Co-Defense and Attack on Clinical Trials

The last week in September saw some contrasting initiatives in the world of clinical trials, ranging from the defensive to the assertive. Underlying all of them were key questions relating to the health and reputation of the health care industry—and only time will tell which will be the most effective.

Peter O'Donnell

The move most evidently linked to clinical trials was the inauguration of the first worldwide clinical trials portal. Its avowed aim is to provide doctors, patients, and their families with simple access to the most complete information on ongoing and completed clinical trials of drugs and vaccines.

By definition, this is not a specifically European initiative. Its godfather is the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA). But it has been heavily backed by the European pharmaceutical industry, and was ceremonially launched by Dr. Daniel Vasella, chairman and CEO of Novartis, and president of the Geneva-based IFPMA.

The portal is an Internet search engine constructed specifically to link to on-line information about clinical trials worldwide. It has been put together since the beginning of 2005 by pharmaceutical industry technical and regulatory experts as well as IBM consultants, and it currently contains more than 250,000 links. These include individual pharmaceutical company sites, sites run by third parties working on behalf of companies, pharmaceutical industry association resources (such as the U.S. pharmaceutical industry association's site, www.clinicalstudyresults.org), and government sites that routinely carry details of industry trials, such as the U.S. National Library of Medicine's www.clinicaltrials.gov.

Information about on-going clinical trials includes title, description in lay terms, trial phase, trial type (e.g., interventional), trial status, trial purpose (treatment/diagnosis/prevention), intervention type (e.g., drug/vaccine), condition or disease, key eligibility criteria (including gender and age), and location of trial and contact information. The other broad category of information to which the portal provides links is the results of completed clinical trials, which are made available in a standard, nonpromotional, summary format by various on-line databases.

Defensive move

The fundamental motivation behind the portal is to demonstrate that the industry is not conspiring behind closed doors to make profits irrespective of patients' health. As Vasella claimed in his launch statement: "The launch of this portal shows the pharmaceutical industry's commitment to full transparency in the interest of patients and healthcare professionals."

Some of the immediate stimulus for the initiative was widespread public concern in late 2004 over the appearance of unexpected adverse side effects with blockbuster products such as Vioxx, and the broader background included the growing calls for increased public access to information about medicines. The drug industry, anxious to prove its credentials, moved into high gear with this clinical trials portal project as a method of countering public suspicion.

By now, readers of ACT may well have already tried out the portal for themselves, and made their own evaluation (it is at www.ifpma.org/clinicaltrials). A rapid skim through it by this columnist was not quite as revealing as its publicity suggests. There were innumerable links to the contents of the U.S. National Library of Medicine's site—but a new portal is hardly necessary for that. Links to direct company information or specifically European trials were, however, not so easy to find—and several of the links proved to be dead or caused problems that closed down this columnist's software.

Some of this disappointment may be ascribed to the incompetence of this columnist, and to the haste with which initial searches were run in compliance with the copy deadlines of ACT. But if the site is intended to widen access to the public, then this columnist—no more than a dumb journalist with a superficial knowledge of clinical trials—is perhaps as good a representative of the public as anyone else. Moreover, anyone from a European country other than the United Kingdom or Ireland will be obliged to work in what—for them—is a foreign language if they want to operate the site.

To be fair to the portal, it admits that this is only the first stage in its development. "Priority was given to putting a useful information-gathering resource into the hands of patients and their carers as quickly as possible," its launch material says. So at present it offers only simple search functions, and only in English.

The pharmaceutical industry "recognises that the ultimate effectiveness of the portal will require further investment to increase its ease-of-use"—with more languages, assistance to searchers with a limited knowledge of medical terminology, multiple criteria searches to allow search by disease, and geographical area or pharmaceutical company name. The scope of the site is also to be expanded: Other on-line clinical trial information resources, such as the European Union's planned Europharm facility, may be linked to it as and when they become available, says IFPMA.

An assertive move

The same week saw the launch of an appeal for the future of health care biotechnology in Europe. The European biotech industry association, EuropaBio, published a Healthcare Manifesto (http://www.healthcare-manifesto.org) setting out what it sees as "key policies to meet the healthcare innovations expected over the next few years to meet unmet medical needs." The emphasis of this pitch for a better working environment for European biotechnology is ostensibly the patient, and there are plenty of references to the 250 million patients who have benefited to date from biotech medicines, and "a more patient-oriented approach to human healthcare."

Some elements of the manifesto correspond to this focus on patient-oriented clinical excellence and appropriate clinical development in a world where many diseases are still untreated: "The views, experiences and expertise of patients—the final beneficiaries—must be integrated into the evaluation process," says EuropaBio, declaring its commitment to creating "products that can substantially improve the quality of life for patients and meet unmet medical needs." And "physicians and other clinical experts must also be involved in the assessment and decision-making. Decisions should not be made without input from clinical experts on the full range of benefits delivered."

Similarly, the manifesto urges the European Union authorities to "facilitate clinical trials in the field of rare diseases, under the EU Clinical Trials Directive." And, in order to promote the emerging fields of cell and tissue engineered products, it calls for new policies and regulations, including a new and harmonized legislative framework to include specific rules for clinical trials.

But the EuropaBio manifesto is as much aimed at the well-being of the innovative industry as the well-being of patients. Its essential subtext is that the EU should encourage national authorities to be more generous in paying for new medicines. Its principal concern is that patients "do not have access to treatments"; and that means putting new products onto national reimbursement or prescribing lists, so that they are not only developed, but actually available. The health authorities should ensure "a better balance between benefits, costs and risk," it says. EuropaBio's Secretary General, Johan Vanhemelrijck, warns that logjams in pricing and reimbursement of new products risk disaster: "Are we going to kill off all the efforts made by the industry and all the support that goes into research because when products are developed they cannot get onto the market?"

The new Chairman of EuropaBio's healthcare council, and Vice President of Health Policy at Serono, Dr. Andrea Rappagliosi, is unequivocal: "We need a predictable stable framework to operate, with no switching off the light at the end of the tunnel when we are investing." In other words, biotech can deliver what patients need, as long as governments are ready to supply what industry needs. It is going to be a hard message to sell in the EU, since the member states all insist on maintaining their own sovereign right to do whatever they damned well please with drug prices and reimbursement.

A constructive move

The third initiative in that eventful final week of September was of a concrete rather than rhetorical nature. The U.S. biotechnology firm Genzyme significantly expanded its engagement in Europe—confounding those who have repeatedly argued that the EU regulatory and business climate is driving investment away. In a $500 million investment program, it is upgrading three of its manufacturing plants and creating a new research center.

Genzyme's new discovery research facility is in Cambridge, UK—its first outside the United States. The 25 scientists currently at the new facility will initially focus on new and emerging antibody technologies to identify new therapeutics in the areas of oncology, renal, inflammatory, and immune-mediated diseases, and within five years the scientific staff level is planned to rise to 150. Genzyme is hoping to build partnerships with academic and biotech partners, right across Europe, and particularly among the 200 local life sciences start-ups, including Cambridge University and its renowned science and clinical research.

At the same time, Genzyme opened a new technology and development center at its Haverhill plant in the United Kingdom, which handles bulk production of therapeutic polymers and small molecules; the expansion will allow process development to support the clinical trials of next-generation products for kidney patients. The next day, it opened its state-of-the-art bio-pharmaceutical production facility in Geel, Belgium, which will produce its alemtuzumab monoclonal antibody for the treatment of B-cell chronic lymphocytic leukemia (currently under evaluation in clinical trials in other cancers and in multiple sclerosis). And the day after it opened a new facility for biological fill and finish operations at its plant in Waterford, Ireland, where just this July its Manufacturing Process Research and Development facility was expanded to support clinical trial work.

Growing capabilities

The company already has a considerable stake in Europe, where it employs over 2000 people. Of its 80 or so clinical trials in progress, 30% involve European sites. In 2004, Genzyme formed a joint venture with Medtronic to conduct a Phase II clinical trial of cell therapy to repair damaged heart tissue at medical centers throughout Europe. It plans to enroll 1000 patients in a Phase III clinical trial at more than 250 centers in Europe, North America, and Australia for Tolevamer, its novel, nonabsorbed polymer therapy that could be the first nonantibiotic treatment for Clostridium difficile-associated diarrhea. Two recombinant anti-TGF beta antibodies are in clinical trials with partner Cambridge Antibody Technology, and preparations are underway to enter the clinic with cancer applications of the GC1008 antibody molecule, a collaboration with Cambridge Antibody Technology.

Five of Genzyme's 10 manufacturing sites are in Europe. In addition to the Haverhill, Geel, and Waterford sites, there is a small molecule, lipid, and peptide production site in Liestal, Switzerland, and a polyclonal bio-manufacturing site in Lyon, France. So too are two of its four sites supplying its diagnostic products (one in Kent, UK, and one in Rüsselsheim, Germany). Meanwhile, Genyzme is expecting European approval in early 2006 for its enzyme replacement therapy for Pompe disease, Myozyme (alglucosidase alfa), for which an authorization application was filed in December 2004.

I leave it up to readers to make their own assessment of which of these three initiatives is likely to do the most to advance the interests of European patients—and of the European pharmaceutical industry.

Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.