**Making sense of a dangerous brew**

Israel’s Teva pharmaceutical giant gambled on a software system, developed by psychiatrist Dr. Roni Shiloh that alerts doctors to conflicts among medications and other parameters that could send patients to the hospital or even result in death.

By JUDY SIEGEL-ITZKOVICH
Perscription drugs (photo credit: Courtesy, Health Ministry)
Perscription drugs
(photo credit: Courtesy, Health Ministry)
Medications may conflict with each other, a patient’s genetic profile, his physiological condition, herbal and other natural supplements he takes, his weight and even the food he eats. The result could be hospitalization and sometimes death.
As the average Israeli 65 years and older now takes seven different medications for chronic illness, the danger of drug conflicts and complications is high.
In this country, adverse drug reactions (ADRs) are responsible for 4.1 percent of all hospital admissions, while it is 5.7% in Germany, 6.5% in Britain and a whopping 12% in Australia.
In England, ADRs caused a 10% annual increase in deaths. A quarter of polypharmacy patients here suffer from actual side effects or other undesirable consequences.
Polypharmacy is the fourth-highest killer in the US, causing more deaths than from accidents, alcohol abuse and homicide. Studies estimate that each year, some 2,000 Israelis and over 100,000 Americans die from drug interactions.
Although pharmacists learn something about drug-drug interactions (DDIs) during their academic studies, medical students are surprisingly taught little on the subject. There are various computer programs that calculate whether two drugs conflict with each other, and the results are given in written summations difficult for doctors to assess in the eight or so minutes he can allocate to each patient. As a result, utilization rates of such DDI checkers is minimal, even lower than 1% according to some studies. Even when doctors receive an automated alert about DDIs, they ignore them in as many as 90% of cases.
Enter Dr. Roni Shiloh, a Jerusalem- born psychiatrist and the medical and regulation director of Teva Pharmaceutical Industries, the country’s largest drug company and the world’s greatest producer of generic drugs. Teva is very well known in medical systems for being one of the world’s largest pharmaceutical companies. Teva is responsible for 17% of medical scripts (presciptions) written in the US, and its drug Copaxone is the number- one drug for multiple sclerosis in the world at $4 billion in sales per year.
Although Teva might have been expected to have no interest in a system that would reduce the purchase and use of unnecessary drugs, the company was intrigued by Shiloh’s web-based software, which he called DDI+ (Drug-Drug Interaction Plus).
‘THERE WERE no physicians in my family,” Shiloh told The Jerusalem Post in a recent interview. “My father, Ya’acov Shiloh, was a caricaturist in the newspaper Ma’ariv, while my mother was an educator. After my service in the Israel Defense Forces, I wanted to study medicine and went to the medical school at the Technion- Israel Institute of Technology.”
He liked to draw and thought he would like to specialize in plastic surgery or neurosurgery, but reconsidered after thinking “that most of medicine is like plumbing. I was accepted for architecture studies at the Technion, but then I switched to psychiatry, because I thought it involved a lot of thinking, creativity and sensitivity. I wrote several books on medications, including one on psychopharmacology.”
He worked for three years as head of a psychiatry department dealing with the most difficult cases at the Geha Mental Health Center. He also served as chief psychiatrist of the smallest health fund, Leumit Health Services. But in 2007, Shiloh decided to work in the pharmaceutical industry, was hired by Teva and based in Netanya. One night a week he continues to accept psychiatric patients in his private clinic – so as not to lose his touch and because he didn’t want to sever his connection to patients.
“I was attracted to the company because its global center is in Israel and it gives importance to the local market and not only the global one,” Shiloh explained. “I realized, however, that there was a need to innovate. Having worked at Geha, I had studied the available electronic medical records and drug interaction alerts it had, but I saw that it didn’t offer a good solution. So at a strategic meeting at Teva, I brought up my idea for DDI+. Surprisingly, they agreed to set up an internal start-up project.”
For three or four years, he spent most of his time studying the field and thinking. He found that three of the four public health funds – Clalit Health Services, Maccabi Health Service and Meuhedet Health Services – had computer programs giving DDI alerts, but that doctors rarely used them, and wanted to find out why. Leumit Health Services had none at all.
People generally have a short-term recall of about five numbers. In conventional drug-interaction systems, there are at least 25 in English text that doctors have to assess before prescribing drugs. Nobody can deal with so much textual data in such a short time. After he had defined what he wanted, he found an information technology firm in Croatia that he hired on behalf of Teva to develop the software, for which pharmaceutical company has a patent pending in most of the world.
The patent application covers dozens of pages and describes the system as a “platform accessible by a user from a web browser/health maintenance organization’s electronic medical record for providing the user with information regarding a patient’s drug regimen as well as generating alerts concerning potential adverse effects to a patient from taking a cluster.
“This includes a plurality of pharmaceutical preparations and various food supplements/herbals, may be in data communication with and configured to obtain information from at least two databases and at least one tool for processing the cluster of pharmaceutical preparations in accordance with the information to generate the alerts to the user.”
After he was satisfied with the result, Shiloh found a manufacturer, the Matrix company, and moved all operations into a Teva facility in Shoham.
According to Teva, DDI+ is the most advanced personalized solution to polypharmacy in the world.
In addition to all the variables, it is constantly updated based on the latest medical research. “It dramatically reduces the dangers to patients’ health,” asserted Shiloh.
Leumit Health Services fed patient data into the system to determine how many ADRs were avoided as a result. Half of the health fund’s doctors used the software and the other half didn’t. At the end of the study, the data of the two groups were compared.
Leumit researchers based the study on more than a million patient visits – the largest such examination in the world.
“We also conducted blood tests of nearly 1,000 Leumit members and obtained a DNA profile to see how they would be affected by prescription drugs. Eight percent of Israelis have DNA that causes their body to handle drugs differently. Our system is the only tool that can inform doctors of this,” says Shiloh.
The intake of certain foods also can affect medications. Shiloh showed that his database warned when patients who drank grapefruit juice (or ate sections of grapefruit) within a few hours of taking drugs to blood reduce cholesterol, for example.
ASKED ABOUT about the possibility that Teva might with this software plant into the medical system a preference for Teva’s generic medications, Shiloh shook his head. “The best drug for the individual patient is suggested, and there is absolutely no advantage for the company’s products,” he declared. In the list of recommended drugs, if the one made by Teva is more expensive than others, it will be on the bottom of the list produced by the system, he continued.
DDI+ suggests not only drugs included in the basket of health services that are paid for by the health funds but also those that are effective but not covered by standard public health insurance.
“Although the system cost the health fund a few millions of shekels a year, it saved Leumit NIS 20 million,” said Shiloh. The study showed that Leumit saved an average of NIS 10,000 per patient over the age of 65.
There are almost two million Israelis in this age group.
Forty percent of its physicians actually changed or eliminated prescriptions they had been giving patients after receiving warnings from DDI+ in real time. And with fewer complications caused by drug interactions, the health fund also had to spend less on its members’ hospitalizations. The system even cut the need for ultrasound, CT and MRI scans on patients.
Although doctors conventionally prescribe the same medication and dose for a specific condition, said Shiloh, variation among patients is huge.
“There are enzymes in the liver that break down medications. The variation is so big – about 10% – that it really alters the ways drugs are handled by the body. One might need a lot more medication if your enzymes work one way or less medication if they work another way.
Doctors don’t know about all the parameters. One patient may need different amounts of drugs than a person with the same condition.
Prescribing drugs is much more complicated for the doctor than it was in the past,” Shiloh said.
As a result of this understanding, he and his team at Teva added much more data to the database about the effects of the liver, kidneys, metabolic condition, pregnancy and other parameters.
The DDI+ system presents alerts with graphic symbols that can be understood at a glance. The use of graphic images such as bars replaces reams of text. The system also suggests alternative drugs suitable to the individual patient when the doctor clicks once with the computer mouse. DDI+ is the only program of its kind in the world than can, in real time, carry out a whole series of checks that significantly reduce complications from drug and other interactions.
“The system gives doctors a new learning capacity. If the physician has a problem and he solves it with DDI+, he can also learn lessons usable for other patients. In 70% of cases, the doctors learned from the solution and didn’t even have to consult DDI+ [the next time].”