Market & technology updates - US and European healthcare, medical device and pharmaceutical industries

American clinical trials in Europe

Many U.S. medical device manufacturers consider moving clinical trials to Europe in order to take advantage of the more favorable regulatory climate. But the idea of using European clinical data to support a U.S. PMA or 510(k) submission may present unexpected challenges for American companies because of differences in European regulatory requirements, variations in disease diagnosis or treatment, and even in classifications of medical specialties.

An ideal situation for U.S. manufacturers is to be able to design a clinical trial so as to satisfy the requirements both of the country in which the trials are being conducted, and the FDA. This is not simple, and professional advice and supervision are essential throughout. According to Dr. Susan Alpert of the CDRH's Office of Device Evaluation, clinical trials cannot be harmonized because of conflicts between U.S. requirements to prove efficacy and European needs to assess performance standards. There are, however, common areas in pre-and post-marketing which are candidates for harmonization and which can provide a basis for the U.S. and Europe to move closer on these critical regulatory questions.

European clinical trial news

European companies are also busy with clinical trials of their own. Some reports from the clinical trials pipeline:

* Phase II trials in England of CDP-571, a mono-clonal antibody specific for tumors necrosis factor (TNF), have shown positive effects in the treatment of Crohn's disease. CDP-571 has been jointly developed by Celltech (Slough, United Kingdom) and Bayer (Leverkusen, Germany). Following the positive results, Bayer now plans full-scale Phase II trials in the U.S.

* Celltech also has completed pre-clinical studies on its CDP-850 monoclonal antibody, directed against selectine-E and intended for use in psoriasis therapy. Application has been made for Phase I clinical trials to start in England.

* Cantab Pharmaceuticals (Cambridge, United Kingdom) has published results of Phase I trials on its live recombinant vaccinia virus TA-HPV human papillomavirus vaccine. TA-HPV encodes modified proteins E6 and E7 of each HPV type 16 and 18. These safety trials also showed that all patients developed anti-vaccinia virus antibodies and 37.5% developed antibodies specific for HPV18 E7. A Phase II trial, supported by the National Cancer Institute (Bethesda, Maryland), started last year in the U.S., while a European multi-center trial was started this year. This trial will be in women with early-stage cervical cancer who are immunocompetent, whereas earlier trials have included immuno-suppressed patients.

* Peptech (Cirencester, United Kingdom) has completed a series of Phase II studies in Russia of its oral glycopeptide drug for psoriasis treatment. Patients in the Russian trials reportedly showed significant reductions in psoriasis lesions. Preliminary open-label studies in the U.K. have shown a marked reduction in the extent and severity of psoriasis.

* PharmaMar (Madrid, Spain), which currently has a Phase I study under way in France for its marine-derived ET-743 anti-cancer drug, has received approval for Phase I clinicals in the U.S., U.K. and the Netherlands.

* The first gene therapy clinical trials in Belgium started in June. Organized by Sandoz (Basel, Switzerland), the aim is to treat multiform glioblastoma, a lethal brain tumor, by in vivo tumoral transduction of a gene coding for thymidine kinase of herpes simplex virus (HSV-TK), followed by the administration of ganciclovir. The Phase II Belgian clinicals are paralleled by similar trials in Canada, Denmark, Austria, Germany, Switzerland, the Netherlands and Sweden. They follow earlier Phase I/Il trials in the U.S., which verified the absence of secondary effects and which supported the induction of an antitumoral response.

Managed care, what's that?

Two recently released studies have emphasized the paradox of managed care and health maintenance organizations (HMOs) in the U.S. health care system.

While HMOs have on the one hand turned back the clock on hospitals' traditional roles as the center of the health care system, on the other, a majority of Americans contacted in a nationwide survey haven't even heard of managed care, and fully a third of them were unfamiliar with HMOs.

James Robinson, of the School of Public Health at the University of California (Berkeley, California), said the proliferation of HMOs, especially strong in his state, has swung the pendulum back from hospital-based care to services in the physician's office or the patient's home, as was the case at the start of this century. "Managed care is shifting the acute-care hospital from the center toward the periphery of the care system," Robinson said.

Another survey, conducted by Louis Harris and Associates, showed that Americans are widely uninformed about managed care, even though more than half of those who have health care coverage are in managed care plans. The study, which had a sample of 1,081 persons, found that many persons covered by employer-sponsored health plans had little idea about differences in the programs they are offered. One-third didn't understand the most basic concept of managed care - that one monthly fee covers nearly all costs, provided the patient uses doctors and hospitals within the plan.

Stem cell transplants: Tomorrow's panacea

Since the 1980s, researchers have been seeking alternatives to bone marrow transplantations. This has been largely because of difficulties in achieving a suitable HLA match between potential donor and recipient. For a transplant to succeed, at least four of the six separate HLA histocompatibility antigens present on a marrow cell must be the same in donor and recipient to avoid rejection. Even finding a matching donor within the same family is not easy, with only a 25% chance of success.

If asking the family does not work, physicians in Europe can turn to a computerized register of potential donors, which lists details of around 1 million people. Even then a match is not guaranteed.

Pablo Rubenstein of the New York Blood Center (New York) and Joanne Kurtzberg of Duke University (Durham, North Carolina) are investigating the possibility of using placental-cord blood (PCB,) which could be collected from maternity units in hospitals and stored frozen. Since 1993, about 25 patients for whom family searches and public registry searches have been unsuccessful have been treated using a PCB bank set up by Rubenstein. One of the attractions in using PCB transplants is that imperfect HLA matches between donor and recipient seem to be less likely to result in failure than when bone marrow is used. Additionally, graft-versus-host disease (GVHD) appears to be less of a problem with PCB transplants.

Apart from these technical considerations, the concept of using PCB transplant has many practical advantages. There is certainly no shortage of PCB potentially available; 4.5 million babies arrive in the U.S. each year, with another 4 million in Western Europe. By contrast, bone marrow is harvested by a surgical procedure with a cost of about $10,000.

Stem cell selection systems from SyStemix (Palo Alto, California), Applied Immune Sciences (Santa Clara, California), CellPro (Bothell, Washington), Baxter Healthcare (Deerfield, Illinois) and Miltenyi Biotech (Bergischgladbach, Germany) have been widely used in Europe in the selection of CD34+ cell subsets. However, some cell purification methods are likely to select second- and third-generation progenitor cells as well as genuine stem cells. These more-developed cells are still capable of multiplying rapidly, but may not be able to produce all types of blood cells. They may also provide a higher-risk malignant contamination. As a result, the companies that have cell selection systems have been concentrating on methods to improve purification. The SyStemix CHSS clinical high-speed sorter is intended to provide significantly higher levels of purification using high-speed flow cytometer technology. The system, as it currently stands, is expensive and is not yet adaptable to large-scale batch use.

While more frequent use of stem cell therapy in oncology is already under way in European cancer treatment centers, other applications for stem cell transplants are being investigated.

Autoimmune diseases such as multiple sclerosis, rheumatoid arthritis and lupus erythematosus are likely to be the next targets, although only the most severe cases are likely to be treated. Researchers at the University of Saarland (Homburg, Germany), the Institute of Clinical Immunology and Rheumatology at the University of Erlangen (Erlangen, Germany) and the Institute of Hematology at Bologna University Hospital (Bologna, Italy) are investigating whether stem cell grafts or transplants can normalize a patient's immune system. The use of stem cells in other genetic diseases and in diseases such as HIV also has been proposed.

Changes seen in drug user act

Biotechnology and pharmaceutical industries are pushing for changes in FDA review procedures within the framework of the recently initiated user fee negotiations. At the same time, the FDA is hoping to increase the fees it collects.

The talks will spell out the conditions under which the Prescription Drug and User Fee Act (PDUFA) will be reauthorized. The 1992 act permitted the FDA to collect fees from companies for reviewing drugs and biologics in return for adhering to set performance goals such as action within one year. However, PDUFA expires at the end of September 1997 and requires explicit congressional reauthorization by Oct. 1, 1997. "The PDUFA program has clearly been a success," said Jim O'Hara, associate commissioner for public affairs at the FDA. "What all sides are trying to do is to build on that success."

Carl Feldbaum, president of the Biotechnology Industry Organization (BIO; Washington), said he agrees that PDUFA has been tremendously successful and has reduced review times, but noted, "We would like to see that the system that we are paying for is more efficient."

The talks, which began in October, include the FDA and representatives from BIO and the Pharmaceutical Research and Manufacturers Association (Washington). The FDA has set a Dec. 20 deadline because it is under pressure from the Office of Management and Budget to submit its financial projections in early January so President Clinton can present his budget proposal to Congress on Jan. 20.

In fiscal year 1996, the FDA collected $88 million in user fees - 40% of the cost of reviewing drugs. The PDUFA money funds 600 reviewing positions at the agency. The FDA has proposed a new schedule that would double the user fees over five years. Allan Goldhammer, director of technical affairs for BIO, questions the industry's willingness to pick up the slack. "Clearly, we will not support the drastic increase in fees that the FDA has set forth in their cost model," Goldhammer said.

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