipeline.
Targeting amyloidosis in age-related diseases
Senexis (Manchester, UK) plans to exploit its unique approach to the diagnosis and treatment of age-related diseases caused by a process called amyloidosis. Kelvin Stott, chief scientific officer and co-founder of Senexis, believes its technology could have applications in the diagnosis and therapy of a number of disorders, including Type II maturity-onset diabetes, Alzheimer's, Creutzfeldt-Jakob, Parkinson's, motor neuron and Huntingdon's diseases.
The Senexis technology uses small methylated peptide fragments, called meptides, which block protein/peptide aggregation and so prevent formation of the toxic oligomers and insoluble fibrillar plaques associated with amyloidosis. Stott explained that amyloidosis is the aggregations which kill cells in specific parts of the body with the protein/peptide and target organ varying with each disease. "For example, Alzheimer's, Parkinson's and Creutzfeldt-Jakob diseases are believed to be caused by the aggregation of amyloid-beta, alpha-synuclein and prion peptides respectively, while Type 2 diabetes is associated with aggregation of IAPP which kills the insulin-producing cells in the pancreas," Stott said.
"Tagged meptide molecules could be used to visualize protein and peptide aggregates in the brain using techniques such as magnetic resonance imaging," he added. "The potential to develop diagnostics could enable us to generate revenues through product development partnerships or collaborations in the relatively near future."
Skiing gets more dangerous
Five million French skiers each year produce between them around 140,000 accidents, 50% of which are sprains or dislocations with 36% concerning the knee almost all a rupture of the anterior cruciate ligament (ACL) that is, 25,000 people each year in France alone. The ACL is found at the center of articulation of the knee, where it assures the stability of the joint. When it is ruptured,there is very little chance of spontaneous healing, resulting in a continuing instability of the joint that can rapidly evolve into chronic joint inflammation.
But there may be hope for the future. Genzyme Biosurgery's (Cambridge, Massachusetts) Synvisc (Hylan G-F20) for knee pain and Corticel cartilage potentially offer long-lasting benefits, according to Ann Merrifield, executive vice president in charge of orthopedics at Genzyme. Other companies in this sector include Anika Therapeutics (Woburn, Massachusetts) and BioSyntech (Laval, Quebec).
Link between schizophrenia, neuregulin gene
deCode Genetics (Reykjavik, Iceland) has reported that collaborative studies with researchers in Scotland have confirmed the company's previously reported link between the Neuregulin 1 gene and schizophrenia. deCode said it also has identified a lead series of compounds directed against targets in the Neuregulin 1 pathway with the aim of progressing with Roche (Basel, Switzerland) drug development under their existing therapeutics alliance.
Separately, the company also released details of recent research mapping a gene on chromosome 16 to psoriatic arthritis. deCode claimed that this is the first genetic factor, with the exception of the major histocompatibility complex region on chromosome 6, to show significant association with a psoriasis-related disorder.
Meningitis vaccine in record time
GlaxoSmithKline, together with the World Health Organization (WHO; Geneva, Switzerland) and the Bill & Melinda Gates Foundation (Seattle, Washington), are making a new meningitis vaccine available just months after an emerging epidemic of a new strain of the disease has been discovered. The new ACW135 vaccine will provide protection against the typical A and C meningitis strains found in Africa as well as the W135 strain which, until last year, was only found sporadically.
Meningitis outbreaks occur almost every year during the dry season in the Africa meningitis belt from Ethiopia to Senegal, but last year there were 14,453 cases of W135 meningitis in Burkina Faso, with 1,743 deaths. In response to this unexpected outbreak, WHO asked for a trivalent vaccine at an affordable price. GSK has responded and developed a vaccine in just a few months, while the Gates Foundation has provided most of the financing needed to buy an initial 3 million doses with first supplies reaching the area in February, and the Belgian National Regulatory Authority speeding through a license for international use (the vaccine is produced at GSK's giant vaccine operation at Rixensart, Belgium).
End stigma, isolation of leprosy
"Diagnosing and treating leprosy through the public health system is vital if we are to avoid continuing stigma and prejudice against leprosy patients," said David Heymann, executive director in charge of communicable disease programs at the World Health Organization. "Continuing to treat leprosy patients through expensive and separate programs has been shown to be the wrong approach for health systems and for the patients they look after," he added.
The continuing existence of specialized leprosy services has in certain countries such as Brazil, India and Nepal been a bone of contention between a number of international non-governmental charities (NGOs) and WHO. Some NGOs do not believe that leprosy can be treated through the public health system, like any other disease. WHO claims that this approach is working and will continue to work. Of 122 countries where the disease was considered endemic in 1985, 108 have now reached the goal of elimination at country level.
Since 1995, leprosy patients worldwide have had access to free drug treatments through the Novartis Foundation for Sustainable Development (Basel, Switzerland). "Novartis is fully committed to ensuring that every leprosy patient in the world receives high-quality drugs free of cost. We will continue our support to the program as long as it is required," said Daniel Vasella, chairman and CEO.
European cancer drug trials
Roche (Basel, Switzerland) and Beaufour Ipsen (Paris) have signed a co-development agreement for diflomotecan, a topoisomerase 1 inhibitor currently in Phase II trials. Roche gets world marketing rights outside Europe and Beaufour Ipsen may receive up to $150 million licensing and milestone payments. Roche said additional clinical trials on a combination of diflomotecan and the anticancer drug Xeloda are starting in Europe this quarter.
E. Merck (Darmstadt, Germany) said it was on track to file for European approval during the first half of this year for cetuximab, a monoclonal antibody for the treatment of colorectal cancer developed by Imclone Systems (New York) and licensed to Merck for development and marketing outside North America.
Pharmexa (Horsholm, Denmark) has reported plans for full Phase II trials of its HER-2 DNA AutoVac therapeutic vaccine against breast cancer. A Phase I/II clinical trial gave promising results in patients with HER-2-positive metastatic breast cancer.