It was a gut feeling and common sense that made Dr. Iwao Kuwajima question a drug for high blood pressure that just about every other doctor in his field was excited about in the 2000s.
Kuwajima, now 72, was the first doctor in the nation to sound the alarm about the hype surrounding Diovan, a hypertension drug marketed with huge fanfare by Novartis in 2000. He questioned the research published in the mid-2000s to early 2010s that purportedly demonstrated the significant advantage of the drug to prevent heart disease and stroke over other drugs. Such favorable “evidence” was widely used by the drugmaker to promote Diovan.
Kuwajima’s loud and persistent questioning prompted inquiries by other researchers and institutions, eventually exposing a massive tampering of data cited in the research.
Novartis and an employee, Nobuo Shirahashi, were charged with false advertising in July 2014. The Tokyo District Court in March ruled that the defendants manipulated clinical evidence in favor of Diovan, but found them not guilty on grounds that academic papers were not considered a form of advertising. Prosecutors have appealed the ruling.
Last year, Kuwajima published a book documenting the saga over the blockbuster drug. Titled “Akai Wana” (“Red Trap”), named after the red-color ads Novartis used to promote Diovan, the 237-page book recently won the Medical Journalists Association of Japan’s annual grand prize for publications. “The book details the process by which a cardiologist exposes misconduct and draws readers in like a detective novel,” the association said in a statement announcing the award last month.
Kuwajima says the Diovan case is a sobering reminder that large-scale clinical trials published in top medical journals should not be blindly trusted, as they can be exploited by drugmakers rushing to sell their products before their patents run out.
“I worked at a research hospital and had opportunities to try new or premarket drugs on patients, so I knew from early on that Diovan and the same class of drugs called ARB wouldn’t work, especially for elderly patients,” Kuwajima recalled in a recent interview at Tokyo Metropolitan Geriatric Hospital, where he has retired from full-time practice but still sees patients two days a week. “I had a strong sense of crisis that hordes of elderly people — whose ranks were growing as the population grayed — would be prescribed a drug that didn’t work.”
Kuwajima said he immediately found the Diovan research suspicious because the results were just too good to be true. This was before Novartis admitted that it had paid five professors conducting studies at their universities a total of ¥1.1 billion in “research grants,” and even had Shirahashi, a Novartis employee purporting to be a university lecturer, help with statistical analyses for the papers.
One of those five studies, called Jikei Heart Study and led by a doctor at the Jikei University School of Medicine, found in 2006 that patients who were prescribed Diovan were 39 percent less likely to experience complications than those prescribed other drugs. A second piece of research, which came out in 2009, called Kyoto Heart Study and involving researchers at Kyoto Prefectural University of Medicine, showed even more astonishing results: Patients on Diovan were 45 percent less likely to have complications than those in the control group.
“It’s simply not possible to have a drug that can prevent (heart problems and strokes) in half the patients,” Kuwajima said. “If that were true, doctors all over Japan would be taking that drug. But that wasn’t happening.”
As suspicions grew and investigations into the research followed — first by an academic society, then by independent committees set up by the universities whose ranks authored the papers, then by the health ministry, and eventually by prosecutors — the Diovan case became one of the biggest medical scandals in Japan.
It has led to systemic changes. In April, the Diet enacted a law aimed at boosting the transparency of clinical research funded by pharmaceutical companies. Such research will need to be prescreened by a state-accredited committee, and all health damage caused by the research will have to be reported to the health ministry. Violators of the law will face a maximum prison sentence of three years or a fine of up to ¥3 million.
But Kuwajima says the law — to take effect next spring — has loopholes, as it does not prohibit “seeding trials.”
In such trials, drugmakers ask doctors to participate in post-market clinical studies by prescribing a new drug to certain patients and monitoring their conditions. The patients are compared with others using older drugs, but, unlike regular clinical trials where the test participants are “randomized,” or randomly assigned to two groups that receive different treatments, doctors in seeding trials are just asked to select a group of patients to be prescribed the drug.
“The trials look easy to carry out, as the doctors are just asked to register some patients as users of the drug and monitor their progress,” Kuwajima said. “The drugmakers would say, ‘a top researcher at this university is heading the study, and we will give you the research funds. If the study is published in a paper, your name will be on it.’ ”
But such trials in fact are thinly veiled attempts by pharmaceutical companies at sowing the seed for future sales of the products because, unless a major problem emerges, the doctors will likely stick to the drugs even after the study ends, Kuwajima said.
“It’s not certain that the new drugs are better,” Kuwajima said. “What’s certain is that they are more expensive. Prescribing new drugs does not always help patients. But it helps doctors and drugmakers.”
So what should be done? Kuwajima said he has a degree of sympathy for drugmakers, which, amid all-out pressure by the government on doctors to switch to generic drugs, are desperate to cover the huge investment they made to develop new drugs before their patents expire in about 10 years. In Japan’s health care system, drug prices are decided by a government panel and are almost always cut after a review every two years.
“I think one way to rectify the situation is to extend the period of patents for some drugs, instead of uniformly making them expire in 10 years,” Kuwajima said. “The government also needs to prevent excessive competition; right now it approves all applications for new drugs, so, for instance, seven or eight diabetes drugs with similar mechanisms are sold at the same time, creating fierce competition.”
But the biggest lesson from the scandal is simple: There is a clear need to improve the morality of doctors involved in clinical studies, he said.
“Pharmaceutical companies and doctors need to keep in mind that they are dealing with something that affects a patient’s life,” Kuwajima said.
Otherwise, the nation will keep falling into the same trap in the future, he warned.
“This is only the tip of the iceberg.”
A Matter of Health covers current research, technology and policy issues relating to health in Japan.