When the multibillion dollar medical device maker Synthes enticed doctors to use its bone cement on people’s spines, patients died on the operating table. The company’s actions led to indictments and prison time for executives.
Journalist Mina Kimes of Fortune magazine investigated how it all happened, talking to doctors who performed the treatments, former company employees and the families of patients who died. Her report, “Bad to the Bone: A Medical Horror Story,” lays out in detail how the company navigated around Food and Drug Administration rules meant to inform and protect patients.
As part of our ongoing interest in patient safety, ProPublica health reporter Marshall Allen interviewed Kimes at ProPublica’s New York office for the #MuckReads podcast. The interview has been edited for clarity and length.
ProPublica: You use the term “human experimentation” to describe what was happening in this story. That sure gets people’s attention.
Kimes: I think that’s what it was. The company held unauthorized clinical trials and released and promoted a product for a use that was unapproved [by the FDA] without informing patients that the product was unapproved. People participate in clinical trials all the time, but they do so knowingly, and I think that's the core transgression here: Some people had knowledge and some people didn't. And ultimately, the people who did not were the patients.
ProPublica: Tell us about the company and the product.
Kimes: Synthes is a Switzerland-based device company that was bought earlier this year by Johnson & Johnson for about $20 billion, the biggest acquisition in J&J's history. Before they were acquired they developed a product called Norian, which is a calcium phosphate bone cement. Many people described the product as miraculous because it had properties that enabled it to stimulate the growth of actual human bone. Norian was approved for use in the skull and the arm.
The story is about the company’s efforts to convince doctors to use the product in the spine as a treatment for vertebral compression fractures – painful fissures in the spine that are a common side effect of osteoporosis. But Norian was never approved for vertebral compression fractures, and the FDA specifically forbade the treatment. So over the course of a couple of years, the company made a series of ill‑fated decisions that led to them promoting it for that use even after some alarming scientific results and patient deaths.
ProPublica: What happened when they used Norian in the spine?
Kimes: Well, this is really at the heart of what they did wrong: They never did a clinical trial on people. When a medical device maker wants to introduce a device for a new purpose, there's a variety of ways in which they can get approval for it. If it's an untested high-risk device, often what they'll have to do is obtain something called Premarket Approval, or PMA, which requires clinical trials. These trials can be long and costly. Some employees estimated that it would take about three years and cost over $1 million. They would have had to convince a large number of patients to do it. And they could fail. One of the things that probably deterred them from doing the clinical trials was that the company had not had a lot of success doing this in the past.
The other way that you can get approval is to establish similarity to an already approved device, which is the approach they took. However, the approval that they got from the FDA said specifically that they could not mix Norian with other materials, which is what they needed to do for the spine treatment. The FDA later said this cannot be used to treat vertebral compression fractures.
Between 2002 and 2004, which was when the illegal trials were going on, there were three deaths. The first one was a 70‑year‑old woman whose X‑rays, in a disturbing twist, were later used in materials to promote the product. Then later on, an 83‑year‑old man and an 83‑year‑old woman died, both on the operating table. In all cases, the patients’ blood pressure dropped extremely quickly and they were unable to be resuscitated.
Experts later theorized that the cement was forming clots and causing blockages in the bloodstream. That's also what happened in a completely separate animal trial conducted at the University of Washington, where scientists injected the cement into a pig that also died for the same reason.
ProPublica: So they did not have FDA approval, but still promoted it for use in the spine. How did the marketing work?
Kimes: We’re talking here about off‑label marketing, an extremely common crime that’s led to huge settlements in recent years for drug companies and device makers. Doctors and surgeons are able to prescribe drugs and use devices in ways that they see fit. However, companies cannot promote them to doctors and surgeons for the unapproved, off‑label uses. As you can imagine this creates a bit of tension, especially when a company recognizes that doctors might be interested in using it in an unapproved fashion, or there's a potential revenue stream.
So what we encountered in this story was that the company expressed interest in this unapproved use, and it was documented that they promoted it for that use. I interviewed many surgeons who were involved in the unauthorized clinical trials. They told me that they talked to some of these sales representatives about this unauthorized use, and that in itself is off‑label marketing.
There are so many ways companies cross the line, whether it's giving information to doctors, bringing these devices into certain surgeries, or giving them instructions on how to use it. Synthes did all of these things and more. In one case, during a training session with surgeons, they explicitly showed them how to do this spinal procedure. They were giving out materials that talked about the procedure. Some of the promotional materials did not include the warning that the FDA had told them to include, saying not to use Norian to treat vertebral compression fractures. So there were many ways in which they committed the crime.
ProPublica: Did regulation fail, or did they flout the regulation?
Kimes: I think they definitely flouted the regulation. The question, I think, of whether or not the regulations were strong or clear enough is a matter of dispute. The FDA had issued a public warning about this procedure being off‑label. There was some confusion amongst surgeons and the company about the label, and I know from my interviews with employees that they knew what they were doing was not right. That said, there's still a lot of gray area.
ProPublica: How much influence do you think the marketing has over physicians?
Kimes: I think there's a great deal of influence. There has to be a confluence of factors. The appetite for the product was already out there. This is a procedure that was growing in popularity at the time. Plus, there was no clear treatment. Vertebroplasties were being conducted using a different kind of cement that had a lot of disadvantages. So there was certainly an audience for it. I imagine it was quite convincing when surgeons were presented with this miraculous‑seeming product and not told about some of the issues, such as the scientific trials. Also, many of the surgeons were flown out to training sessions where they had dinners and golf outings and whatnot. And at those training sessions, they were told all the good things about it and all the potential for it, and many walked away thinking it was a really wonderful opportunity.
One of the most surprising things I learned while reporting this story was that in all of these surgeries there was a sales representative from the company in the room. I didn't know that before. And I think that's emblematic of the relationship between doctors and companies, which is intermeshed and in some ways co-dependent.
ProPublica: What did this story tell you in general about patient safety?
Mina: Much of this has to do with knowledge. I mean, when you make a health care decision, you should be equipped with the best knowledge possible. This story was about the withholding of that knowledge at many crucial points, but especially to these patients who died not knowing that this product had been used in animal trials where there were very alarming results, and not knowing that it wasn't actually approved for the procedure that they were about to go into. The risks weren't properly communicated.
All the patients’ families maintain that they were not told about the unapproved nature of the product, about the animal trials and the risks associated with them. There were three deaths that took place during the clinical trials, but there was another death that occurred in July of 2009 after the company had been indicted. So if that particular family had simply known the name of the product — and they say they weren't told the name — they could've Googled it and seen a criminal indictment filed two weeks earlier.