May 18, 2015 -- The new weight loss drug Contrave was in the headlines last week when researchers ended a study that looked at its safety.
So the FDA asked the drug’s maker to keep studying it to make sure it didn’t raise risks like heart attacks and strokes.
Because the study ended early, researchers can’t say for sure that there’s no heart risk tied to the drug. Lead study researcher Steve Nissen, MD, chairman of cardiovascular medicine at the Cleveland Clinic, says he is confident Contrave doesn’t double a person’s risk of a heart attack or stroke. But he admits he can’t be sure it doesn’t cause smaller increases in those risks.
If you’re taking Contrave now or are thinking about taking it, and you’re wondering what the flap was about, here’s a quick explainer.
A Compromised Study
Contrave is a combination of two older drugs, bupropion and naltrexone. Bupropion, which has been sold under the brand names Zyban and Wellbutrin, has been used to help people quit smoking and to treat depression. Naltrexone is used to curb cravings to addictive drugs like alcohol and narcotics.
Experts had hoped that the two-drug combo would work to treat obesity in a new way -- by making food less rewarding and possibly less addicting.
Bupropion on its own has been linked to a greater risk of high blood pressure. It can also increase the risk of suicidal thoughts, and Contrave carries a warning about that on its label, too.
When Contrave was approved last year, the FDA allowed it onto the market with only some of the safety data -- 25%, to be exact -- in hand.
And those early results looked really good. Rather than raising heart risks as initially feared, it looked like the drug might actually protect people from serious episodes of chest pain, heart attacks, strokes, and heart-related deaths. The results were submitted to the FDA in November 2013, as the agency was considering whether or not to allow the drug on the market.
Those results looked great to the drug’s maker, Orexigen, too. By April 2014, documents show the company had widely shared those early findings with more than 100 people, including potential investors and members of its board of directors, who had a financial stake in the outcome of the trial. Those disclosures violated an agreement Orexigen had signed with the FDA just 3 months prior to keep the data secret.
Secrecy is important in clinical trials. Reliable results depend on keeping everyone involved -- doctors and patients -- from knowing the bigger picture until after the study is over. That’s because having an expectation about what the drug might or might not be doing can influence how well it seems to work. It’s known as the placebo or nocebo effect. And it’s been proven time and again.
The FDA agreed to approve the drug in September 2014, but told Orexigen it wouldn’t accept the results of the compromised safety study. The agency encouraged the company to finish the study, though.
Instead, the agency told the company it would need to do a brand new trial to fulfill its legal requirement to study the drug. The estimated cost of that study is $200 million.
After that, the company filed for a patent to protect its right to sell the drug as a potential treatment for heart disease. Patent filings are public, so the early trial data was released to patients, investors, and most seriously, to people who were still participating in the safety study. The company’s stock price soared.
In an interview with Forbes, John Jenkins, MD, head of the FDA’s Office of New Drugs, said that trying to predict the risks or benefits of a drug based on “misleading” early trial data is like “trying to understand who is going to win a football game at the end of the first quarter.”
And Jenkins said he worried patients and their doctors might make decisions based on “highly unreliable” information.
The doctors who were leading the study weren’t happy, either. That’s because at the halfway point of the study, last December, the results looked different. Rather than showing a heart benefit for people taking the drug, the new data found no significant difference in heart risks between people taking the drug and those who were taking a placebo pill.
Those doctors publicly released the results, in part, to correct any impression that the drug offered benefits beyond weight loss.
Nissen will also lead the new safety study that he thinks will finish in 2022.
Meanwhile, Orexigen says it never misled patients or investors. The entire statement from the company is here.
For now, Nissen says researchers “have ruled out a serious safety hazard.”
‘Puzzling’ Rush to Market
Other experts say half of the data is not enough information to go on, and they question why the drug was allowed on the market without more rigorous testing.
“You can’t tell how safe or effective a drug is with 50% of the data,” says Donald Light Jr., PhD, professor of comparative health at Rowan University in Stratford, N.J. He studies trends in the drug approval process.
Light says that commercial pressure is leading more and more drugs to be approved on the partial results from clinical trials.
“It puts patients at great risk from misleading evidence,” he says.
Aaron Kesselheim, MD, JD, is an associate professor at Harvard Medical School. His recent research has shown that sped-up drug approvals have become the norm, rather than the exception.
“There’s something to be said for reviewing new products quickly and efficiently and not letting undue delays happen, but only if they’re important new drugs for unmet medical needs or treating life-threatening conditions,” Kesselheim says.
He says the rush to bring Contrave to market is puzzling, especially because it’s not a brand new drug, and it’s not meeting an unmet medical need. There are other treatments for obesity.
The goal should be to answer safety questions about drugs “as comprehensively as possible” before medications come on to the market, he says.
Eric Pahon, an FDA press officer, says regulators don’t have any plans to take the drug off the market. But if the companies involved don’t complete the new safety study, the agency could fine them, seize the drug, or revoke its approval.
Nissen says people should have a thorough discussion with their doctors about the risks and benefits of taking a pill to lose weight.
“And via a good discussion with their doctors, they can come to a conclusion about what they want to do,” he says.
One thing to consider is that the medication seems to have some unpleasant side effects. According to FDA documents, in the discontinued safety study, 62% of the people who were given Contrave stopped taking it, mostly because they couldn’t tolerate the side effects like nausea, headaches, and constipation. (It’s worth noting that 73% of people in the placebo group also stopped their pill, but in that case it was because they weren’t losing any weight.)
Contrave also doesn’t seem to work for everyone. In a different clinical trial of 4,500 obese and overweight people without significant health problems like diabetes, Contrave helped 42% of people taking it lose at least 5% of their starting weight compared with 17% of people on a placebo. That means 58% of people on the drug didn’t lose very much weight on the drug, if they lost any at all.