Over the past five years, U.S. and other overseas pharmaceutical companies have been utilizing Israel as a regular site in their multinational clinical trials. When American medical and biotech companies begin approaching the arduous stage of conducting clinical trials for their products, increasingly, their sights are focusing on Israel. Israel has become a vital location for U.S. companies conducting multinational clinical trials: over the past five years, U.S. and other overseas pharmaceutical companies have been utilizing Israel as a regular site in their multinational clinical trials.

About 150 to 200 multinational clinical trials currently are taking place in Israel, estimates Dr. Avi Livnat, the former CEO of Quintiles Israel, a leading contract research organization. Israel’s popularity as a site for clinical trials increased rapidly after the country received FDA recognition as an approved site for FDA clinical trials in 1997.

One American company Inotek Corp., a U.S. pharmaceutical company based in Beverley Mass., has gone one step further by deciding to set up a center located in Ra`anana, Israel to manage its worldwide clinical operations. The Israeli subsidiary will be responsible for managing and monitoring clinical trials of drugs being developed by Inotek at sites around the world.

“It’s a twist on the usual model where a strong, international drug company may use Israel as one of its trial sites but supervises from abroad,” says Dr. Chaim Brickman who serves as Inotek`s Medical Director and Director of Clinical Operations.

Brickman expects to begin supervising the company`s first clinical trial in the spring with Phase II studies of a drug targeting illnesses involved in ischemia/reperfusion injury.

Brickman, working with a team expected by March to include 25 CRAs (Clinical Research Associates), regulatory, QA, QC, data acquisition and statisticians, will monitor all of the company`s international trial sites. This will include hospitals in Israel, Hungary, Western Europe, the U.S. and possibly Australia.

Brickman told ISRAEL21c that there were two primary reasons that Inotek decided on Israel as the location to monitor the international trial sites.

“First, the president and CEO of Inotek, Dr. Andrew Salzman is a Zionist and wants to invest in Israel. It’s why he’s opening up the clinical operations here as well as setting up a manufacturing plant in Dimona,” he says. “The second reason is that it’s logistically easier to conduct and supervise studies that are taking place in Israel, and western and eastern Europe from a location closer to the studies. Until now the pre-clinical studies have taken place in the U.S., but with the stage of intense studies about to take place, the decision was made that Israel would be the best place to run things from.”

One of the company’s missions is to develop novel small-molecule drugs that prevent necrosis, a form of cell death that is the end-stage cause of most life-threatening diseases. Necrosis is triggered by oxidants that enter the nucleus and induce DNA breaks, which in turn activate the nuclear DNA repair enzymes poly ADP-ribose polymerases (PARP).

During a heart attack or stroke, PARP activation consumes all of a cell’s energy, resulting in necrosis and tissue infarction. Inotek is developing an ultrapotent PARP blocker called Pardex. Company officials say they are in tests for the drug, which could come to fruition in several years.

Inotek is just one of many companies which has put its trust in Israel’s ability to conduct and manage reliable clinical trials. Today, U.S. headquartered Johnson & Johnson is conducting “tens of clinical trials in Israel,” said Ron Hashmonay, CEO of Janssen Cilag, which manages Johnson & Johnson’s clinical R&D in Israel.

“Our main motivation for undertaking trials in Israel is the quality and performance of researchers, as well as the fact that trials are much easier to manage here than in American centers such as New York, Chicago or Los Angeles,” Hashmonay told BioIsrael. “Israel is included in many multinational, multicenter trials.”

Johnson & Johnson’s clinical trials in Israel are in the areas of oncology, CNS disorders in neurology and psychiatry, diabetes and endocrine diseases.

The size of the clinical trials niche in Israel is estimated at $100 million in research, but that includes monitoring research and regulation services provided by contract research organization (CRO) companies, such as Quintiles Transnational Corporation and the Aecon Group.

American companies have ample motivation for performing their trials in Israel, says Rivi Rosenblum, Business Development Manager at Quintiles Israel. Quintiles currently manages close to 30 clinical studies for multinational clients in Israel, and has managed a total of about 60 clinical trials since it began operations in the country in 1997.

“In Israel, the entire population belongs to one of the large health funds, which have a full history of each member’s health. The system makes it very easy to locate patients and to follow up with these patients over time,” Rosenblum said.

Israel can also provide the types of populations needed for FDA trials. Clinical trial patient populations must reflect the United States’ own diverse populations, Rosenblum said, and Israel’s ethnic diversity offers an important advantage over countries that lack such diversity.

Yair Gibor, former Manager of Teva Pharmaceutical’s Clinical Trials Division and an instrumental figure in the U.S.-Israel Science and Technology Commission’s efforts to establish Israel as a clinical trials center in the mid-1990’s, observes that Israel’s medical system is organized in a way that makes it easy to keep track of patients.

“Israel has what are known as ‘evaluable’ patients, who can be monitored from start to finish,” said Gibor. “If a patient drops out in the middle of a trial he becomes non-evaluable and his data cannot be used, increasing the time and cost of the clinical trial. Israel’s medical system makes it very easy to track individuals during the course of a trial.”

Israel’s dropout rate is less than 10 percent, compared to 35 percent in the U.S. As a result, companies need to recruit less patients to get the same quantity of data that would come from larger, and more expensive recruitments elsewhere.

Until Israel was recognized as a site for FDA clinical trials in 1997 there was little opportunity for American companies to undertake trials in Israel. Gibor worked with USISTC beginning in late 1995 to demonstrate the quality of Israel’s medical environment in order to interest the FDA in Israel’s potential as a clinical trials site and, eventually, to undertake the training of Israelis in GCP and GMP guidelines.

An important point in Israel’s favor was the positive track record Teva had achieved running trials for European clients in Israel.

“We felt that Israel had a number of critical advantages, including the high quality medical professionals, easy to recruit and easy to follow patient populations, and excellent audit results from European pharmaceutical companies of their trials in Israel,” Gibor said.

The FDA sent clinical trials trainers to Israel in 1996, and over 400 people were trained in FDA clinical trial practice in two, one-week seminars. With a critical mass of qualified GCP personnel, Israel gained FDA recognition in 1997. The economic results were dramatic: net revenues from international trials conducted in Israel rose from $15 million to $120 million between 1994 and 1999.

Israel also made a timely decision in being the first country to accept International Conference on Harmonization (ICH) guidelines for Good Clinical Practice, which were laid out in 1997. The guidelines provide a unified standard for the European Union, Japan and the United States to facilitate mutual acceptance of clinical trial data by regulatory authorities. Israel’s early acceptance of these standards was another factor helping to draw an increased number of American trials to the country, said Gibor.

The number of clinical trials referred to American Medical Laboratories, Israel’s largest private laboratory, has risen substantially in recent months.

The number of clinical trials is an indication of recovery, says AML general manager Dave Shafir. “The confrontation with the Palestinians has greatly harmed business in Israel in the past two years. International companies slowed the pace of their operations, but things are now really getting back to normal.

“Before the intifada, we had external supervision from Europe or the US once every two months. After the intifada started, we didn’t have that supervision, and sometimes we had to hire a subcontractor to do it.”

Shafir says that the situation began to improve four months ago. “It’s not related to the recession; it has to do with Israel,” he told Globes.

AML is currently conducting 40 clinical trials in Israel, which are taking place at an average of six centers per trial, with 10-20 patients participating in each trial. As is customary in the industry, the duration of the trials varies from three weeks to seven years. The company, which has existed for 20 years, has an NIS 11 million ($2.5 million) yearly turnover, but this also includes tests for private clinics and hospitals, as well as veterinary tests. Israel Shafir, Dave Shafir’s father, founded the company, which currently has 35 employees working in shifts, covering 24 hours a day.

The company began conducting clinical trials eight years ago. How did they begin? “We discovered a niche in the global market,” Dave Shafir says. “Trials have always been conducted here, and the US Food and Drug Administration (FDA) preferred Israel. For many years, Israel had no facilities to conduct regular laboratory tests. When the FDA stiffened its standards, they began sending samples to overseas laboratories, to companies such as Laboratory Corporation of America (LabCorp) and Covants. That procedure, however, is expensive and inconvenient. It involves logistical problems very few companies actually send samples, except for unusual samples that have to be frozen.”

Young companies used to tend to conduct early stage clinical trials without registration acceptable to the FDA, and apparently still do so. Shafir therefore decided to develop comprehensive laboratory services, which are called central lab services. This concept includes managing projects, data, computers, documentation, creating an archive, etc.

“The tests themselves are only 5% of the work in clinical trials,” Shapir explains, “but you need registration. The FDA might come to see what happened in the trial, even five years later.”

Incidentally, AML signed a cooperation agreement with LabCorp a year ago. When LabCorp has a trial in Israel, AML fulfills the contract for them. Recently the company also received authorization for the ISO 15189 international medical laboratory quality standard from the Israel Laboratory Accreditation Authority (ISRAC).

Damchiner-Pearl says that the ISRAC is recognized by the corresponding regulatory agencies in Europe, which means that a test performed in an AML laboratory will now be recognized in 30 European countries. The standard has been authorized for only one other laboratory in Israel the hematology laboratory of the Sheba Medical Center at Tel Hashomer blood bank.

AML is the first private concern to obtain the authorization. “It’s a milestone for us,” says Shafir. “We’ve been working on this for over five years, constantly improving our system.”

Shafir explains that even the pharmaceutical giants need centralized laboratory services for their clinical trials, since they comply completely with FDA requirements, including external monitoring. Furthermore, he says, the great fluctuation in the size of the pipeline requires frequent changes in the number of trials, which an external entity is better equipped to handle.

(Based on reports in BioIsrael and Globes)