Will the Real CRO Please Stand Up

"I don't want to be [given a lot of bull] by CROs, so I need to know myself what's at the heart of clinical trials." This uncompromising statement from a top executive in a flourishing young European biotech company should provoke some reflection within the clinical trials community.

Peter O'Donnell

The author of the remark was Andre Hoekema, the senior vice president of corporate development at the Belgian company Galapagos, during a presentation of his company to journalists in June. Hoekema is no novice. He has 20 years of biotech experience, including as managing director or business development director of Invitrogen, Molecular Probes, and Crucell, and research and project management at DSM Life Sciences, MOGEN, and Genentech. He is the inventor of over 20 series of patent applications, resulting in 15 patents issued in the United States. So, he already knows a thing or two.

Galapagos is no bubble, either. It has a market capitalization of around €190 million ($250 million), a cash position of over €50 million, 450 employees, and has raised nearly €90 million in private placements and share offers since it was created in 1999. It has a portfolio of promising drug discoveries, a revenue-generating range of pharma services, and a strategic alliance with GSK in osteoarthritis. And in 2007, it expects revenues to top €55 million and to double last year's R&D investment to reach €33 million.

So what's behind Hoekema's combination of skepticism and curiosity about clinical trials?

The circumstantial reason is that the company now has a product on the threshold of Phase IIb: oestradiol glucoside, developed for treatment of menopausal symptoms. Out of an extensive pipeline ranging from rheumatoid arthritis to cachexia, and from osteoarthritis to bone metastasis and osteoporosis, this is the first time the company has progressed itself to the end of Phase IIa. Although the company strategy so far has been to develop its products through to clinical proof of concept, it now wants to take a product further to provide it with experience that it believes will be valuable in planning development of its upcoming bone and joint disease candidates. "We've never designed trials," admits Hoekema. In his view, "The biggest problem is patient accrual...and we need to get our feet wet in that area."

That explains the need for information. It doesn't, however, explain the reserved attitude toward contract research organizations (CROs). That can come only from a deep-rooted suspicion—or at the very least from a perception—that, to put it slightly more politely than Hoekema, not all CROs are always entirely reliable or credible.

A perception of nondelivery

This should give pause for thought to CROs. Rightly or wrongly, justifiably or not, the impression is current among senior and serious players in significant and growing companies that some CROs are not delivering what their potential customers expect, and are even trading on the credulity or gullibility of inexperienced clients.

If Galapagos was the only company likely to be looking for CRO services in the near future, the matter might hardly merit comment. But it isn't. Belgium isn't the biggest country in Europe or the most fertile in drug development. But even this pint-sized state boasts a wealth of up-and-coming drug firms with product pipelines stretching increasingly into clinical trials—and is therefore in the market for CRO services.

Belgium has only 2% of the European Union's population and less than 1% of its area, but it has 100 biotech companies together employing over 8304 biotech employees, spending €500 million in biotech R&D, and generating an estimated €3.2 billion in biotech-related revenues. These companies are embedded in an innovative pharma industry that has a headcount of almost 30,000 employees.

In Flanders alone, which is more or less the northern half of Belgium, focused discovery-and-development pharma companies have been raking in venture capital funding for their early development programs: At the top of the range, Ablynx, with its program of antibodies targeting oncology and immune diseases. The company raised €40 million last year. Actogenix raised €20 million for its therapeutic programs targeting gastrointestinal diseases, auto-immunity, allergy, and metabolic diseases.

There were plenty of other signs of health, too: Tigenix raised €14.5 million to back its work in regenerative medicine, joint surface repair, adult stem cells, and targeted therapeutics. Pronota obtained the same sum for its protein biomarkers. And in early 2007, Movetis—a spin-out from Janssen Pharmaceutica—raised €49 million.

One of the key attractions for venture capital investors in Flemish companies is the exit opportunity via initial public offerings. In contrast to many other countries, Flanders sees multiple successful biotech IPOs and, equally as important, significant value increases post IPO.

Moving toward clinical trials

Increasingly, these companies are bringing their projects through to clinical trials. During June, Movetis, which specializes in developing compounds for gastrointestinal disorders, announced the start of a Phase IIa multiple-dose trial with one of its lead products, M0002, an orally-active selective vasopressin antagonist that inhibits water re-absorption from the kidneys. Although it is only six months old, Movetis already has a portfolio of four clinical and four preclinical compounds, and proclaims its intention of bringing innovative therapeutics to the market for the treatment of gastrointestinal disorders.

There is a perceptible dynamic toward growth and expansion in the region. TiGenix announced in June that it was acquiring a cell expansion facility from Cell Genesys of Memphis, Tennessee, to manufacture ChondroCelect, its lead product for cartilage repair, for the North American markets and to allow it to start comparability testing of the product as a prerequisite for a U.S. regulatory filing, anticipated in 2008. The product has successfully completed a randomized Phase III clinical trial and will be launched in Europe and/or in the United States in due course.

A May update from ThromboGenics of its preclinical development portfolio revealed renewed focus on its advanced preclinical programs, notably on TB-403 (anti-P1GF—a humanized monoclonal antibody that blocks the formation of new blood vessels in solid tumors, reducing the growth and spread of cancer cells). Toxicology studies are well advanced and the product is expected to proceed to Phase I clinical trials by the end of this year.

At the same time, PlGF, a vascular growth factor for the treatment of heart failure, is moving through preclinical evaluation and route of manufacture, with toxicology studies expected by the year end. Anti-VPAC, a humanized monoclonal antibody that increases the number of blood platelets after bone marrow suppression with chemotherapy, is currently under test in experimental animal models, and should move into toxicology studies by 2008.

Following its successful February private placement of €31 million, DevGen says that progress in its pharmaceutical programs is on track, and it has ample resources to bring them toward clinical candidates and collaborations with pharmaceutical companies. Its diabetes program has also identified targets for rheumatoid arthritis and inflammatory bowel disease, and several models of inflammation are to be investigated further in 2007. In its cardiac arrhythmia program, additional efficacy studies are planned this year on compounds that have performed well in cellular and in vivo disease and safety models, with the aim of developing a chronically administered oral compound for the treatment of atrial fibrillation.

What is true of Belgium is true, to a greater or lesser extent, across Europe: Numerous new biopharmaceutical companies with promising early-stage development and portfolios are moving toward the point where they need clinical trials expertise. At present, few of these companies have that expertise—and they are looking for it. So, who's out there to answer their call without any bull?

Personalized drug therapy

Meanwhile, June saw the European Union devote further attention to personalized drug therapy. Germany, in the rotating chair of the EU until mid-2007, organized an expert meeting on "New Opportunities for Patients" in a bid to define the scope and limits of current drug innovation. Opening the meeting, Dr. Klaus Theo Schröder, state secretary at the German Federal Ministry of Health, set the tone with his remarks that personalized pharmacotherapy not only aims to tailor medicines to individual patients and groups of patients—thus increasing the effectiveness and safety of drug therapy—but that "this therapeutic approach is meant to contribute toward the more effective use of resources in the health care system."

The agenda was as political as it was scientific. As the German Presidency made plain at the outset, "new knowledge in diagnostics and treatment in the field of genetics, as well as developments in biotechnology, will have an impact on the national health systems. Moreover, the success—and hence the future position—of the European pharmaceutical industry vitally depends on how European companies and research centers working in this field are able to position and establish themselves in the face of international competition."

The conference acknowledged that pharmaceutical innovation is hugely dependent on uniform regulation and authorization of pharmaceutical products within the EU, and on guaranteeing and optimizing the accessibility of the newest and best pharmaceutical products for all patients. At the same time, it recognized that member states' ethical principles had to be respected in every aspect of pharmaceutical research and production.

Inadequate trials

The penalties of ill-designed trials were, incidentally, demonstrated recently by the European Medicines Agency's rejection of a marketing authorization request for Amgen's Vectibix infusion for metastatic carcinoma of the colon or rectum. The application was for Vectibix to be used on its own after failure of treatment with a combination of anticancer medicines including 5-fluorouracil, irinotecan, and oxaliplatin. The active substance in Vectibix, panitumumab, has been designed to bind to the epidermal growth factor receptor, which can be found on the surface of certain tumor cells.

The supporting documentation covered one main study involving 463 patients, where the effects of Vectibix in addition to best supportive care were compared with best supportive care alone. The main measure of effectiveness was the time before the disease started to get worse or the patient died. The patients receiving best supportive care alone had the option to start receiving Vectibix once their disease had started to get worse.

The major concerns that led the Agency's experts to recommend the refusal of the marketing authorization were insufficient evidence to show a benefit of Vectibix, due to the way the main study was designed. In the first few weeks of the study, many of the patients originally receiving best supportive care alone started to receive Vectibix after their disease had got worse, making it difficult to compare the effects of Vectibix and best supportive care alone. In addition, Vectibix only had a very small effect in increasing the time until the disease got worse or the patient died, in comparison with best supportive care. Studies also showed that patients receiving Vectibix had increases in side effects. The judgement therefore was that the benefits did not outweigh the risks.

More work for CROs?

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